In Vitro Diagnostic Industry in China 9811623155, 9789811623158

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In Vitro Diagnostic Industry in China Haibo Song Jian’er Yao Editors

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In Vitro Diagnostic Industry in China

Haibo Song • Jian’er Yao Editors

In Vitro Diagnostic Industry in China

Editors Haibo Song China Association of In Vitro Diagnostics Shanghai, China

Jian’er Yao Tellgen Corporation Shanghai, China

The printed edition is not for sale in Mainland of China. Customers from Mainland of China please order the print book from Shanghai Scientific & Technical Publishers. ISBN 978-981-16-2315-8    ISBN 978-981-16-2316-5 (eBook) https://doi.org/10.1007/978-981-16-2316-5 © Shanghai Scientific and Technical Publishers 2021 Jointly published with Shanghai Scientific and Technical Publishers This work is subject to copyright. All rights are reserved by the Publishers, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publishers, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publishers nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publishers remain neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

China’s in vitro diagnosis industry (hereafter referred to as IVD) began in the 1980s. In the past 40 years, the Chinese IVD industry has been following the trend of national reform and opening up and has made great achievements in the world. At present, China’s IVD has developed into a complete industrial chain from reagent instrument system to raw materials and from the domestic market to the global market. Its products have covered all the subdivided fields of the industry and become one of the countries with the most complete product lines of IVD industry in the world. In 2019, the market capacity of China’s IVD industry was close to 110 billion yuan (about US $15 billion), which was the largest segment of China’s medical device industry. As of the end of September 2019, there were nearly 1600 imported and domestic IVD manufacturers, including 39 IVD companies listed in A-share market, 3 in the Hong Kong stock market, and 70 enterprises listed on the new OTC market. China’s IVD enterprises and products have gone abroad and into the world. At present, the development of IVD in China is gradually standardized, the format is increasingly mature, and new technologies and new products have emerged in an endless stream. High-throughput technology, CTC circulating tumor cell detection, the third-generation single-molecule sequencing, ddPCR, mass spectrometry platform detection, microfluidic chip and artificial intelligence, and other hotspot technologies are having a strong incoming. Intelligent operation from laboratory to clinical, from laboratory to individual, and from laboratory to home is realized through the Internet, and data sharing is realized through digital laboratories. China’s IVD products are developing in the direction of automation, serialization, miniaturization, personalization, speediness, intellectualization, and informatization and towards the direction of high integration and automatic assembly line, which has become one of the fastest growing IVD industries in the world. The In Vitro Diagnostics Industry in China is jointly composed by China Professional Community of Experimental Medicine and National Association of Health Industry and Enterprise Management, China Association of In Vitro Diagnostics. This book illustrates the development of chinese In Vitro Diagnostics industry, including immunoassays, biochemical assays, molecular diagnostics, POCT, liquid biopsy, and microbiological assays. The report also covers research and development of IVD products, the market analysis of various segments, and market forecast of the IVD industry in the future. The publication of The In Vitro v

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Preface

Diagnostics Industry in China provides a platform for production, technology, products, and information exchange for the global IVD industry and boosts the development of industry as a whole. After 40 years of development, China’s IVD industry has become the world’s second largest sales market, the second largest production base, and the fastest growing market. In the future, IVD in China will maintain a growth rate of approximately 15% for many years to come. China has made contributions to the development of global IVD industry and to human health. Shanghai, China Shanghai, China 

Haibo Song Jian’er Yao

Contents

Part I Overview of In Vitro Diagnostics Industry in China 1 Interim Market Analysis ��������������������������������������������������������������������������   3 Haibo Song, Yaoyi Zhu, Linda Zhang, Qi Chen, and Wenting Xiao 2 Opportunities and Challenges������������������������������������������������������������������  11 Yaoyi Zhu, Linda Zhang, Qi Chen, and Wenting Xiao Part II Immunoassay 3 R&D, Manufacture, and Market��������������������������������������������������������������  19 Zengli Yang, Xuedong Zhang, Peng Li, Guangpu Sha, and Guangyu Fu 4 Representative Products��������������������������������������������������������������������������   27 Yong Tang, Kang Yu, Tengxiang Long, Weijia Wang, and Yang Yang 5 Immunoassay Outlook������������������������������������������������������������������������������  37 Yang Yang, Zengli Yang, Xuedong Zhang, and Peng Li Part III Clinical Chemistry 6 R&D and Manufacture Status������������������������������������������������������������������  45 Ting Li and Yaoliang Ding 7 Market of Clinical Chemistry ������������������������������������������������������������������  57 Bingde Zou, Lishan Wu, Yaoliang Ding, and Ting Li 8 Representative Products����������������������������������������������������������������������������  67 Bingde Zou and Liang Fang Part IV Molecular Diagnostic 9 Molecular Diagnostic Market ������������������������������������������������������������������  85 Chen Chao 10 Important Companies��������������������������������������������������������������������������������  97 Jack Shao and Crystal Lin vii

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11 R&D and Manufacture Status������������������������������������������������������������������ 107 Zhongping Deng, Weimin Miao, Kang Wu, Bozhi Ji, Xiaomei Ren, and Deyong Tan 12 Representative Products���������������������������������������������������������������������������� 119 Ming Li, Niancai Peng, Zheng Li, Yinqiang Li, Jun Zhu, Biao Peng, and Lei Fan 13 Review of NMPA-Approved Molecular Diagnostic Products and Innovative Medical Devices���������������������������������������������������������������������� 139 Lizhong Dai, Rangjiao Liu, Jia Liu, Xinwu Guo, Jinliang Li, and Yingjuan Ai Part V POCT 14 R&D, Manufacture, and Market�������������������������������������������������������������� 147 Yaping Zhao and Le Ying 15 POCT Products Outlook �������������������������������������������������������������������������� 161 Fugang Li, Jianxin Xu, Ding Wang, Dongxu Wang, and Yong Shang 16 Representative POCT Products���������������������������������������������������������������� 175 Lili Chen, Ying Wang, Hairong Guo, Youwen Zhao, and Honghua Zhang Part VI Hematology, Coagulation, Urinology and Others 17 Cytometer �������������������������������������������������������������������������������������������������� 193 JiaRui Xi, Daisy Day, and Guang Yang 18 Coagulation Analyzer�������������������������������������������������������������������������������� 201 Zuojun Zou, Dan Sheng, Yanshang Ma, Ran Ji, and Wanwan Zhu 19 Urine Analyzer ������������������������������������������������������������������������������������������ 221 Jianwen Ding, Xiaoxia Duan, and Zhanhong Wu 20 Sperm Quality Analyzer���������������������������������������������������������������������������� 229 Yufeng Cui, Zhongxiong Chen, and Yanyan Kang 21 Vaginal Secretion and Cervical Analyzer������������������������������������������������ 235 Jie Song, Lichun Liu, and Hui Cheng Part VII Microbiology 22 R&D, Manufacture, and Market�������������������������������������������������������������� 247 Wei Xiong, BinBin Zeng, JiPing Chen, and Mei Wang 23 Microbiology Outlook�������������������������������������������������������������������������������� 261 Yue Chen and Ming Zhang

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Part VIII Listed Companies and M&A in 2018 24 Performance of Listed Companies in 2018���������������������������������������������� 267 Wei Zheng and Yang Li 25 Investment, Financing, and M&A of Listed Companies in 2018���������� 271 Wei Zheng and Yang Li Appendix: List of Selected Chinese IVD Manufacturers ����������������������������  277

Part I Overview of In Vitro Diagnostics Industry in China

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Interim Market Analysis Haibo Song, Yaoyi Zhu, Linda Zhang, Qi Chen, and Wenting Xiao

New advances have taken place in the medical environment, medical device industry, and in vitro diagnostics field from 2019 to 2020. For the whole industry and all Chinese professionals, these changes are both difficulties and possibilities. This article performs an industry analysis and presents the situation analysis of in vitro diagnostics industry.

