Improvements in the health-related quality-of-life benefit of cancer drugs approved in China, 2005-2020: an observational study.

Background: Health-related quality of life (HRQoL), along with overall survival (OS), is a critical study endpoint for measuring the clinical benefits of cancer drugs. Previous studies have examined the OS benefit of new cancer drugs approved in China. However, their HRQoL benefits have not been systematically evaluated. We aimed to characterise the measurement and improvement of HRQoL associated with cancer drugs approved in China. Methods: This mixed-methods study comprises of a literature review and a cross-sectional study, including all antineoplastic agents approved in China between January 1, 2005 and December 31, 2020. A systematic search was conducted on December 31, 2023 to extract HRQoL information of identified drugs. We extracted information on the characteristics of HRQoL assessment and statistically significant HRQoL gains compared with the control treatment. Findings: A total of 64 novel cancer drugs, corresponding to 115 cancer indications, supported by randomised clinical trials were approved in China between 2005 and 2020. Among the indications, 78 (67.8%) used HRQoL as an endpoint in the pivotal trial. By December 31, 2023, after a median follow-up of 5.3 (range, 3.0-18.8) years from approval, HRQoL information was available for more than half of the indications (75, 65.2%). Thirty-three indications (28.7%) reported statistically significant improvement in HRQoL, with 22 (19.1%) also having documented OS benefit. Approximately one-third of the indications (39, 33.9%) showed no difference in HRQoL, with 21 (18.3%) having documented OS gains. Three indications (2.6%) reported worsening HRQoL. The most commonly used HRQoL measurements were individual disease-specific instruments (62 of 75, 82.7%) while the most frequently employed analysis metric was the mean change scores from baseline (56 of 75, 74.7%). Interpretation: Fewer than one-third of cancer indications approved in China had shown HRQoL improvements. There was considerable heterogeneity in the analysis and reporting of HRQoL benefits associated with new cancer drugs approved in China. These findings emphasise the important role of HRQoL evaluation and analysis in clinical research and the necessity of improving the standardization of HRQoL assessment. Funding: National Natural Science Foundation of China (72274004).

Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis.

BACKGROUND: New cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. METHODS: In this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries (ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. FINDINGS: During the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3-12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8-2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2-4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. INTERPRETATION: Fewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. FUNDING: None.

Cancer drug indication approvals in China and the United States: a comparison of approval times and clinical benefit, 2001-2020.

Background: Perceived delays in cancer drug approvals have been a major concern for policymakers in China. Policies have been implemented to accelerate the launch of new cancer drugs and indications. This study aimed to assess similarities and differences between China and the United States in the approvals, timing, and clinical benefit evidence of cancer drug indications between 2001 and 2020. Methods: This study retrospectively identified all cancer drugs and indications approved in both China and the United States from January 1st, 2001 to December 31, 2020, and described differences in approval times as well as in submission and review times. Information on the availability of overall survival benefit evidence by December 31, 2020, was collected. Univariate and multiple logistic regression analyses were used to assess whether evidence of benefit and other factors affected the propensity and timing of approvals of cancer drug indications in China. Findings: Between 2001 and 2020, 229 indications corresponding to 145 cancer drugs approved in the United States were identified. Of those, 80 indications (34.9%) were also approved in China by the end of 2020. Cancer drug indications were approved in China at a median of 1273.5 days after approval in the United States. The median submission and review time differences for cancer drug indications in China were 1198.0 days and 180.0 days respectively. Submission time differences accounted for most of the approval time differences (p < 0.001). Indications supported by overall survival benefit evidence had shorter median review time differences (145.0 days) than those without such evidence (235.0 days, p = 0.008). Indications with overall survival benefit evidence were 3.94 times more likely to be approved in China compared to those without such evidence (p = 0.001), controlling for approval year, cancer type, and the prevalence of cancer by site. Interpretation: FDA-approved cancer drug indications demonstrating a survival benefit were more likely to receive approvals in China with shorter regulatory review times compared to indications without such evidence. Given that manufacturer submission times were the main driver of cancer drug approval times in China, factors influencing submission timing should be explored. Funding: No funding.

Evaluation of pharmacist-led medication reconciliation at county hospitals in China: A multicentre, open-label, assessor-blinded, nonrandomised controlled study.

