Diphtheria-tetanus-pertussis-containing vaccines (DTPCVs) represent the forefront of combination vaccine development globally. However, the licensing of high-valent DTPCVs varies worldwide owing to diverse regulatory requirements. Some national regulatory authorities (NRAs) have adopted flexible strategies to fast-track the approval and uptake of critical DTPCVs to address public health needs. This study examined the global regulatory status of combination vaccines, using descriptive and comparative analyses to highlight pivotal registration issues for DTPCVs. Specifically, it sheds light on the regulatory approaches of the Food and Drug Administration (FDA), European Medicines Agency (EMA), National Medical Products Administration (NMPA), and other Asian regulators through a case study of hepatitis B-containing DTPCVs. Drawing on these findings, this study advocates the initiation of regulatory convergence efforts, establishment of practical regulatory strategies, and swift approval and wider adoption of high-valent DTPCVs.

Background Tuberculosis is the second most deadly infectious disease after COVID-19 and the 13th leading cause of death worldwide. Among the 30 countries with a high burden of TB, China ranks third in the estimated number of TB cases. China is in the top four of 75 countries with a deficit in funding for TB strategic plans. To reduce costs and improve the effectiveness of TB treatment in China, the NHSA developed an innovative BP method. This study aimed to simulate the effects of this payment approach on different stakeholders, reduce the economic burden on TB patients, improve the quality of medical services, facilitate policy optimization, and offer a model for health care payment reforms that can be referenced by other regions throughout the world.Methods We developed a simulation model based on a decision tree analysis to project the expected effects of the payment method on the potential financial impacts on different stakeholders. Our analysis mainly focused on comparing changes in health care costs before and after receiving BPs for TB patients with Medicare in the pilot areas. The data that were used for the analysis included the TB service claim records for 2019-2021 from the health insurance agency, TB prevalence data from the local Centre for Disease Control, and health care facilities' revenue and expenditure data from the Statistic Yearbook. A Monte Carlo randomized simulation model was used to estimate the results.Results After adopting the innovative BP method, for each TB patient per year, the total annual expenditure was estimated to decrease from $2,523.28 to $2,088.89, which is a reduction of $434.39 (17.22%). The TB patient out-of-pocket expenditure was expected to decrease from $1,249.02 to $1,034.00, which is a reduction of $215.02 (17.22%). The health care provider's revenue decreased from $2,523.28 to $2,308.26, but the health care provider/institution's revenue-expenditure ratio increased from -6.09% to 9.50%.Conclusions This study highlights the potential of BPs to improve medical outcomes and control the costs associated with TB treatment. It demonstrates its feasibility and advantages in enhancing the coordination and sustainability of medical services, thus offering valuable insights for global health care payment reform.

BACKGROUND:Adherence to TB drugs is crucial for improving treatment outcomes. Digital adherence technologies can improve adherence; however, there is a lack of evidence on cost-effectiveness. This study aimed to explore the cost-effectiveness of medication event reminder monitors (MERM) in China compared with the standard of care, using results from a pragmatic, cluster-randomised superiority trial of an electronic MERM in China. METHODS:We collected primary unit cost data from the societal perspective, both at and above the health facility level. We estimated the incremental cost-effectiveness of MERM using a Markov model with a 20-year time horizon; a 3% discount rate was applied to costs and outcomes. We explored uncertainty through a series of sensitivity and scenario analyses. RESULTS:The incremental cost of MERM was $27.22 per patient. Probabilistic sensitivity analysis showed significant uncertainty about the intervention's cost-effectiveness. Changing assumptions around key parameters substantially affected our estimated incremental cost-effectiveness ratio. CONCLUSIONS:Although the incremental cost of the MERM box was low, current evidence does not indicate that the intervention would be cost-effective. However, the intervention's cost-effectiveness could improve if implemented as part of a broader strategy, including enhanced patient management.

Influenza vaccines faced significant challenges in achieving sufficient protective efficacy and production efficiency in the past. In recent decades, novel influenza vaccines, characterized by efficient and scalable production, advanced platforms, and new adjuvant technologies, have overcome some of these weaknesses and have been widely licensed. Furthermore, researchers are actively pursuing the development of next-generation and universal influenza vaccines to provide comprehensive protection against potential pandemic subtypes or strains. However, new challenges have emerged as these novel vaccines undergo evaluation and authorization. In this review, we primarily outline the critical challenges and advancements in research and development (R&D) and highlight the improvements in regulatory responses for influenza vaccines.