1.1

Market Analysis of IVD Industry

1.1.1 M  arket Overview of Domestic Enterprises and Market Summary of 77 Enterprises Listed on the NEEQ Market According to the market summary, China’s in vitro diagnostics market’s total market value was at 100 billion RMB (equivalent to 14 billion US dollars) in 2019, with a year-on-year growth of 15%. The imported products account for 55% of the market. In 2019, the total revenue of 77 listed companies was 73.49 billion RMB, showing a YOY growth of 19.9%. Furthermore, the total net profit is 7.95 billion RMB, which shows a YOY decrease of 3.04%. By the end of 2019, the total market value of 27 listed companies in the in vitro diagnosis industry of mainboard, small and H. Song China Association of In Vitro Diagnostics, Shanghai, China Shanghai Academy of Experimental Medicine, Shanghai, China e-mail: [email protected] Y. Zhu IVD Branch of China Association of Medical Devices Industry, Beijing, China L. Zhang (*) · Q. Chen · W. Xiao Shanghai Fosun Long March Medical Science Co., Ltd., Shanghai, China e-mail: [email protected]; [email protected]; [email protected] © Shanghai Scientific and Technical Publishers 2021 H. Song, J. Yao (eds.), In Vitro Diagnostic Industry in China, https://doi.org/10.1007/978-981-16-2316-5_1

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medium-sized board, technology innovation board was 471 billion RMB, with an average static P/E ratio of 44.01.

1.1.2 Market Segments 1.1.2.1 Biochemistry Biochemical testing accounts for 25% of the in  vitro diagnostics market, and the growth rate is estimated to be 5%.China’s biochemical diagnosis market is capable of providing biochemical analyzers and biochemical reagents. However, most of them are clustered in the low-end market. Domestic products occupy more than 50% of the biochemical analyzer market. Moreover, the overall technology development level has reached the international level of the same period. Considering the biochemical analyzer with relatively high technical requirements, although domestic products have relative competitive advantages, there is still a big gap between domestic products and the imported products in terms of detection accuracy and performance stability. International communities recognize and use a closed system for a biochemical diagnosis. The Chinese market will follow that same direction of a closed system with instruments and reagents in the future. Domestic manufacturers should continuously improve the overall design, production process, and track function of biochemical diagnosis instruments and coordinate instrument and reagent development. 1.1.2.2 Immunology: The Largest and the Newest Market In Vitro Immunodiagnosis is the largest and newest segment driven by the chemiluminescence market in recent years. At present, it accounts for about 35% of the in vitro diagnostics market, and the growth rate is expected to reach more than 15%. In 2019, the market share of domestic products in the immune market is 20%–30%. The low-cost enzyme-linked immunosorbent assay (ELISA) is still the leading testing platform in primary hospitals and many basic projects. Domestic products account for 60%–70%. However, with the increased spending on research and development, chemiluminescence will replace ELISA with a more economic-­ friendly development. At present, chemiluminescence is mainly imported products, accounting for 70%–80%. With the progressing development of medical policy on reimbursement control, China is establishing an incentive mechanism for the active use of domestic medical resources, focusing on promoting the implementation and distribution of domestic medical equipment in tertiary hospitals. And chemiluminescence will further expand import substitution. Enterprises with good compatibility, a large amount of detection, and rich detection projects have strong competitive advantages. In the future, chemiluminescence instruments will develop into high-throughput, modular, and assembly line. 1.1.2.3 Molecular Diagnostics: In Vitro The molecular diagnostics market is still dominated by overseas brands, with domestic products taking only 20%–30% of the market majorly by PCR products. PCR instruments and gene chip instruments in the middle reaches of molecular

1  Interim Market Analysis

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diagnosis have been partially localized. Chemiluminescence quantitative PCR is the mainstream platform, and advanced PCR with ultra-high sensitivity is still under development in the early stage. The market scale of PCR diagnosis accounts for more than 30% of the molecular diagnosis market. PCR is estimated to be the mainstream technology in the next 3–5 years. Looking forward, the biggest implementation of molecular diagnosis will be in the field of cancer, including tumor susceptibility gene screening, early diagnosis, concomitant diagnosis, medication guidance, and post-treatment monitoring. With the rise of specially targeted medicine and personalized treatment, the application of molecular diagnosis will be broader. At present, the domestic molecular diagnosis market is still in its early stage, but under the promotion of nationwide policies, the molecular diagnosis industry will have a robust development.

1.1.2.4 Blood and Body Fluid The blood and body fluid testing market includes coagulation testing, blood cell analysis, urine analysis, and urine visible analysis. The overall market accounted for about 10% of the in vitro diagnostics market, with a growth rate of 10%. At present, Western enterprises have an absolute advantage in China’s coagulation market, which is forecasted to occupy more than 80% of the market share. The market value of low-end and medium-end blood coagulation instruments will grow significantly under the development of grading diagnosis and treatment policy in recent 2 years; and the continuous promotion of community hospitals and other related concepts. On the other hand, with the introduction of the concept of automated blood coagulation, the high-end market will gradually integrate and upgrade to automation. Hematology analyzer market is the most successful and a relatively mature market segment of the IVD industry in China, with domestic products accounting for more than 50% of the total market. The three-part differential instruments are mainly domestic, and the imported products are penta-differentiated. As one of the routine medical detection means, urine analyzer plays an important role in medical devices. In the past, foreign brands have occupied a high proportion of the market share in this field, and they are in a leading position in research and development. With the maturedomestic brand technology and a large number of domestic suppliers, the market share of imported brands has declined, and domestic brands have gradually replaced imports, with a market share of more than 50%. 1.1.2.5 POCT Presently, the overall market scale of POCT accounts for more than 10% of the total market value of in vitro diagnostics, with a growth rate of more than 15%. POCT is one of the fastest-growing areas in the in vitro diagnostics industry. With the development of precision medicine in recent years, there are higher requirements for IVD instruments’ accuracy. Biochip technology and microfluidic technology are scaling rapidly in the field of POCT. For medical enterprises, the sensitivity and repeatability of future products will be the crucial area of competition. But POCT on autoimmune items and molecular diagnostics will have a bright future, whereas domestic products account for about 50% of the Chinese POCT market now.

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Due to the increasing implementation of hierarchical diagnosis and treatment and a chest pain center’s construction, POCT products will have more opportunities in primary hospitals, heart failure centers, and other departments. Besides, in the era of Internet plus, such as big data, cloud computing, and the Internet of things, the big POCT platform with smart POCT as the core will bring the gospel to most patients.