Background: Due to a lack of related research, we aimed to determine the effectiveness of a pharmacist-led medication reconciliation intervention in China. Methods: We conducted a multicentre, prospective, open-label, assessor-blinded, cluster, nonrandomised controlled study at six county-level hospitals, with hospital wards serving as the clusters. We included patients discharged from the sampled hospitals who were aged ≥60 years; had ≥1 studied diagnoses; and were prescribed with ≥3 medications at discharge. Patients in the intervention group received a pharmacist-led medication reconciliation intervention and those in the control group received standard care. We assessed the incidence of medication discrepancies at discharge, patients' medication adherence, and health care utilisation within 30 days after discharge. Results: There were 429 patients in the intervention group (mean age = 72.5 years, standard deviation (SD) = 7.0) and 526 patients in the control group (mean age = 73.6 years, SD = 7.1). Of the 1632 medication discrepancies identified at discharge, fewer occurred in the intervention group (1.9 per patient on average) than the control group (2.6 per patient on average).The intervention significantly reduced the incidence of medication discrepancy by 9.6% (95% confidence interval (CI) = -15.6, -3.6, P = 0.002) and improved patients' medication adherence, with an absolute decrease in the mean adherence score of 2.5 (95% CI = -2.8, -2.2, P < 0.001). There was no significant difference in readmission rates between the intervention and control groups. Conclusions: Pharmacist-led medication reconciliation at discharge from Chinese county-level hospitals reduced medication discrepancies and improved patients' adherence among patients aged 60 years or above, though no impact on readmission after discharge was observed. Registration: ChiCTR2100045668.

LiNbO3 Coating and F- Doping Stabilize the Crystal Structure and Ameliorate the Interface of LiNi0.88Co0.06Mn0.03Al0.03O2 to Improve the Electrochemical Properties and Safety Capability.

Ni-rich layered materials Li[NixCoyMnzAl1-x-y-z]O2 (x > 0.8) are regarded as the competitive cathode for practical applications in lithium-ion batteries owing to the large discharging capacity. Nevertheless, the strong oxidation activity, the poor structure, and the thermal stability at the electrode-electrolyte interface would lead to much trouble, for example, inferior electrochemical properties and acute safety issues. To ameliorate the above problems, this work reports a strategy for the double modification of F- doping and LiNbO3 covering in LiNi0.88Co0.06Mn0.03Al0.03O2 cathode via using high-temperature calcining and ball-milling technology. As a result, the cathodes after F- doping and LiNbO3 covering not only demonstrate a more stabilized crystal structure and particle interface but also reduce the release of high-activity oxygen species to ameliorate the thermal runaway. The electrochemical tests show that the LiNbO3-F--modified cathode displays a superior rate capability of 159.3 mAh g-1 at 10.0 C and has the predominant capability retention of 92.1% in the 200th cycle at 25 °C, much superior than those (125.4 mAh g-1 and 84.0%) of bare cathode. Thus, the F- doped and LiNbO3-coated Ni-rich oxides could be a promising cathode to realize the high capacity and a stabilized interface.

Prevalence of aggressive care among patients with cancer near the end of life: a systematic review and meta-analysis.

Background: Aggressive care near patients' end-of-life (EOL) entails limited therapeutic values, high costs, and compromised quality of life (QoL). In this study, we aimed to estimate the global prevalence of aggressive care in patients with cancer and explore potential subgroup differences. Methods: We searched PubMed, Embase, and the Cochrane Library from database inception to Feb 16, 2024. Eligible studies reported the prevalence of aggressive EOL care using at least one quantifiable measure. Random-effects models were used to derive the pooled prevalence and subgroup analyses were performed to investigate differences in the prevalence of aggressive care across regions, the country's level of economic development, tumor types, ages, and sample sizes. This review is registered with PROSPERO, number CRD42023467839. Findings: A total of 129 studies were included in this systematic review, of which 118 (91.5%) were from high-income countries. Studies were mostly conducted in the Americas (60, 46.5%), Europe (34, 26.4%), and Western Pacific (31, 24.0%). Measures of aggressive care were inconsistent across studies, with the most commonly used measure being the use of chemotherapy in the last 14 days of life (DOLs) (n = 87, 67.4%) and intensive care unit (ICU) stay in the last 30 DOLs (n = 87, 67.4%). The prevalence of the five claims-based measures of aggressive care, i.e., chemotherapy in the last 14 DOLs, ICU stay in the last 30 DOLs, repeated hospital admission in the last 30 DOLs, repeated emergency room (ER) visit in the last 30 DOLs, and hospice care <3 days before death were 11.6% (95% CI, 9.8%-13.4%), 14.4% (95% CI, 11.8%-17.0%), 17.9% (95% CI, 14.4%-21.4%), 14.8% (95% CI, 12.0%-17.6%), and 14.4% (95% CI, 11.2%-17.6%), respectively. Regional differences were statistically significant in the prevalence of ICU stay and repeated hospital admission in the last 30 DOLs (p < 0.01; p = 0.03). Patients with hematologic malignancies were more likely to receive aggressive care than those with solid tumors, as seen in their higher rates of chemotherapy in the last 14 DOLs (21.7% versus 11.6%; p = 0.03), ICU stay in the last 30 DOLs (25.5% versus 10.8%; p < 0.01), and hospice care <3 days before death (26.7% versus 14.2%; p < 0.01). In addition, the prevalence of chemotherapy in the last 14 DOLs (26.2%; p < 0.01) and repeated hospital admission in the last 30 DOLs (31.4%; p < 0.01) were highest among pediatric patients with cancer. Interpretation: This meta-analysis found that aggressive EOL care was common in patients with cancer, regardless of the definition used, and varied by regions and populations. It is necessary to be aware of the global burden of aggressive care for patients with cancer near their EOL and take prompt action to address it. Funding: National Natural Science Foundation of China (Grant No. 72274004).

