摘要

目的

      在国家采取“腾笼换鸟”策略，将促进专利过期药市场竞争节约的基本医疗保险基金用于加强创新药公共保障，平衡患者可及与医保基金可持续性的背景下，本研究以曲妥珠单抗为例，分析具有成本优势的国产生物类似药在中国的临床替代情况，从卫生体系、医生和患者视角探索影响类似药临床替代及决策的因素，为中国制定有针对性的促进国产生物类似药临床替代政策提供决策依据。

方法

基于中国医院药品统计报告提供的全国及30个省不少于100张床位医院的药品销售数据，及某省级肿瘤医院单中心的医院信息系统数据，从全国、省级及医院单中心三个层面分析曲妥珠单抗生物类似药在中国的临床替代情况。采用间断时间序列模型分析曲妥珠单抗及其原研生物药的全国使用量在原研生物药纳入国家基本医疗保险药品目录后进一步降价，及其首个国产生物类似药在中国上市后的水平和趋势变化。采用潜类别轨迹模型分析30个省的曲妥珠单抗月度使用量及其国产生物类似药替代率的变化轨迹，识别趋势相似的省份，分析省间差异及卫生体系视角可能影响国产类似药临床替代的政策措施和激励机制。采用二元多因素逻辑回归模型和边际效应分析，结合患者电话随访和医生线上问卷调查，进一步从医、患视角挖掘影响曲妥珠单抗国产生物类似药临床替代决策的因素。

结果

      曲妥珠单抗首个国产生物类似药自2021年在中国上市以来，替代率逐步提升。到2023年2月，全国层面的替代率达到27.5%。曲妥珠单抗首个国产生物类似药在中国上市后，原研生物药的使用量月均变化率由增转降，月均降低速率为0.5%（P < 0.01），相比上市前下降了1.1%（P = 0.02）。2023年2月，国产生物类似药替代率在30个省中最高达48.9%，最低4.6%。潜类别轨迹模型将30个省的替代率水平及趋势变化分为快速和低速增长组。快速增长组省份的国家基本医疗保险人口覆盖率较高，城镇人口数量占比、城镇职工医保参保人数占基本医疗保险参保人总数比例、人均GDP、人均卫生总费用及个人现金卫生支出占卫生总费用比例均较低。曲妥珠单抗首个生物类似药在中国上市后的2021年1月至12月，在某省级肿瘤医院诊疗的446名HER2阳性乳腺癌女性患者中，仅85人（19.1%）选择国产类似药治疗。年龄较大的患者、城乡居民医保参保患者、初治患者、主治医生为年轻医生、女性医生及主任医师的患者更有可能选择类似药治疗（P < 0.05）。在控制其他因素的情况下，当患者的主治医生职称为副主任医师时，患者年龄每增加1岁，选择国产生物类似药治疗的概率增加0.8%（P = 0.01）。患者年龄在26至60岁之间时，由主任医师治疗的患者选择国产类似药治疗的可能性高于副主任医师治疗的患者（P < 0.05）。15名采用国产生物类似药治疗并完成电话随访的患者均希望通过选择类似药治疗减少个人支出，其中13人认为乳腺癌治疗给家庭带来了较大经济压力。446名患者的24名主治医生中，12人接受了线上问卷调查，均表示了解生物类似药相关概念。其中10人表示会向患者介绍进口原研生物药和国产生物类似药两种治疗方案，开出的曲妥珠单抗原研生物药处方数量比生物类似药处方数量多。9名医生会向采用进口原研生物药治疗的患者提出转换至国产生物类似药治疗的建议。

结论

      曲妥珠单抗自首个国产生物类似药在中国上市以来，类似药替代率不断提升，但仍低于欧洲发达国家。医保支付方式改革可能有利于曲妥珠单抗国产生物类似药的临床替代，多数公立医院相对滞后的药品准入模式不利于临床替代。患者收入、医保待遇、年龄、既往原研生物药治疗经历、对国产生物类似药疗效的认知等因素对曲妥珠单抗类似药临床替代决策有重要影响。患者的主治医生性别、年龄和职称等因素也存在类似影响。为了促进中国国产生物类似药临床替代，应当及时将新上市的生物类似药纳入医院药品目录，并对使用国产类似药给予适当经济激励，加强患者和医生对类似药的认识教育和培训，并完善类似药临床研究和不良反应监测信息公开制度。

Abstract

Objective

In the context of China's strategy to promote market competition of off-patent medicines and redirect cost savings of the basic health insurance funds toward strengthening the public coverage of innovative medicines, and ensuring a balance between patient access and financial sustainability of the basic health insurance funds, this study took trastuzumab as an example to analyze the clinical substitution of local cost-advantaged biosimilars in China, explored factors associated with biosimilar clinical substitution and decision-making from the perspectives of health system, physician and patient. The study aimed to inform evidence-based policy and decision-making related to the adoption of local biosimilars.