Background Drug-sensitive tuberculosis treatment requires 6 months of therapy, so adherence problems are common. Digital adherence technologies might improve tuberculosis treatment outcomes. We aimed to evaluate the effect of a daily reminder medication monitor, monthly review of adherence data by the health-care provider, and differentiated care for patients with adherence issues, on tuberculosis treatment adherence and outcomes.Methods We did a cluster-randomised superiority trial across four prefectures in China. 24 counties or districts (clusters) were randomly assigned (1:1) to intervention or control groups. We enrolled patients aged 18 years or older with GeneXpert-positive, rifampicin-sensitive pulmonary tuberculosis, who were receiving daily fixed-dose combination treatment. Patients in the intervention group received a medication monitor for daily drug-dosing reminders, monthly review of adherence data by health-care provider, and management of poor adherence; and patients in the control group received routine care (silent-mode monitor-measured adherence). Only the independent endpoints review committee who assessed endpoint data for some participants were masked to study group assignment. Patients were followed up (with sputum solid culture) at 12 and 18 months. The primary outcome was a composite of death, loss to follow-up, treatment failure, switch to multidrug-resistant tuberculosis treatment, or tuberculosis recurrence by 18 months from treatment start, analysed in the intention-to-treat population. Analysis accounted for study design with multiple imputation for the primary outcome. This trial is now complete and is registered with ISRCTN, 35812455.Findings Between Jan 26, 2017, and April 3, 2019, 15 257 patients were assessed for eligibility and 3074 were enrolled, 2686 (87%) of whom were included in the intention-to-treat population. 1909 (71%) of 2686 patients were male, 777 (29%) were female, and the median age was 44 years (IQR 29-58). By 18 months from treatment start, using multiple imputation for missing outcomes, 239 (16% [geometric mean of cluster-level proportion]) of 1388 patients in the control group and 224 (16%) of 1298 in the intervention group had a primary composite outcome event (289 [62%] of 463 events were loss to follow-up during treatment and 42 [9%] were tuberculosis recurrence). The intervention had no effect on risk of the primary composite outcome (adjusted risk ratio 1.01, 95% CI 0.73-1.40).Interpretation Our digital medication monitor intervention had no effect on unfavourable outcomes, which included loss to follow-up during treatment, tuberculosis recurrence, death, and treatment failure. There was a failure to change patient management following identification of treatment non-adherence at monthly reviews. A better understanding of adherence patterns and how they relate to poor outcomes, coupled with a more timely review of adherence data and improved implementation of differentiated care, may be required.

亚临床结核病是结核病自然史的一部分，目前主流文献对其的定义是无结核病相关症状的结核病患者。近年来，随着对结核病自然史的重新分析与对亚临床结核病群体的公共卫生意义的探索，这类患者受到越来越多的关注。本综述总结了目前对于亚临床结核病的认知及其流行病学、诊断、治疗、预后方面的研究进展，并提出了这一领域待解决的问题。

为解决我国"仅供出口"疫苗出口供给全球存在的障碍,分析监管路径中的问题,为我国监管协调路径的建立提供参考借鉴.采用文献研究法和比较研究方法,对美国、欧盟、韩国"仅供出口"药品的监管路径及其优劣势进行研究,发现美国建立分类出口产品审评体系,欧盟建立"仅供出口"产品科学意见程序,韩国则对"仅供出口"产品单独审评.建议我国药品监管机构建立"仅供出口"疫苗的受托审查、受托批签发和GMP检查程序,落实《疫苗管理法》第九十八条鼓励疫苗出口的监管路径.

China has made remarkable progress in reducing tuberculosis cases and deaths during the past three decades; however, it is still far from achieving the targets set out in the WHO End TB Strategy. Since the 2000s, China has tried to transform its vertical tuberculosis control programme led by the Chinese Center for Disease Control and Prevention (CDC) into an integrated system under the collaboration of CDC, tuberculosis-designated hospitals, and primary health centres. Such a transition has faced many challenges. Profit-driven practices in hospitals designated to tuberculosis and an absence of adequate tuberculosis-related training for health professionals are partially jeopardising the quality of tuberculosis care. In addition, primary health-care providers are not incentivised to make referrals and manage cases effectively. The CDC does not have the administrative power to influence hospital practices or deploy resources to support community-based tuberculosis control activities. Furthermore, an absence of policy coherence and effective coordination causes challenges for quality tuberculosis care that is affordable and accessible. Improving policy dialogues and multi-level coordination within the government is fundamental to successfully ending tuberculosis in China and other countries facing similar challenges.