Outpatient Antibiotic Prescribing Patterns in Children among Primary Healthcare Institutions in China: A Nationwide Retrospective Study, 2017-2019.

There is scarce evidence to demonstrate the pattern of antibiotic use in children in China. We aimed to describe antibiotic prescribing practices among children in primary healthcare institutions (PHIs) in China. We described outpatient antibiotic prescriptions for children in PHIs from January 2017 to December 2019 at both the national and diagnostic levels, utilizing the antibiotic prescribing rate (APR), multi-antibiotic prescribing rate (MAPR), and broad-spectrum prescribing rate (BAPR). Generalized estimating equations were adopted to analyze the factors associated with antibiotic use. Among the total 155,262.2 weighted prescriptions for children, the APR, MAPR, and BAPR were 43.5%, 9.9%, and 84.8%. At the national level, J01DC second-generation cephalosporins were the most prescribed antibiotic category (21.0%, N = 15,313.0), followed by J01DD third-generation cephalosporins (17.4%, N = 12,695.8). Watch group antibiotics accounted for 55.0% of the total antibiotic prescriptions (N = 52,056.3). At the diagnostic level, respiratory tract infections accounted for 67.4% of antibiotic prescriptions, among which prescriptions with diagnoses classified as potentially bacterial RTIs occupied the highest APR (55.0%). For each diagnostic category, the MAPR and BAPR varied. Age, region, and diagnostic categories were associated with antibiotic use. Concerns were raised regarding the appropriateness of antibiotic use, especially for broad-spectrum antibiotics.

The changes of different restriction level adjustments on antibiotic use in China.

This quasi-experimental study aimed to investigate the changes in antibiotic use tailored by adjusting provincial antibiotic restriction lists in China using interrupted time-series analysis from 2013 to 2019. Antibiotic use was assessed as defined daily dose (DDD) per 1000 patients per day. Trends and level changes were analysed with segmented regression. The study identified 19 antibiotic formulations in four provinces with adjusted restriction levels (intervention group) and 110 formulations in the rest provinces without adjustments (comparison group). Antibiotics restriction level changed between two categories: (1) between 'highly-restricted' and 'restricted' and (2) between 'restricted' and 'non-restricted'. Analysis revealed distinct trend changes for antibiotics moving between 'highly-restricted' and 'restricted' (ß = 0.0211, P = 0.003) and 'restricted' to 'highly-restricted' (ß = -0.0039, P = 0.128) compared to the comparison group. After a 2-y adjustment period, when moving from 'restricted' to 'highly-restricted', absolute antibiotic utilisation significantly decreased (P < 0.001), with a relative decrease of 100.8% (P < 0.001) compared to the comparison group. Besides, individual antibiotics with higher consumption displayed greater responsiveness to adjustment. These findings underscore the changes in restriction level adjustments on antibiotics, highlighting antibiotic restriction list policies as crucial tools for antimicrobial stewardship.

Use of suboptimal control arms in randomized clinical trials of investigational cancer drugs in China, 2016-2021: An observational study.