1.1.2.6 Microbiology Microbiological diagnosis in China started relatively late, with a share of about 5% and an increase of about 10%. The microbiological diagnosis provides the basis for the prevention, diagnosis, treatment, and curative effect observation of clinical infectious diseases through etiological diagnosis and drug sensitivity analysis. From 2019 to 2020, microbial detection is developing in two directions. On the one hand, microbial detection is advancing rapidly on the road of integration. And major manufacturers have launched a series of overall solutions for each project of microbial detection through process optimization and information integration; on the other hand, POCT diagnostic products have the advantages of fast and simple, high efficiency, low cost, short test cycle, and less sample consumption. It has attracted growing attention from the clinical industry. However, over 80% of the microbiology market is still dominated by imports. 1.1.2.7 Pathology Pathology generally includes histopathology, cell pathology, and molecular pathology. In China, pathology takes less than 5% of the IVD market at a steady annual growing rate of 10%. As the most commonly used pathological diagnosis method, immunohistochemistry has an important and extensive clinical application value in tumor diagnosis, differentiation, and treatment. Domestic products account for 20%–30% of the pathological market in 2020. In cytopathology, liquid-based cell technology puts exfoliated cells in the preservation solution that can better preserve DNA information and greatly improve the positive detection rate. Nowadays, the commonly used molecular pathological detection techniques are chromosome karyotype analysis, chemiluminescence in situ hybridization, PCR, gene chip, and first-generation sequencing. In targeted medicine, molecular pathology has substantial applications in the detection of the tumor, infectious diseases, and genetic diseases. As a result, high throughput will become the main trend of molecular pathology technology.

1.2

Industry Distributions

1.2.1 Regional Distribution of Domestic IVD Enterprises (Fig. 1.1) By the end of 2018, there are about 1450 IVD manufacturers in China and nearly 50,000 distributors and dealers (excluding pharmacies and business enterprises with class I certificates) [1].

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Regional Distribution of Domestic IVD Enterprises 300 278 250

232 228 219

200

155

150 102

100

53 47 40 34 28 27 26 24 21 17 16 16 13

50 0

Regional Distribution of Domestic

Fig. 1.1  Number of IVD Enterprises by Region in 2019 Manufacture r, 1500

CRO, Dealer, Distributor, Independent Lab, 58000

Product Segments of Manufacturers Mass Spectrum Coagulometer Microbiology Electrolyte Specific Protein Plain Tube Urine Analyzer Molecular Diagnostics Chemilluminescence, Immunofluorescence POCT Biochemical Instruments & Assays

37 38 38 38 43

0

94 113 120

100

152 200

216

287 300

Fig. 1.2  Distribution of in vitro diagnostics industry segments

1.2.2 Distribution of Subdivided Fields [1] (Fig. 1.2)

1.3

Listed Companies Overview (Fig. 1.3)

In 2019, there were 108 listed companies in the industry, including 8 on the mainboard, 3 on the small and medium-sized board, 15 on the growth enterprise board, 7 on the science and technology innovation board, 70 on the new third board, and 5 on the Hong Kong stock market [1].

1.4

Organization Category (Table 1.1)

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Listed Companies Overview 5, Hong Kong Share Market

A-share Market 3, Gem

7, Second Board

8, Medium & Small Board

70, New Third Board

33, Main Board

New Third Board

Hong Kong Share Market

Main Board

Medium & Small Board

Gem

Second Board

Fig. 1.3  Listed companies of IVD In 2019 (Fr: Making the correct judging of IVD situation and current situation by Haibo Song) Table 1.1  In vitro diagnostic industry association Order 1 2 3 4 5 6 7 8 9 10 11

Name Laboratory Branch of the Chinese Medical Association Laboratory Physicians Branch of Chinese Medical Association Laboratory Medicine Committee of Chinese Society of Integrated Traditional Chinese and Western Medicine Clinical Laboratory Management Committee of the Chinese Hospital Association Laboratory Medicine Committee of medical science and Technology Commission of PLA Medical Laboratory Industry Branch of National Health Industry Enterprise Management Association Experimental Medicine Branch of National Health Industry Enterprise Management Association In Vitro Diagnosis Branch of China Medical Device Association Laboratory Medicine Branch of China Medical Equipment Association POCT Equipment Technology Branch of China Medical Equipment Association Laboratory Medicine Branch of Chinese Geriatric Society

Subject Academia Academia Academia Academia Academia Business Academia and Business Business Academia and Business Academia and Business Academia and Business (continued)

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Table 1.1 (continued) Order 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

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Name Laboratory Medicine Committee of Chinese Society of Research Hospitals Molecular Diagnostic Medicine Committee of Chinese Research Hospital Association Microbiology and Immunology Branch of Chinese Medical Association Clinical Applied Biochemistry and Molecular Biology Branch of Chinese Society of Biochemistry and Molecular Biology Laboratory Medicine Branch of Chinese Society of Traditional Chinese Medicine Chinese Society of Immunology Labelling Immunoassay Committee of China Association for Analysis and Testing (LIC) China National Accreditation Service (CNAs) Laboratory Committee Medical Committee Chinese Society of Geriatric Health Laboratory Experimental Diagnosis and Social Service Professional Committee of China Medical and Health Culture Association Medical Laboratory Engineering Branch of Chinese Society of Biomedical Engineering Rheumatism and Molecular Immunity Branch of National Health Industry Enterprise Management Association Bethune Psychiatric Society Laboratory Medicine Branch Clinical Diagnosis and Experimental Medicine Branch of China Maternal and Children Healthcare Association Clinical Molecular Diagnosis Branch of Chinese Society of Biophysics Genetic Diagnosis Branch of Chinese Genetic Society National Technical Committee for Standardization of Medical Clinical Laboratory and in Vitro Diagnostic System

Subject Academia Academia Academia Academia Academia Academia Academia Academia Academia and Business Academia and Business Academia and Business Academia and Business Academia and Business Academia and Business Academia and Business Academia and Business Academia and Business

Product Registration

According to the Announcement on Approval and Registration of Medical Device Products launched by the National Medical Products Administration of China each month, the approval data is counted by the first registration. Statistics show that in 2019, the National Medical Products Administration approved 524 domestic (class III) and imported in vitro diagnostic products’ registration. There are 352 domestic in vitro diagnostic products (class III, 67% of the total. 172 imported ones, 33% of the total. There is no exact data for the approval and registration of domestic class II and class I products by provincial and municipal bureaus [2]. Compared with the past 4 years, see Table 1.2 for details.

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Table 1.2  Aata analysis of registered medical device products (first registered medical device) released by NMPA Project content Approval and registration of medical device products In vitro diagnostic products Class domestic diagnostic products Imported diagnostic products

2016 1966

2017 1386

2018 1193

2019 1717

Growth 44%

712 530 182

540 366 174

307 172 135

524 352 172

71% 105% 27%

The noteworthy points are: 1. The number of registered medical devices approved in 2019 is the highest in the recent 3 years. 2. In 2019, the proportion of in vitro diagnostic products in the total approved registered medical device products increased by about 5% compared with that in 2018, which was 31%; in 2018, it was 26%. 3. This data also shows that the number of in vitro diagnostic products of class III and imported diagnostic products made in China in 2019 is far higher than that in 2018, but still slightly lower than that in 2017. 4. Compared with the number of approved registrations of imported diagnostic products, the increase in the number of annotated registrations of domestic diagnostic products (class III) in 2019 dramatically exceeds the imported diagnostic products.