迄今为止,结核病仍然是严重危害人类健康的重大传染病,特别是新型冠状病毒肺炎全球大流行对全球结核病的防控带来了新的挑战.本文中,笔者力图通过回顾以"三新一加强"结核病综合防治服务模式的验证、示范与推广为核心的中国国家卫生健康委员会-比尔及梅琳达·盖茨基金会结核病防治合作项目的十年历程,以期为加强中国和全球结核病防治工作推进提供借鉴.

Tuberculosis (TB) is one of the main infectious diseases to simultaneously cause poverty and be caused by poverty. Reducing the economic burden of TB patients in China is essential to improving patient compliance and reducing the impact of the TB epidemic. In accordance with the national reform of the medical and health system and the current status of the country’s TB prevention and treatment service system, representatives of the government proposed the concept of a multichannel financing mechanism. This mechanism is in harmony with the overall government strategy for TB. Key provisions are that after accessing free government services, the medical expenses of TB patients should be reimbursed using medical insurance first and then the remainder should be covered by local funds. Three provincial-level administrative divisions (PLADs) have used this approach and introduced policy documents to improve the medical security and reduce the economic burden for TB patients.

Rationale: Tuberculosis treatment lasts for 6 months or more. Treatment adherence is critical; regimen length, among other factors, makes this challenging. Globally, analyses mapping common types of nonadherence are lacking. For example, is there a greater challenge resulting from early treatment cessation (discontinuation) or intermittent missed doses (suboptimal dosing implementation)? This is essential knowledge for the development of effective interventions and more “forgiving” regimens, as well as to direct national tuberculosis programs.Objectives: To granularly describe how patients take their tuberculosis medication and the temporal factors associated with missed doses.Methods: The present study included patients with pulmonary tuberculosis enrolled in the control arm of a pragmatic, cluster-randomized trial in China of electronic reminders to improve treatment adherence. Treatment was the standard 6-month course (180 d), dosed every other day (90 doses). Medication monitor boxes recorded adherence (box opening) without prompting reminders. Patterns of adherence were visualized and described. Mixed-effects logistic regression models examined the temporal factors associated with per-dose suboptimal dosing implementation, adjusting for clustering within a participant. Cox regression models were used to examine the association between early suboptimal dosing implementation and permanent discontinuation.Results: Across 780 patients, 16,794 (23.9%) of 70,200 doses were missed, 9,487 of which were from suboptimal dosing implementation (56.5%). By 60 days, 5.1% of participants had discontinued, and 14.4% had discontinued by 120 days. Most participants (95.9%) missed at least one dose. The majority of gaps were of a single dose (71.4%), although 22.6% of participants had at least one gap of 2 weeks or more. In adjusted models, the initiation–continuation phase transition (odds ratio, 3.07 [95% confidence interval, 2.68–3.51]) and national holidays (1.52 [1.39–1.65]) were associated with increased odds of suboptimal dosing implementation. Early-stage suboptimal dosing implementation was associated with increased discontinuation rates.Conclusions: Digital tools provide an unprecedented step change in describing and addressing nonadherence. In our setting, nonadherence was common; patients displayed a complex range of patterns. Dividing nonadherence into suboptimal dosing implementation and discontinuation, we found that both increased over time. Discontinuation was associated with early suboptimal dosing implementation. These apparent causal associations between temporal factors and nonadherence present opportunities for targeted interventions.Clinical trial registered with the ISRCTN Registry (ISRCTN46846388).