BACKGROUND: The use of suboptimal controls in randomized trials of new cancer drugs can produce potentially unreliable clinical efficacy results over the current standard of care and expose patients to substandard therapy. We aim to investigate the proportion of randomized trials of investigational cancer drugs that used a suboptimal control arm and the number of trial participants at risk of exposure to suboptimal treatments in China. The association between the use of a suboptimal control and concluding statistical significance on the primary endpoint was also examined. METHODS AND FINDINGS: This observational study included randomized controlled trials (RCTs) of cancer drugs that were authorized by specific Chinese institutional review boards between 2016 and 2021, supporting investigational new drug applications of these drugs in China. The proportion of trials that used a suboptimal control arm and the total number of trial participants at risk of exposure to suboptimal treatments were calculated. In a randomized trial for a specific condition, a comparator was deemed suboptimal if it was not recommended by clinical guidelines published in priori or if there existed a regimen with a higher level of recommendation for the indication. The final sample included 453 Phase II/III and Phase III randomized oncology trials. Overall, 60 trials (13.2%) adopted a suboptimal control arm. Among them, 58.3% (35/60) used comparators that were not recommended by a prior guideline for the indication. The cumulative number of trial participants at risk of exposure to suboptimal treatments totaled 18,610 by the end of 2021, contributing 15.1% to the total number of enrollees of all sampled RCTs in this study. After adjusting for the year of ethical approval, region of participant recruitment, line of therapy, and cancer site, second-line therapies (adjusted odds ratio [aOR] = 2.7, 95%CI [1.2, 5.9]), adjuvant therapies (aOR = 8.9, 95% CI [3.4, 23.1]), maintenance therapies (aOR = 5.2, 95% CI [1.6, 17.0]), and trials recruiting participants in China only (aOR = 4.1, 95% CI [2.1, 8.0]) were more likely to adopt a suboptimal control. For the 105 trials with publicly available results, no statistically significant difference was observed between the use of a suboptimal control and concluding positive on the primary endpoint (100.0% [12/12] versus 83.9% [78/93], p = 0.208). The main limitation of this study is its reliance on clinical guidelines that could vary across cancer types and time in assessing the quality of the control groups. CONCLUSIONS: In this study, over one-eighth of randomized trials of cancer drugs registered to apply for regulatory approval in China used a suboptimal comparator. Our results highlight the necessity to refine the design of randomized trials to generate optimal clinical evidence for new cancer therapies.

Potentially inappropriate medications among older patients with Parkinson's disease: a cross-sectional analysis of a national health insurance database in China.

BACKGROUND: With the rapid aging trend of China's population, the issue of drug rational use in older adults has become more and more prominent. Parkinson's disease (PD) is the one of the most common age-related neurodegenerative disorders. Pharmaceutical treatment plays a cardinal role in alleviating motor and non-motor symptoms to improve the quality of life of patients with PD. Patients with PD have complex medical needs yet little is known about the use of potentially inappropriate medications (PIM) among them in China. We quantify the prevalence of PIM use and identify its predictors among older persons with PD in China. METHODS: We conducted a cross-sectional analysis using a national representative database of all medical insurance beneficiaries across China, extracting records of ambulatory visits of older adults with PD between 2015 and 2017. Beneficiaries aged 65 and above were eligible for inclusion. The prevalence of patients exposed to overall PIMs and PIMs related to motor and cognitive impairment was calculated based on Beers Criteria 2015 version. Potential predictors of PIM concerning patients' characteristics were estimated using multivariate logistic regression. RESULTS: A total of 14,452 older adults with PD were included. In total, 8,356 (57.8%) patients received at least one PIM; 2,464 (17.1%) patients received at least one motor-impairing PIM and 6,201 (42.9%) patients received at least one cognition-impairing PIM. The prevalence of overall PIM use was higher in patients of older age group (54.7% [65-74] vs. 59.5% [75-84; OR, 1.22; 95% CI, 1.14-1.31] vs.65.5% [≥ 85; OR, 1.58; 95% CI, 1.38-1.80) and females (61.4% [female] vs. 55.0% [males; OR, 0.77; 95% CI, 0.72-0.82). CONCLUSIONS: Prescribing PIMs for older adults with PD was common in China, especially for females and older age groups, yet younger patients were more inclined to be prescribed with motor or cognition-impaired PIMs. Our findings represent a clear target awaiting multidimensional efforts to promote the rational prescribing of medications for this vulnerable population.

Evaluation of prescription review and feedback policy on rational antibiotic use in primary healthcare settings in Beijing, China: a qualitative study using the Theoretical Domains Framework and the behaviour change wheel.