Methods

Using the China Hospital Pharmaceutical Audit medicines sales data collected from hospitals with at least 100 beds at national and provincial levels, and the Hospital Information System data from a provincial oncology hospital, this study analyzed the clinical substitution of trastuzumab biosimilars at national, provincial and single-center levels. Interrupted time-series (ITS) analysis was employed to assess the level and trend changes of national-level usage of trastuzumab and its originator before and after further price reduction of the originator following being included in the national basic health insurance medicines list, and the market approval of its first local biosimilar in China. The latent class trajectory model (LCTM) was used to explore the dynamic trajectories of monthly usage and substitution rate of trastuzumab local biosimilar across 30 provinces, identifying provinces that shared similar trends and examining inter-provincial differences, respective policies and incentive mechanisms that may influence the clinical substitution of trastuzumab local biosimilar with health system perspective. Binary multiple logistic regression and marginal effect analysis, as well as patient telephone follow-up and physician online survey were conducted to further investigate the factors affecting clinical substitution and treatment decision-making of trastuzumab local biosimilar from the perspectives of both physicians and patients.

Results

Since the approval of the first trastuzumab local biosimilar in China in 2021, the national-level substitution rate of local biosimilar continued to increase and reached 27.5% by February 2023. The monthly changing rate of usage of the originator shifted from increase to decrease after the approval of the first local biosimilar in China, decreased at a monthly rate of 0.5% (P < 0.01)，declined 1.1% (P = 0.02) comparing with pre-approval. As of February 2023, the highest and lowest substitution rate of local biosimilar was 48.9% and 4.6% respectively across 30 provinces. Using the LCTM analysis, the 30 provinces were divided into two groups based on the substitution rates of local biosimilar, the rapid-growth and slow-growth groups. Provinces in the rapid-growth group had higher national basic health insurance population coverage rates, lower proportion of urban population among the total population, lower proportion of population covered by the urban employee health insurance among the total insured population, lower per capita GDP, lower per capita total health expenditures, and lower proportion of out-of-pocket health spending. Among the 446 female HER2-positive breast cancer patients treated in a provincial oncology hospital between January and December 2021, after the first trastuzumab local biosimilar gained market authorization, only 85 patients (19.1%) chose local biosimilar. Older patients, patients covered by the urban and rural resident health insurance, newly treated patients, and patients treated by younger, female, and chief physicians were more likely to choose local biosimilar (P < 0.05). Controlling for other factors, for patients treated by associate chief physicians, each additional year of patient age increased the probability of choosing local biosimilar by 0.8% (P = 0.01). When patients were aged between 26 and 60, those treated by chief physicians were more likely to choose local biosimilar compared to those treated by associate chief physicians (P < 0.05). All 15 patients who used local biosimilar and completed the telephone follow-up indicated that they chose biosimilar with the intention to reduce individual spending, 13 of them reported significant financial pressure from breast cancer treatment. Among the 24 attending physicians treating the 446 patients, 12 completed the online survey. All 12 physicians considered themselves familiar with the concept of biosimilars. 10 physicians would inform patients that there were two choices of treatment, with either the imported originator or local biosimilar, and all of them prescribed imported originator more often than local biosimilar. 9 physicians were willing to recommend patients under treatment with imported originator to switch to local biosimilar treatment.

Conclusions

The uptake of trastuzumab local biosimilar continued to grow after the approval of the first local biosimilar, although still lower than that in the developed European countries. The provider payment reform may be in favor of local biosimilar substitution, while the comparatively slow medicines formulary inclusion process implemented by most public hospitals may not be conducive to local biosimilar substitution. Patient income, health insurance coverage, age, treatment experience with imported originator, and perception of the efficacy of local biosimilar significantly influenced the decision-making of trastuzumab local biosimilar clinical substitution, as did the characteristics of their attending physicians, such as gender, age, and professional rank. To promote local biosimilar clinical substitution, newly approved local biosimilars should be given immediate inclusion in the hospital medicines formulary, and local biosimilar substitution should be awarded with appropriate financial incentives. Additionally, patient education and physician training about local biosimilar and substitution should be strengthened, and transparency around clinical data as well as adverse drug reaction monitoring information should also be improved.