References 1. Haibo Song. A Correct Analysis of the Status and Situation of IVD Market. http://www. caivd-­org.cn/ArticleDetail/Index?combId=77c01bda-­b765-­4916-­97a6-­2a50147c7227,77c01 bda-­b765-­4916-­97a6-­2a50147c7227&articleId=7cbfbad1-­68d5-­454f-­a1d1-­e5e1dbc3bfa5. 2. National Medical Products Administration. Announcement on Approved Registration of Medical Device Products. https://www.nmpa.gov.cn/ylqx/ylqxjgdt/20200317152701797.html

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Opportunities and Challenges Yaoyi Zhu, Linda Zhang, Qi Chen, and Wenting Xiao

2.1

Opportunities

2.1.1 The Medical Industry Is on the Rise According to China’s medical industry’s statistical bulletin in 2019 [1], the total national health expenditure in 2019 is expected to reach 6519.59 billion RMB, with 4656.7 RMB per capita, accounting for 6.6% of GDP. According to the outpatient and inpatient statistics, in 2019, the total number of services by medical and health institutions in China reached 8.72 billion, with the increase of 410 million (4.9%) over the previous year. In 2019, the average outpatient cost of the hospital was 290.8 RMB, which is 6.1% higher than that of the previous year and 3.1% higher than that of the comparable price; the average hospitalization cost is 9848.4 RMB, which is 6.0% higher than that of the previous year and 3.0% higher than that of the comparable price.

2.1.2 The Market Demand for Gene Sequencing Increases The cancer rate is growing worldwide, and China ranks first in the world [2]. As the cancer rate is closely related to individual gene information, and each person’s gene information is different, individualized precision medicine is becoming the mainstream, and gene sequencing technology is an essential part of personalized cancer treatment. With the reform of the medical insurance payment structure and the Y. Zhu IVD Branch of China Association of Medical Devices Industry, Beijing, China L. Zhang (*) · Q. Chen · W. Xiao Shanghai Fosun Long March Medical Science Co., Ltd., Shanghai, China e-mail: [email protected]; [email protected]; [email protected] © Shanghai Scientific and Technical Publishers 2021 H. Song, J. Yao (eds.), In Vitro Diagnostic Industry in China, https://doi.org/10.1007/978-981-16-2316-5_2

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increase of national investment in medical insurance, a variety of mainstream targeted drugs have been added to medical insurance since 2017, with the obvious price reduction. Because the medical insurance policy requires patients to go through target detection before using targeted drugs to avoid the waste of medical insurance funds, the expansion of the targeted drug market also means the corresponding increase of domestic market demand for molecular diagnosis of targeted drugs in tumor precision medicine.

2.1.3 Pathogen Screening Promotes Instant Diagnosis In vitro diagnostics has obvious advantages in detecting and preventing infectious diseases and can play an important role in pathogen screening. There is a huge demand for diagnosing and treating seasonal diseases and detecting common respiratory and intestinal diseases. The rise of the incidence rate of infectious diseases has greatly promoted the in  vitro diagnostic industry’s development. Meanwhile, with the increasing control of infectious diseases in the country, the in vitro diagnostic market’s development will be further promoted.

2.1.4 A  ging Populations Push Chronic Disease Monitoring and Health Management Aging According to the statistical bulletin of health development in 2019, residents’ average life expectancy increased from 77.0 years in 2018 to 77.3 years in 2019 [3]. With the aggravation of China’s aging society and the promotion of family doctor mode under the hierarchical diagnosis and treatment policy, the demand for family chronic disease management is also increasing, promoting the development of diabetes rapid detection, myocardial infarction rapid detection, and home coagulation market. Simultaneously, with the development of big data and Internet technology, in  vitro diagnostic products and technologies will play an essential role in prevention, early screening, treatment, drug screening, and treatment prognosis monitoring in the research of elderly health and chronic disease management.

2.1.5 Possible Application of AI in IVD According to the data of Tractica, a famous American market research institution, it is estimated that by 2025, medical institutions will pay more than 34 billion US dollars for artificial intelligence technology [4]. In 2019, the application of medical AI in diagnosis, imaging, disease prediction and analysis, and medical management will continue to grow. The demand of the medical and health industry for AI comes from the following aspects:

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Irregular diagnosis and treatment behavior. Demand for precision medicine for data analysis. The increase of outpatient surgery in pursuit of timeliness. Continuous development of telemedicine.

2.1.6 Promotion and Policy of Medical Insurance in IVD The government policy on medical insurance makes the hospital constantly grapple between testing quality and cost control. Domestic high-quality IVD products gradually get the opportunity of import substitution, and the policy accelerates import substitution. In primary hospitals, the implementation of hierarchical diagnoses and treatments policy increases the number of diagnosis and treatment on the one hand and increases the demand for essential testing equipment on the other hand. The impact of the slight reduction of testing price on domestic IVD leading companies is far less than the market share increase brought by import substitution and hierarchical diagnosis and treatment.

2.1.7 Registration System Under the medical device registrant system, innovators focus on product development that can be directly entrusted to qualified enterprises. This can restrain the low-level repetitive construction of the medical device industry, reduce the early investment, accelerate the pace of innovation and launching, and stimulate the vitality of industrial innovation and development to enhance the ability of innovation and R&D. OEM enterprises can give full play to their manufacturing advantages and provide sample production conditions for R&D personnel. After the product is approved, OEM enterprises can apply for a production license to maximize existing plants, equipment, and labor efficiency. The industrial layout and social division of labor will be further refined, R&D and production will perform their respective duties and hold their certificates, and the allocation of social resources will be significantly optimized.

2.1.8 Active M&A in IVD Industry Compared with the global market, China’s IVD industry is still very scattered, including more than 1400 local manufacturers and more than 50,000 distributors. The distribution industry of IVD in China has been relatively scattered. In recent years, large companies have been acquiring small local distributors, and the distribution industry has been concentrated. Besides, if the new “two invoices” regulation is extended to the procurement of in vitro diagnostic products (which is still mainly limited to prescription drugs), the merger trend will accelerate.

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2.1.9 Global Influences in China IVD Market Unlike many import-dependent developing countries, domestic manufacturers in China are increasingly prominent in mature fields such as clinical chemistry, hematology, and urine analysis and in high growth fields such as immunoassay and molecular diagnosis. Domestic manufacturers have made progress in new technologies, including mass spectrometry, NGS, and liquid biopsy. Multinational companies are facing more and more confident domestic competitors who benefit from the improvement of R&D capability and are supported by government initiatives and policies, such as centralized procurement and laboratory fee reform. Although the performance of China’s high-end market has declined in recent years, compared with its population size and GDP, the proportion of China’s market income in the global market has been very small, which means that there will be sufficient growth opportunities in the next few years, especially in the global low-end market.