Objectives: To decelerate antibiotic resistance driven by inappropriate antibiotic prescribing, a prescription review and feedback (PRF) policy is implemented in primary healthcare institutions (PHIs) in Beijing, China. However, evaluation of PRF implementation in PHIs is scarce. This study aims to systematically identify the barriers and facilitators of PRF policy implementation to provide evidence for antimicrobial stewardship. Methods: We conducted key informant interviews with 40 stakeholders engaged in the implementation of PRF in Beijing, including physicians, pharmacists and administrators. Interviews were audio recorded and transcribed verbatim. We coded the interview transcripts and mapped informant views to domains of the Theoretical Domains Framework. We then used a behaviour change wheel to suggest possible behavioural interventions. Results: Procedural knowledge (Knowledge) and skills (Skill) of PRF were possessed by stakeholders. They felt responsible to promote the appropriate use of antibiotics (Social/professional role and identity) and believed that PRF could help to change inappropriate provider behaviours (Behavioural regulation) in prescribing antibiotics (Beliefs about consequences) under increased intention on antibiotic use (Stages of change). Moreover, informants called for a more unified review standard to enhance PRF implementation (Goals). Frequently identified barriers to PRF included inadequate capacity (Skill), using punishment mechanism (Behaviour regulation), reaching consistently lower antibiotic prescription rates (Goals), lack of resources (Environmental context and resources) and perceived pressure coming from patients (Social influences). Conclusions: Stakeholders believed that PRF implementation promoted the rational use of antibiotics at PHIs in Beijing. Still, PRF was hampered by inconsistencies in review process and resources needed for PRF implementation.

Exploring Facilitators and Barriers to Delayed Antibiotic Prescribing in Rural Northwest China: A Qualitative Study Using the Theoretical Domains Framework and Behavior Change Wheel.

BACKGROUND: Antimicrobial resistance, exacerbated by antibiotic misuse, poses a global threat. Though delayed antibiotic prescribing (DAP) can mitigate antibiotic overuse, its adoption in developing nations, such as China, is limited. This study probed barriers and facilitators to DAP in Xinjiang, characterized by extensive rural landscapes and primary care institutions (PCIs). METHODS: Adopting a qualitative methodology, we conducted key informant interviews with thirty participants across six county hospitals in Xinjiang using VooV Meeting. Employing a two-stage sampling method targeting economically diverse areas, our interviews spanned physicians, pharmacists, patients, and caregivers. We organized the data according to the Theoretical Domains Framework (TDF) and the Behavior Change Wheel (BCW), spotlighting behavioral and policy elements impacting DAP. RESULTS: Our research included thirty interviewees. Twelve physicians contemplated delayed prescriptions, while five adult patients and six caregivers encountered recommendations for delayed antibiotic prescriptions. Six patients sought pharmacists' advice on antibiotic necessity. Prominent TDF domains were memory, attention, and beliefs about consequences. Critical intervention functions included education and environmental restructuring, while vital policy categories encompassed communication/marketing and guidelines. CONCLUSIONS: Countering antibiotic misuse and resistance in China necessitates overcoming barriers through strategic resource distribution, comprehensive education, rigorous training, and consistent monitoring, thereby promoting DAP adoption. The adoption of DAP in rural healthcare settings in China has the potential to significantly reduce antibiotic misuse, thereby mitigating the global threat of antimicrobial resistance.

Sponsorship bias in published pharmacoeconomic evaluations of national reimbursement negotiation drugs in China: a systematic review.

BACKGROUND: China's National Reimbursement Drug List (NRDL) has become the primary route for drug reimbursement in China. More recently, the authority has made pharmacoeconomic evaluation an integral part of the application for NRDL inclusion. The underlying financial conflict of interests (FCOI) of pharmacoeconomic evaluations, however, has the potential to influence evidence generated and thus subsequent decision-making yet remains poorly understood. METHODS: We searched for studies published between January 2012 and January 2022 on the 174 drugs added to the 2017-2020 NRDLs after successful negotiation. We categorised the study's FCOI status into no funding, industry funding, non-profit funding and multiple fundings based on authors' disclosure and assessed the reporting quality of included studies using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. We compiled descriptive statistics of funding types and study outcomes using t-tests and χ2 tests and conducted multivariate regression analysis. RESULTS: We identified 378 records and our final sample included 92 pharmacoeconomic evaluations, among which 69.6% were conducted with at least one funding source. More than half (57.6%) of the evaluations reached favourable conclusions towards the intervention drug and 12.6% reached a dominant result of the intervention drug over the comparison from model simulation. The reporting quality of included studies ranged from 19 to 25 (on a scale of 28), with an average of 22.3. The statistical tests indicated that industry-funded studies were significantly more likely to conclude that the intervention therapy was economical (p<0.01) and had a significantly higher proportion of resulting target drug economically dominated the comparison drug (p<0.05). CONCLUSION: The study revealed that FCOI bias is common in published pharmacoeconomic evaluations conducted in Chinese settings and could significantly influence the study's economical results and conclusions through various mechanisms. Multifaceted efforts are needed to improve transparency, comparability and reporting standardisation.