BackgroundIn response to the COVID-19 epidemic, China implemented a series of interventions that impacted tuberculosis (TB) control in the country.MethodsBased on routine surveillance data and questionnaires, the study analyzed TB notification, follow-up examinations, and treatment outcomes. The data were split into three phases in relation to outbreak, lockdown and reopen when the nationwide COVID-19 response started in 2020: control (11 weeks prior), intensive (11 weeks during and immediately after), and regular (4 additional weeks). Data from 2017–2019 were used as baseline.FindingsThe notified number of TB patients decreased sharply in the 1st week of the intensive period but took significantly longer to rebound in 2020 compared with baseline. The percentages of TB patients undergoing sputum examination within one week after 2 months treatment and full treatment course in the intensive period were most affected and decreased by 8% in comparison with control period. 75•2% (221/294) of counties reallocated CDC and primary health care workers to fight the COVID-19 epidemic, 26•9% (725/2694) of TB patients had postponed or missed their follow-up examinations due to travel restrictions and fear of contracting COVID-19.InterpretationIn the short term, the COVID-19 epidemic mostly affected TB notification and follow-up examinations in China, which may lead to a surge of demand for TB services in the near future. To cope with this future challenge, an emergency response mechanism for TB should be established.FundingNational Health Commission of China–Bill & Melinda Gates Foundation TB Collaboration project (OPP1137180).

What is already known about this topic? China’s national health information system provides important support and means for deepening the country’s medical and health reform, for improving relevant delivery services, for enhancing the level of scientific management of health, and for promoting the goal of basic medical and health services for everyone in China. What is added by this report? To further the construction of the national health information system, the National Center for Tuberculosis Control and Prevention of China CDC, started a pilot project for a new tuberculosis (TB) integrated health (iHealth) surveillance system, which was integrated with regional health information platforms. The goal was to explore automatic data exchange between hospitals and disease control facilities to reduce the workload of data-entry. What are the implications for public health practice? This pilot proved that data sharing and automatic exchanges between different information systems can be achieved through a unified surveillance dataset, which could provide a reference point for the construction of surveillance systems for other infectious diseases or for the entire public health information system.

OBJECTIVE: To evaluate the accuracy of molecular diagnostics for the detection of drug-resistant tuberculosis (TB) in Chinese patients.METHOD: Seven databases were searched for eligible studies that evaluated the accuracy of molecular diagnostics against drug susceptibility testing (DST) for detecting drug resistance. A bivariate random-effects meta-analysis was conducted to pool sensitivity and specificity by the index test and drug resistance type.RESULTS: A total of 159 studies were included. Compared with DST (reference standard), Xpert® could diagnose rifampicin (RMP) resistant TB accurately, with a pooled sensitivity and pooled specificity of 92% (95%CI 90-94) and 98% (95%CI 97-98), respectively. Line-probe assays (LPAs) also performed well for RMP resistance, with a pooled sensitivity of 91% (95%CI 88-93) and pooled specificity of 98% (95%CI 96-99), but not for isoniazid (INH) or second-line drugs due to lower sensitivity (<80%). The pooled sensitivity of GeneChip® microarrays for RMP, INH and multidrug resistance was 89% (95%CI 86-91), 79% (95%CI 75-82) and 79% (95%CI 73-84), respectively, and the specificities were all >97%. Similarly, the MeltPro® TB/STR assay had better sensitivity and specificity for first-line drugs, varying from 87% to 89% and 97% to 98%, respectively, than for second-line drugs.CONCLUSION: The Xpert assay, LPA, GeneChip assay, and MeltPro assay are credible methods with high accuracy for RMP resistance detection, but they may not be appropriate for other anti-tuberculosis drugs due to low sensitivity.

Objective Poor compliance with existing guidelines for tuberculosis (TB) care and treatment is an issue of concern in China. We assessed health service use by TB patients over the entire treatment process and compared it to the recommended guidelines. Methods We collected insurance claims data in three counties of one province of Eastern China. Patient records with a diagnosis of 'pulmonary TB' in 2015 and 2016 were extracted. Treatment duration, number of outpatient (OP) visits and hospital admissions, as well as total cost, out-of-pocket (OOP) payments and effective reimbursement rates were analysed. Results A total of 1394 patients were included in the analysis. More than 48% received over the 8 months of treatment that TB guidelines recommend, and over 28% received less. 49% of Urban and Rural Resident Basic Medical Insurance (URRBMI) TB patients were hospitalised while 30% of those with Urban Employee Basic Medical Insurance (UEBMI) had at least one admission. Median total cost for patients with hospital admission was almost 10 times that of patients without. By comparison, the average OOP was 5 times higher. UEBMI patients had a shorter treatment period, more outpatient visits but considerably fewer hospital admissions than URRBMI patients. Conclusions We found an alarming extent of TB over- and under-treatment in our study population. There is an urgent need to improve compliance with treatment guidelines in China and to better understand the drivers of divergence. Extending the coverage of health insurance schemes and increasing reimbursement rates for TB outpatient services would seem to be key factors in reducing both the overall cost and financial burden on patients.