2.2

Challenges

2.2.1 Expenditure Control of Medical Insurance In 2018, the national primary medical insurance fund’s total expenditure was 1782.2 billion RMB, an increase of 23.6% over the previous year. Medical expense’s rapid growth brought tremendous pressure on the medical insurance fund’s smooth operation [5]. In 2018, the total balance of the national primary medical insurance fund was 2344 billion RMB. From the perspective of expenditure, these balances can only maintain the total expenditure of the national basic medical insurance fund for 1 year, and the risk resistance is not high. To mitigate the perils of collapse of the medical insurance fund, it is imperative to control medical insurance expenditure. With the deepening of the medical reform, the medical expenses will be controlled continuously, which will inevitably affect the testing fees, and the testing fees will continue to decline. It will inevitably affect the use of diagnostics products, especially new technology and new products.

2.2.2 DRG Payment System Application and Recommendations Although DRG can help hospitals contain unreasonable expenses, it also has some limitations. Due to the price of current medical charges, it is roughly calculated according to the average value of medical expenses that the cost can vary. The same disease diagnosis may lead to prominent differences in medical expenses due to different manufacturers of the instruments. At the same time, the DRG cost control system will also affect the innovation of medical technology. To control costs, hospitals may be cautious in using new technologies and carrying out new projects. Besides, to control the cost, the hospital will guide the patients to bear at their own

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expense, which does not apply to the outpatients and special diseases, which is easy to lead to the increase of outpatient expenses.

2.2.3 Bidding Procurement Under the pressure of medical reform in China, the in  vitro diagnostics industry faces a lot of pressure, such as bidding price reduction, procurement policy, and two-bill system. Simultaneously, with the increasing pressure of domestic and global medical insurance payments, end customers will increase the weight of product cost-effectiveness when purchasing products. The market competition pattern is increasingly fierce, which puts forward new challenges for the company to improve its market competitiveness continuously. If the product price is greatly reduced, it may affect the company’s future profitability.

2.2.4 Tightening Industry Supervision In the past 2 years, the admittance threshold of in vitro diagnostics industry has been relaxed. The policies such as license separation, pilot of the registrant system, and newly revised medical device catalog free of clinical trials have promoted the industry, including shortening the time to market of specific products, bringing products with core technology invention and significant clinical value into the priority examination channel, but regulating the product quality in the middle and back end. Especially after the vaccine incident, the frequency of flight inspection increased significantly.

2.2.5 New Uncertainties Brought by Sino-US Trade War In November 2018, the US Department of Commerce issued an export control framework for the latest 14 categories of key technologies and related products, including genome and genetic engineering-related technologies [6]. On September 17, 2019, the US Treasury Department issued a proposed regulation to fully implement the Foreign Risk Review Modernization Act (FIRRMA), refining sensitive personal data. This proposal asked CFIUS to review all investments contributed to us genetic research projects; the scope includes cancer, personalised medicine, genomics, and regenerative medicine [7].

2.2.6 Market Competition China’s in  vitro diagnostics industry is in the stage of rapid development. At the same time, due to the large gap between the overall market size and per capita consumption and the mature market, the domestic in vitro diagnosis market has a broad market space. It will maintain a rapid growth rate in the future under the influence

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of economic development, medical system reform, aging population, and the increase of resident income. These factors will attract many in  vitro diagnostic enterprises at home and abroad to join the competition. The level of market competition will also change from price and resource orientation to technology and application orientation, and the degree of market competition will become increasingly fierce.

References 1. National Health Commission of the People’s Republic of China. China’s Statistical Bulletin on the Development of Health Services in 2019. http://www.nhc.gov.cn/guihuaxxs/ s10748/202006/ebfe31f24cc145b198dd730603ec4442.shtml. 2. World Health Organization (WHO). Global Cancer Report 2014. https://www.who.int/cancer/ publications/WRC_2014/en. 3. National Health Commission of the People’s Republic of China. China’s Statistical Bulletin on the Development of Health Services in 2019. http://www.nhc.gov.cn/guihuaxxs/ s10748/202006/ebfe31f24cc145b198dd730603ec4442.shtml. 4. Vcbeat. These Phenomena will Affect Breakthroughs in Medical AI in 2019. https://med.sina. com/article_detail_111_2_60914.html. 5. National Healthcare Security Administration. 2018 National Statistical Communique on the Development of Basic Medical Security. http://www.nhsa.gov.cn/art/2019/6/30/ art_47_1476.html. 6. US Department of Commerce, Bureau of Industry and Security (BIS). Advanced Notice of Proposed Rulemaking (ANPRM). https://www.commerce.gov/news/press-­releases/2019/05/ department-­commerce-­amends-­countervailing-­duty-­process. 7. US Department of the Treasury. Foreign Investment Risk Review Modernization Act (FIRRMA). https://www.treasury.gov/resource-­center/international/Documents/Summary-­of-­ FIRRMA.pdf.

Part II Immunoassay

3

R&D, Manufacture, and Market Zengli Yang, Xuedong Zhang, Peng Li, Guangpu Sha, and Guangyu Fu

The rapid development of immunology has brought many new thoughts and ideas for clinical immunology assays. In the era of clinical pathway management, personalized medicine, and precision medicine, the clinical laboratory testing and management system consisting of immunoassay reagents, instruments, quality controls, and software need to offer better service to the clinical application. Several key questions remained to all IVD companies such as how to catch up the trends and changes immune equipment and reagents accurately, to establish more sufficient pathway of clinical immunoassay, to integrate the concepts to the pathway management, to promote the application of personalized medicine and precision medicine, and to develop the proper technique and products required for clinical application. This chapter combines the history of immunological detection technology, the development of major immunological instruments and reagents domestic and abroad, and the status and capacity analysis of manufacturers and elaborates on the current status and thinking in this subdivided field.

3.1

Development of Immunoassay Technology

Throughout the history of the entire immunoassay development, it could be roughly divided into the classical immunoassay period, the modern immunoassay period, and the automated immunoassay period; and it is currently entering the period of intelligent immunoassay.

Z. Yang · X. Zhang (*) · P. Li · G. Sha · G. Fu Autobio Diagnostics Co., Ltd., Zhengzhou, Henan, China e-mail: [email protected] © Shanghai Scientific and Technical Publishers 2021 H. Song, J. Yao (eds.), In Vitro Diagnostic Industry in China, https://doi.org/10.1007/978-981-16-2316-5_3

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3.1.1 The Period of Classical Immunoassay Classical immunoassay techniques included immunological precipitation, immunological agglutination, and complement fixation. At present, immunological agglutination and immunological precipitation are still applied in clinical laboratories. The following briefly introduces immunological precipitation and immunological agglutination.