Overall survival benefits of cancer drugs in the WHO Model List of Essential Medicines, 2015-2021.

INTRODUCTION: We examined overall survival (OS) benefits for targeted cancer drugs recommended for List of Essential Medicines (EMLs) since 2015. We assessed consistency of decisions in 2019 and 2021 with more specific criteria: OS benefit >4 months and high scores on European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). METHODS: We identified applications for cancer drug in WHO EMLs from 2015 to 2021. We extracted evidence of OS benefit documented in WHO Technical Report Series (TRS) and compared it to evidence from pivotal trial(s) documented in Food and Drug Administration-approved labels. We retrieved published ESMO-MCBS scores. We summarised availability and magnitude of OS benefit and ESMO-MCBS scores and assessed consistency of inclusion decisions against WHO criteria. RESULTS: 22/54 targeted cancer drug indications were recommended. Among them, 68.2% and 31.8% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Among those not recommended, 59.4% and 56.3% had OS benefit evidence documented in WHO-TRS and pivotal trials, respectively. Of 11 cancer drug indications recommended in 2019 and 2021, 54.5% and 9.1% had evidence of OS benefit >4 months in WHO-TRS and pivotal trials, respectively; 45.5% met ESMO-MCBS criteria. Ten targeted cancer drugs had more than one application for the same indications. Five of those were eventually recommended, including three without new evidence of OS benefit. Additional factors, such as reduced cost, and increased treatment options, seemed to be important factors in the selection. CONCLUSION: While WHO has defined approval criteria for cancer drugs EML, we identified areas where adherence of these criteria and communication of the EML approval decision-making processes can be improved.

The barriers and facilitators for the implementation of clinical practice guidelines in healthcare: an umbrella review of qualitative and quantitative literature.

OBJECTIVES: To identify barriers and facilitators of clinical practice guidelines (CPGs) implementation, and map those factors to the theoretical domains framework (TDF) and behavior change wheel (BCW). METHODS: We conducted an umbrella review of systematic reviews. PubMed, Embase, and the Cochrane Library were searched. Two investigators independently screened the studies, extracted the data, and assessed the methodological quality. The identified barriers and facilitators of CPG implementation were categorized and mapped to the TDF domains and BCW components. RESULTS: Thirty-seven studies were included, and 193 barriers and 140 facilitators were identified. Intrinsic aspects (35 barriers and 28 facilitators) mainly included the CPGs' impracticality, complexity, and inaccessibility. Extrinsic aspects (158 barriers and 113 facilitators) mainly included lack of resources, training, funding, or awareness of CPG content in barriers; audits and feedback; strong leadership and management support; and educating and training about CPGs in facilitators. Environmental context and resources (n = 97, 19.48%) were the most reported barriers in TDF domains. Physical opportunity and social opportunity were the most frequently mentioned models in BCW. CONCLUSION: Multiple barriers and facilitators for healthcare CPG implementation are identified, with further links to TDF and BCW. Future knowledge translation strategies should be developed accordingly in specified health care settings.

The impact of government reimbursement negotiation on targeted anticancer medicines use and cost in China: A cohort study based on national health insurance data.