This systematic review assesses the accuracy of molecular diagnostic methods for the detection of pulmonary tuberculosis in studies performed in China, published in Chinese and English. We searched for studies that assessed the accuracy of molecular diagnostics for pulmonary TB in China in the China National Knowledge Infrastructure, the Wanfang Database, SinoMed, VIP Information, Pubmed, Embase, and the Cochrane Library. For each index test, a summary estimation for sensitivity and specificity was calculated using the bivariate random-effects model. A total of 59 studies were included in our analysis. Loop-mediated isothermal amplifcation (LAMP) assay (six studies; pooled sensitivity 90%, 95% CI 78–95%; specificity 93%, 85–97%), line probe assay (LPA) (one study; 87%, 84–90%; 94%, 92–95%) and polymerase chain reaction (PCR) (FQ-PCR and RT-PCR) (four studies; 90%, 55–99%; 93%, 71–99%) showed good diagnostic performance in the meta-analysis. The highest pooled sensitivity was from Xpert MTB/RIF (20 studies; pooled sensitivity 91%, 95% CI 87–94%). The highest pooled specificity was from cross-priming amplification (CPA) (six studies; pooled specificity 97%, 95–99%). The lowest pooled sensitivity and specificity were from simultaneous amplification and testing (SAT)-TB (three studies; 79%, 66–88%; 72%, 48–88%). In subgroup analysis, molecular diagnostics demonstrated higher sensitivity for pulmonary TB detection in smear-positive specimens. Xpert MTB/RIF, LAMP, LPA, CPA and PCR demonstrated high accuracy overall for pulmonary tuberculosis detection, while SAT-TB had poor performance.

The increase in drug-resistant tuberculosis in China calls for scaling up rapid diagnosis. We evaluated introduction of rapid resistance testing by line-probe assay for all patients with a diagnosis of pulmonary tuberculosis in 2 prefectures in middle and eastern China. We analyzed sputum samples for smear-positive patients and cultures for smear-negative patients. We used a before-after comparison of baseline and intervention periods (12 months each) and analyzed data for 5,222 baseline period patients and 4,364 intervention period patients. The number of patients with rifampin resistance increased from 30 in the baseline period to 97 in the intervention period for smear-positive patients and from 0 to 13 for smear-negative patients, reflecting a low proportion of positive cultures (410/2,844, 14.4%). Expanding rapid testing for drug resistance for smear-positive patients resulted in a 3-fold increase in patients with diagnoses of rifampin-resistant tuberculosis. However, testing smear-negative patients had limited added value because of a low culture-positive rate.

Treatment for drug-sensitive tuberculosis (TB) is taken for at least 6 months and problems with adherence are common. Therefore, there is substantial interest in the possible use of eHealth interventions to support patients to take their treatment. Electronic medication monitors have been shown to improve adherence to TB medication, but the impact on clinical outcomes is unknown. We aim to evaluate the impact of a medication monitor-based treatment strategy for drug-sensitive TB patients on a composite poor outcome measured over 18 months from start of TB treatment.

Poor initiation and implementation and premature discontinuation of anti-tuberculous therapy, all forms of nonadherence, are major reasons for treatment failure, the development of drug-resistant tuberculosis, and transmission to other non-infected individuals. Directly Observed Therapy (DOT) has been the worldwide standard, but implementation of DOT is burdensome for providers and patients, especially in resource-limited settings, where most of the burden of active TB is located. Among the alternatives to DOT is electronic monitoring (EM) of drug dosing histories. Here we report a usability study of a newly-designed, modular electronic monitor product, called the MERM (Medication Event and Reminder Monitor), that is compatible with TB medication formats and supply chains in resource-limited settings. This study, done in a rural setting in China, showed that the use of the MERM for EM of TB medications was associated with a high degree of user performance, acceptability, and satisfaction among both TB patients and medical staff. Based on these data, EM is becoming the standard of care for drug-susceptible TB patients in China and scaled implementations in several other countries with high TB burden have begun. In addition, the MERM is being used in MDR-TB patients and in clinical trials involving patients with TB/HIV and latent TB.