3.1.1.1 Immunological Precipitation Immunological precipitation includes one-way immunodiffusion, two-way immunodiffusion, immunoelectrophoresis, immuno-transmission turbidimetry, and immuno-scatter nephelometry. The development of the immunological precipitation reaction at this point could basically be considered as the development stage of classic immunological precipitation. The so-called classical immunological precipitation was limited not only by a narrow measurement range (10 ~ 100 μg/ml) and low sensitivity but also by tedious and time-consuming operation and unable to be automated. Therefore, based on the principle that antigens and antibodies can quickly bind to each other in the liquid phase, micro-immunological precipitation was invented, namely, immuno-transmission turbidimetry, immunolatex turbidimetry, and immuno-scatter nephelometry. These turbidimetry methods have been used for the determination of specific protein content in clinical body fluids; there were now a variety of automated instruments used in clinical testing, especially for immuno-scatter nephelometry. 3.1.1.2 Immunological Agglutination Immunological agglutination included direct agglutination, indirect agglutination, and autologous red cell agglutination assay. No specific instrument was required by the classic immunological test technology, which was based on immunological precipitation and immuno-agglutination reaction, except for immuno-turbidimetry. It was simple and convenient for operation, and by some specific measurement methods, even for nowadays, there is still a certain application. Nonetheless, the limitations of immunoassay technology based on immunological precipitation and immunoagglutination were still very obvious, such as low detection sensitivity, qualitative determination for most items, etc. These defects greatly limited its application in pathogens detection, determination of biologically active substances in body fluids, and quantitative detection of immunoassay markers.

3.1.2 The Period of Modern Immunoassay The development of modern immunoassay benefited from the development of labeled immunological technology. The clinical problems, which classical immunoassay could not solve, can be solved by modern immunoassay. It mainly included fluorescent labeling technology, radioimmunoassay, enzyme-linked immunoassay (ELISA), chemiluminescence immunoassay, and solid-phase membrane immunoassay.

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3.1.2.1 Fluorescent Labeling The initial labeling used in labeled immunoassay technology was fluorescein. Currently, indirect immunofluorescence tests were used to detect bacteria, viruses, parasites, tissue cell antigens, tumor-specific antigens, and autoimmune disease markers. Automation was available for time-resolved fluorescence and fluorescence polarization immunoassay which have been widely applied in diagnosis of various diseases. 3.1.2.2 Radio-Immunoassay (RIA) The radio-immunoassay which is highly sensitive at that time has solved the problem of detection for biological-active substances such as hormones that were previously difficult to measure accurately. Although radio-immunoassay was a milestone in the development of immunoassay, due to short half-life, difficulty of waste handling and environmental pollution, it has gradually withdrawn from its application in routine clinical application. The use of non-radioactive labeling has become the most chosen option. 3.1.2.3 Enzyme-Linked Immunoassay (ELISA) After the appearance of this simple and convenient technology, the enzyme-linked immuno-sorbent assay (ELISA) not only became a very simple tool for research, but was also quickly applied to the clinical detection of various biological substances and markers, which is replacing RIA step by step. Various techniques have been invented one after another, such as one-step sandwich method, different homogeneous enzyme-labeled or radionuclide-labeled methods, and so on. However, people were still seeking new methods to reduce the problems in this technique such as errors in manual operation, labor-intensive, time consuming, many undetermined results, difficult to be quantified, batch by batch, and low sensitivity and specificity. 3.1.2.4 Chemiluminescence Immunoassay Chemiluminescence immunoassay has been rapidly developed, which has been widely used in domestic and foreign markets, because of the good sensitivity and specificity, wide detection range, stable reagents, and no radioactive contamination. It is mainly used in microplate-based and magnetic particle–based immuno-­ chemiluminescence detection systems. The development of chemiluminescence immunoassay system was mainly focused on the development and improvement of two core technologies: solid phase and luminescence system: (1) The solid phases widely used were plastic particles, super paramagnetic particles, elastic plastic tubes, plastic beads, etc. Among them, magnetic particles were convenient for a large amount of coating and easy to be automated. The chemiluminescence immunoassay analyzer with carousel incubator was mainly designed with micron-sized super paramagnetic particles as a solid phase, which directly connected bio-substances to the surface of the magnetic particles by chemical bonds, or by biotin-streptavidin or fluoresin-fluoresin antibody. (2) The chemiluminescence systems were enzymatic chemiluminescence, direct chemiluminescence, and electrochemiluminescence. The classification of chemiluminescence was shown in Table 3.1.

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Table 3.1  Classification of chemiluminescence immunoassay Type Enzymatic (CLEIA) Direct (CLIA)

Principle Substrate added after immunoreaction Chemiluminescent labeling

Electro (ELCIA)

Combination of electricity and chemical reaction

Substance Luminol AMPPD Acridinium ester Isoluminol Tris(2,2′-bipyridyl)ruthenium(II)complex (Ru(bpy))

3.1.2.5 Membrane-Based Immunoassay Membrane-based immunoassay was a new in vitro diagnostic technology developed on the basis of enzyme-linked immunosorbent assay, fluorescent immunoassay, colloidal gold immunotechnology, and membrane as solid phase. Common methods used were colloidal gold chromatography, fluorescent chromatography, dot percolation tests, dot enzyme immunoadsorption, and immunoblotting, which were easy to operate, without large equipment and less time-consuming.

3.1.3 The Period of Automated Immunoassay Various automated immunoassay analyzers were applied in clinical lab using different principles, which offered great convenience to our daily work in the laboratory, with more stability and accuracy than manual operation. The automated procedure of clinical immunoassay was to control each step in the whole immunoassay procedure such as sampling, adding reagents, mixing, incubation, solid-phase separation, signal detection, data processing, result interpretation, and instrument cleansing. This procedure was done by the specific methodology and corresponding analyzer. The automated analyzers currently in the market were analyzers of immunoscattering turbidimetry, chemiluminescence immunoassay, fluorescence immunoassay, and automated analyzers for ELISA. The selection and application of the automation system should be considered with specific situation and requirement of the clinical laboratory itself, including the performance of the system, the facilities and environmental conditions for the instruments, the laboratory testing throughput, information system of lab, and balance of cost and benefit.

3.1.4 The Period of Intelligent Immunoassay Immunoassay has been developed from manual version to semi-automatic then to fully automatic. It now has been intelligentized by internet throughout from lab to clinics, from lab to individual, and from lab to family. Root level medical organization could be equipped by digital lab system for data sharing and individual data review, which was part of the Medical Cloud and future of intelligentization.

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Considering the demand of precision medicine, in addition to clinical diagnosis, challenges emerged for more accurate, more scientific, and more rapid testing for screening of more diseases, surveillance, and prognosis. With the continuous stepping ahead of immunoassay technology, laboratory and clinical testing instruments have gradually been changed from semi-automated to fully automated, of which the working flow has also been evolved from the automatic operation of a single unit to the current total laboratory automation (TLA) or fully automated work flow. The intelligentization should be integrated in every single step of identification, transmission, processing, detection, storage, re-testing, and reporting with whole process to shorten the TAT. Throughout 100 years’ history of immunoassay, this technology based on specific interaction between antigen and antibody has become an irreplaceable method for searching the unknown bio-materials. Specific interaction was the structure and frame of the technique while labeling, mono/polyclonal antibody, solid/liquid phase, signal and detection, QC, information system, and automation were the bricks and decoration of the frame. In theory, as long as any kind of substance in the body could be obtained, corresponding immunoassay methods could be established for clinical testing with the antibodies or antigens. However, under current technical conditions, some disease target markers were not clear and difficult to be tested. Therefore, scientific researchers who were in this industry should continue to work hard to find more specific and sensitive markers, and to develop more accurate and convenient tests. IVD companies should offer better service to clinical lab with cost-effective and stable products by combination of industry.