Background: High prices of targeted anticancer medicines (TAMs) result in financial toxicity for patients and the health insurance system. How national price negotiation and reimbursement policy affect the accessibility of TAMs for cancer patients remains unknown. Methods: In this population-based cohort study, we used national health insurance claims data in 2017 and identified adult patients with cancer diagnoses for which price-negotiated TAMs were indicated. We estimated the half-month prevalence of price-negotiated TAMs use before and after the policy implementation in September 2017. We calculated direct medical costs, out-of-pocket (OOP) costs, and the proportion of OOP cost for each cancer patient to measure their financial burden attributable to TAMs use. We performed segmented linear and multivariable logistic regression to analyse the policy impact. Results: We included 39 391 of a total 118 655 cancer beneficiaries. After September 2017, the prevalence of price-negotiated TAMs use increased from 1.4%-2.1% to 2.9%-3.1% (P = 0.005); TAMs users' daily medical costs increased from US$261.3 to US$292.5 (P < 0.001), while median daily OOP costs (US$68.2 vs US$65.7; P = 0.134) and OOP costs as a proportion of daily medical costs persisted (28.5% vs 28.5%; P = 0.995). Compared with resident beneficiaries, the relative probability of urban employee beneficiaries on TAMs uses decreased after the policy (adjusted odds ratio (aOR) = 2.4 vs aOR = 2.2). Conclusions: The government price negotiation and reimbursement policy improved patient access to TAMs and narrowed disparities among insurance schemes. China's approach to promoting the affordability of expensive medicines provides valuable experience for health policy decision-makers.

The Impact of Prescribing Monitoring Policy on Drug Use and Expenditures in China: A Multi-center Interrupted Time Series Study.

BACKGROUND: A prescribing monitoring policy (PMP) was implemented in November 2015 in Anhui province, China, the first province to pilot this policy to manage the use and costs of select drugs based on their large prescription volumes and/ or costs in hospitals. This study evaluated the impact of PMP on the use and expenditures of different drugs in three tertiary hospitals in Anhui. METHODS: We obtained monthly drug use and expenditures data from three tertiary hospitals in Anhui (November 2014 through September 2017). An interrupted time series (ITS) design was used to estimate changes in defined daily doses (DDDs per month) and drug expenditures (dollars per month) of policy-targeted and non-targeted drugs after PMP implementation. Drugs were grouped based on whether they were recommended (recommended drugs) by any clinical guidelines or not (non-recommended drugs), or if they were potentially over-used (proton pump inhibitors, PPIs). RESULTS: After PMP, DDDs and costs of the targeted PPIs (omeprazole) declined while use of non-targeted PPIs increased correspondingly with overall sustained declines in total PPIs. The policy impact on recommended drugs varied based on whether the targeted drugs have appropriate alternatives. The DDDs and costs of recommended drugs that have readily accessible appropriate alternatives (atorvastatin) declined, which offset increases in its alternative non-target drugs (rosuvastatin), while there was no significant change in those recommended drugs that did not have appropriate alternative drugs (clopidogrel and ticagrelor). Finally, the DDDs and costs of non-recommended drugs decreased significantly. CONCLUSION: PMP policy impact was not the same across different drug groups. PMP did help contain the use and costs of potentially over-used drugs and non-recommended drugs. PMP did not seem to reduce the use of first-line therapeutic drugs recommended by clinical treatment guidelines, especially those lacking alternatives; such drugs are unlikely appropriate candidates for PMP.

Appropriate use of antibiotics for acute respiratory infections at primary healthcare facilities in China: a nationwide cross-sectional study from 2017 to 2019.

Background: The appropriateness of antibiotic use for acute respiratory infections (ARIs) in Chinese primary healthcare facilities (PHFs) remained uncertain. We aimed to evaluate to what degree antibiotic prescribing for ARIs were aligned with guideline recommendations in primary settings across China. Methods: We collected outpatient prescriptions from 262 Chinese PHFs in 27 cities of six provinces between 2017 and 2019. The appropriate antibiotic prescribing was defined as prescribing antibiotic classes that were recommended by Chinese clinical guidelines, if patients were prescribed antibiotics. We evaluated the magnitude of antibiotics prescribed for acute upper respiratory infections (AURIs), acute bronchitis, and community-acquired pneumonia (CAP) and their appropriateness. Findings: Overall, 55.1% (87,684/159,150), 66.8% (30,836/46,153), and 68.5% (4615/6733) of outpatients with AURIs, acute bronchitis, and CAP treated at PHFs in China were prescribed with antibiotics. Of all antibiotic prescriptions, only 20.0% (17,542/87,684), 18.6% (5724/30,836) and 69.6% (3211/4615) used antibiotic classes that were recommended by the guidelines for AURIs, acute bronchitis, and CAP, respectively. Patients residing in the Chinese central region (17.0%, 15.4%, 69.3% for AURIs, acute bronchitis, and CAP, respectively) were less likely to be prescribed with antibiotics that were appropriately selected. Interpretation: Unnecessary antibiotics were widely prescribed for patients with AURIs or acute bronchitis and most patients with ARIs did not receive guideline-recommended antibiotic classes in Chinese PHFs. Interventions to promote evidence-based treatment and the appropriate use of antibiotics are urgently needed at the primary level across China. Funding: This work was supported by the National Natural Science Foundation of China [grant number 72074007, 81973294].

Site-specific performance of 68Ga-DOTATATE PET/CT in detecting tumors with ectopic adrenocorticotropic hormone secretion.

Objective: The aim of this study was to assess the detection ability of 68Ga-DOTATATE in pulmonary versus extrapulmonary tumors with ectopic adrenocorticotropic hormone secretion (EAS). Methods: Images of 68Ga-DOTATATE PET/CT from 74 patients with suspected EAS were retrospectively reviewed. EAS tumors were confirmed in 39 patients through surgical resection or biopsy. Image findings were compared with the histopathological results. Results: EAS tumors were pathologically confirmed via surgery or biopsy in 39 patients. Among those 39 patients, 25 were with pulmonary neuroendocrine tumors (NETs), and the remaining 14 were with extrapulmonary NETs. 68Ga-DOTATATE PET/CT correctly identified the tumor in 26 patients, rendering an overall detection rate of 66.7%. On a site-based analysis, 68Ga-DOTATATE PET/CT correctly identified the EAS tumor in 13 of 25 patients with pulmonary NETs, yielding a detection rate of 52%; for the 14 patients with extrapulmonary NETs, 68Ga-DOTATATE PET/CT correctly identified the EAS tumor in 13, yielding a detection rate of 92.9%. The detection rate of 68Ga-DOTATATE was significantly higher in extrapulmonary NETs than in pulmonary NETs (92.9%% vs. 52%, P = 0.013). For the 13 patients with positive pulmonary NETs, the tumor SUVmax ranged from 1.1 to 7.4 with an average SUVmax of 3.1 ± 2.1. For the 13 patients with positive extrapulmonary NETs, the tumor SUVmax ranged from 2.7 to 21.8 with an average SUVmax of 9.9 ± 6.3. The tumor SUVmax was significantly higher in extrapulmonary tumors than pulmonary tumors (P = 0.015). The tumor size was smaller in pulmonary tumors than in extrapulmonary tumors, while the difference was not significant (P = 0.516). Conclusion: 68Ga-DOTATATE showed site-specific difference in detecting tumors with EAS secretion. Specifically, 68Ga-DOTATATE performed better in the extrapulmonary EAS tumors than in pulmonary ones with both higher detection rate and uptake. Combination of anatomic imaging techniques are necessary for the correct diagnosis of pulmonary EAS tumors.

Evidence of clinical benefit of WHO essential anticancer medicines for children, 2011-2021.

Background: Access to essential cancer medicines is a key determinant of childhood cancer survival. WHO published the Model List of Essential Medicine for Children (EMLc) and updated it every two years since 2007 to promote better access to medicines for children. This study aimed to assess whether the inclusion of essential anticancer medicines for respective indications for children was based on evidence of significant clinical benefit between 2011 and 2021. Methods: We identified all anticancer medicine indications added to the WHO EMLc Section 8 since 2011 and extracted evidence of benefit documented in the corresponding technical reports. Evidence in children was defined as evidence that included participants under 12, and graded into five levels, according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. We analyzed whether each anticancer medicine indication was listed with documented OS benefit or improvements in surrogate measures based on the highest level of documented evidence in children. Findings: A total of 115 anticancer medicine indications were added to the EMLc from 2011 to 2021, of which 101 (87.8%) had some clinical evidence in children and 4 (3.5%) were added without any clinical evidence. Among the 101 medicine indications, none were added with level-1 evidence in children, and 43 (42.6%), 11 (10.9%), 41 (40.6%), and 6 (5.9%) were listed with level-2, level-3, level-4, and level-5 evidence in children, respectively. Only eight (7.9%) medicine indications were reported to have OS benefit, another 12 (11.9%) were reported to have improvements on surrogate measures, and 81 (80.2%) were listed in the EMLc without documented improvements in either OS or surrogate measures. Interpretation: Most anticancer medicine indications of the WHO EMLc were added based on limited evidence of statistically significant clinical benefit in children. Our results suggest that WHO should refine requirements for clinical benefit criteria and permissible forms, quality, and reporting of evidence of essential anticancer medicines for children, specify whether anticancer medicine indications have required evidence of clinical benefit in children, and provide further details in its technical reports that summarise the available evidence. Funding: Not applicable.