3.2

R&D and Production of Instruments and Reagents

The immunoassay market has been the main driven force for the development of the in vitro diagnostics industry in recent years. The market was sensitive to technological innovation, which led to huge market share when new tech was available. Compared with the entire IVD market, the market share occupied by industry giants were much higher in immunoassay market, such as Roche, Abbott, Danaher, Siemens, Sysmex, PerkinElmer Inc., Diasorin, etc. At present, the China’s immunoassay market, especially the high-end part, was basically monopolized by worldwide players, of which the domestic supply rate was the lowest one in all IVD aspects. In recent years, some Chinese manufacturers have achieved breakthroughs in many applications, such as infectious diseases, tumor markers, cardiac markers, and thyroid function markers, in both high-end (high-level hospitals) and low-end markets (midand low-level hospitals) for replacing the imported systems. Drawing attention to the history of import substitution of clinical biochemistry, the future of import substitution for immunoassay was transparently obvious under the boosting by the upgrading of Chinese manufacturers. There are two types of imports: one is directly replacing domestic brands in the high-end market; the other is acquiring low-end domestic market in China rapidly with a high cost efficiency. At present, there are more than 70 Chinese manufacturers of chemiluminescence immunoassay, of which some players could be found in Sect. 3.3.2 of this chapter.

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 he Market Capacity of In Vitro T Diagnostic Immunoassay

In vitro diagnostic products were important tools used in the medical field for diagnosis, monitoring, and prevention of diseases, of which detection principles or methods involved immunology, microbiology, and molecular biology, offering different types of products. Multiple technical fields were involved, such as medicine, machinery, electronics, and composite materials. In recent years, the bioengineering and pharmaceutical industries became one of new booming points, of which the IVD as one of the most branches was boosting with high growth rate in China. Immunoassay was the largest sub-industry in IVD, in which chemiluminescence technique has become the dominant technology. The following was an estimation of the volume of the IVD market in 2018.

3.3.1 China IVD Market 1. According to the data and report from the American IQVIA for global and China IVD market, in 2016, market volume of China market was up to 8 billion USD, with more than 15% growth by local currency, which was much higher than worldwide average. 2. According to “Global IVD Market (10th Edition)” released by KaloramaInformation, the growth rate of China’s IVD market in 2016–2021 would be around 15%. The same growth rate would be kept in the recent 3–5 years in China. The growth rate of IVD would be more than other medical markets due to the low basis of previous market volume, fast decreasing demand, and upgrading of the technology. 3. According to the statistics of the “Report of Competition Pattern and Leading enterprise Analysis on China Medical Treatment Apparatus Industry” released by FORWARD Business Information, the market of the medical devices in China has exceeded 500 billion CNY in 2018, reaching 525 billion CNY, with a year-­ on-­year increase of 18%, and the growth rate from 2013 to 2018 was 20%. On analysis for structure of China’s medical device market in 2018, the China’s medical devices had a high share in imaging, in vitro diagnostics, and low-value consumables, accounting for 16%, 14%, and 13 respectively. Top 7 sub-field occupied 68% share of whole market, including cardiovascular equipment. According to the above analysis of various data, China’s IVD market capacity in 2018 was about 70 billion CNY.

3.3.2 China Immunoassay Market By rapid development of China’s immunoassay, the market share of chemiluminescence has gradually expanded. Immunoassay diagnosis was already the largest sub-­ field of the market in China, currently accounting for about 35% (Fig. 3.1).

3  R&D, Manufacture, and Market Others DiaSorin, Hitachi, CHIVD, Tellgen, KHB, Wantai, etc㸧 11%

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China Immunoassay Market in 2018

Maccura 1%

YHLO 1%

Mindray 2% Autobio 5% SNIBE 5%

Roch 36%

Sysmex 2% Siemens 8% Beckman Coulter 14%

Abbott 15%

Fig. 3.1  Immunoassay market structure in China 2018. Data source: public data of the industry, public data and investigation of various enterprises (investigation and analysis of the annual report of the enterprise, etc.)

Chemiluminescence immunoassay was the widely used technology in clinical application, as same as the international market. In recent years, chemiluminescence immunoassay has occupied a huge amount of the high-end market share worldwide because of features that it was highly automated, highly precise, and fast for results. It was more than 75% share of the market for chemiluminescence in China immunoassay market which was mainly composed of chemiluminescence and ELISA. ELISA would be replaced contentiously by chemiluminescence since the chemiluminescence was with high sensitivity, wide range, and easy operation. The market volume for chemiluminescence would be further expended in the future, from the current 20 billion CNY, by upgrading of techniques and increasing of the market itself. The China’s chemiluminescence market is basically monopolized by foreign giants, for example, Roche, Abbott, Siemens, and Beckman Coulter. The Chinses top 3A hospitals were the main target group of these players because of their requirements for higher accuracy, huge sample numbers, and numerous testing items. At the same time, because almost all chemiluminescence systems were basically closed system, instruments and reagents would be sold in bundle contract, from which these players got a huge amount of profit from the continuous consumption of reagents. For hospitals of level 2 or below, it was not commonly available of those systems out there due to less samples and high costs, which left a huge market for local manufacturers.

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As the chemiluminescence market capacity was increasing, import substitution would be one of the trends of chemiluminescence, because of the new medical policy for regional centralized laboratory and primary care system which were potentially favorable to local players. The core competitiveness of Chinses manufacturers of chemiluminescence was “R&D + price + distribution channel.” 1. R&D: The threshold for chemiluminescence R&D was high; therefore, imported systems would be the first choice of level 3A hospitals because of the accuracy and full test manual, which were the representative of the R&D capability. However, local systems have caught up after the investment to R&D in Chinses manufacturers. Two typical models, A2000Plus and A2000 from Autobio, released in 2018, were issued with certificates of more than 80 tests available in the test manual, which covered infectious diseases, tumor markers, pre-natal screening, endocrine and hepto-fibrosis, etc. More than 3000 end users have chosen these systems, among which more than 1500 are level 3 hospitals, consisting of 60% of total level 3 hospitals in China. More than 400 units from Maccura were installed in 2015 and 200–300 units were predicted in 2017, after which a new model i3000 was released in 2018. More than 50 tests were issued certificate in 2015 to ensure the steady growth of the market share. Import substitution was done by Mindray and YHLO as well. 2. Price: Under the same situation, the economic benefits for hospitals by using local systems were much greater than imported systems. 3. Distribution channel: From 2012 to 2015, the industry gradually switched to a small investment mode; that is, distributors got the profit from the reagent and consumables with free or low payment for instrument. A new business way, centralized purchasing service, has changed the whole industry a lot. It was all covered by the manufacturer for the construction, purchasing, aftersale services, and value-added services for the clinical laboratories, which significantly reduced the cost and increased the efficiency in the lab. The centralized purchasing service would change the whole environment of distribution, which needed the powerful manufacturers with wide production line to combine the resources for rapid growth in future. Generally speaking, chemiluminescence would be with 20–25% increasing of whole industry, indicated by industry analysis, with rapid import substitution in this largest sub-field of IVD market in recent 3–5 years. Those players with high capability of R&D, full test manual, and wide distribution way would be superior than others during future competition.

4

Representative Products Yong Tang, Kang Yu, Tengxiang Long, Weijia Wang, and Yang Yang

There are multiple classification criteria for immunodiagnostic techniques, the most commonly used of which are classified into labeled immunoassays and non-labeled immunoassays according to whether they are labeled or not. The non-labeled include latex particle-enhanced turbidimetric immunoassay; and the labeled include enzyme-linked immunosorbent assay, time-resolved fluoroimmunoassay, colloidal gold technique, and chemiluminescence immunoassay. From the development and application of immunological techniques, labeled immunoassay has become the mainstream. This section introduces the chemiluminescence immunoassay in labeled immunological techniques.

4.1

 ain China-Made Automatic M Chemiluminescence Immunoanalyzers

4.1.1 D  istribution of Automatic Chemiluminescence Immunoanalyzer Manufacturers There are 70 registered manufacturers of automatic chemiluminescence immunoanalyzers according to statistics of the National Medical Products Administration (NMPA) by April 2019, which may not be exhaustive since some manufacturers provides open chemiluminescence detection systems. Most of the manufacturers adopt magnetic particle–based chemiluminescence immunoassay. Regionally, chemiluminescence immunoassay manufacturers are distributed in the Yangtze River Delta, the Pearl River Delta, and the Beijing-Tianjin-Hebei Region. If counted by cities, Beijing and Shenzhen gather the most manufacturers, including 12 automatic

Y. Tang · K. Yu (*) · T. Long · W. Wang · Y. Yang Maccura Biotechnology Co., Ltd., Chengdu, Sichuan, China e-mail: [email protected] © Shanghai Scientific and Technical Publishers 2021 H. Song, J. Yao (eds.), In Vitro Diagnostic Industry in China, https://doi.org/10.1007/978-981-16-2316-5_4

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12

12

5

5 3

3

3 2

Guangdong Jiangsu

Beijing

Zhejiang Shandong

Sichuan

Shanghai

Henan

Hubei

2

Hebei

2

Fujian

1

1

1

1

1

Chongqing

Tianjin

Jilin

Hunan

Anhui

Fig. 4.1  Distribution of automatic chemiluminescence immunoanalyzer manufacturers (Source: Inquiry of registration information at NMPA)

chemiluminescence immunoanalyzer manufacturers, respectively. They are also two places with the most concentrated distribution of in vitro diagnostic manufacturers (Fig. 4.1).

4.1.2 D  istribution of Detection Methodologies of Main Automatic Chemiluminescence Immunoanalyzers Methodologically, enzymatic chemiluminescence detection is adopted in over half of the manufacturers, most of which are ALP-labeled chemiluminescence manufacturers. In recent years, more and more manufacturers use direct chemiluminescence detection, which is dominated by acridinium ester labeling technology. Currently, five manufacturers have their open chemiluminescence detection instruments registered, and they may make some adjustments to software and hardware according to the requirements of reagent manufacturers to meet different chemiluminescence detection principles (Fig. 4.2).

4.1.3 D  istribution of Stand-Alone Detection Speeds of Main Automatic Chemiluminescence Immunoanalyzers Different customers have different requirements for automatic chemiluminescence immunoanalyzers. The detection speed, reagent position, sample position, and intelligence level are all the main considerations when the customers choose an

4  Representative Products Fig. 4.2  Distribution of methodologies of main automatic chemiluminescence immunoassay system (Source: Inquiry of registration information at NMPA and public data)

29 45

18

5 2 Enzymatic Direct chemiluminescence chemiluminescence

Open system

ECL

Volume Large

Medium

Maccuta IS 1200 Zecen CIA 1200 Ranos IMS 1200

Small Autobio AutoLumo A1000 Lifotronic eCL8000 Zecen CIA 600 UUIDIAG UD90DT

< _100T/h

Mindray CL-900i Snibe Maglumi 800 YHLO iFlash3000-H

< _150T/h

GeteinBiotech Magical 6800 KIIB ZY Cl 1800 Zecen CIA 1800 LEADMAN CI 1000 Dacheng AUIJA200

Snibe Maglumi 4000 Mindray CL-2000i Ilybiome AE-240 Zecen CLA2800 LEADMAN Cl 2000 KHB Polaris i2400

Maccura i 3000 Mindray CL-600i Snibe Maglumi X8 YIILO iFlash3000

Snibe Maglumi 2000 Aulobio AutoLumo A2000 plus Wanlai Cariy200 WHCO AUTOLUMIS 2000

Mindray CL-1200i Hybiome AE-180 BIOSCIENCE Axceed 260

 C), MTRR (c.66A > G) CYP2C9*2 (c.430C > T), CYP2C9*3 (c.1075A > C), CYP4F2*3 (c.1297G > A), VKORC1 (−1639G > A) CYP2C19*1 (wild type), CYP2C19*2 (c.681G > A), CYP2C19*3 (c.636G > A), CYP2C19*17 (−806C > T) APOE (c.388T > C), APOE (c.526C > T), SLCO1B1 (c.388A > G), SLCO1B1 (c.521T > C) ALDH2 (c.1510G > A) CYP2D6*10, CYP2C9*3, ADRB1 (1165G > C), AGTR1 (1166A > C), ACE (I/D), NPPA (2238T > C), CYP3A5*3

Future Development Trends

China’s genetic testing industry has developed rapidly, and has kept pace with international development and application of science and technology. The national level also attaches great importance to the development of the genetic testing industry, and has mentioned in many important policy documents that it supports the development of genetic testing. The current medical model is undergoing major changes, from empirical medicine, evidence-based medicine to precision medicine, from treating disease to treating disease, and from secondary or tertiary prevention of disease to primary prevention. It is also described in the Outline of Healthy China 2030 Plan. Focusing on precision medicine, biological therapy, chronic disease prevention, and control as the key development direction, and molecular diagnosis is an important part of precision medicine, chronic disease prevention and control. Therefore, although there are still many problems in the application of molecular diagnostics, such as the unclear guidance of national policies and systems, the lagging of authoritative guidelines, the lack of support for genetic big data, and the cognitive differences among clinicians, their application needs and growth are obvious. In the context of increasing attention to chronic disease prevention and control, domestic population restructuring, and multidisciplinary cross-integration to solve clinical problems, molecular diagnostics will usher in a new period of rapid development. According to the “China Cardiovascular Disease Report 2018” compiled by the National Cardiovascular Center and the “Medium and Long-Term Plan for the Prevention and Treatment of Chronic Diseases in China (2017–2025)” released by the State Council General Office in January 2017, the death rate of cardiovascular disease remains. It ranks first and has an upward trend (Fig. 9.5). There are currently 270 million people with hypertension in China, while only 88.35 million people are under management, accounting for only 32.7%; 120 million people with diabetes, 26.14 million are under management, accounting for only 21.7%. There are 140 million hyperlipidemic patients, and the adult prevalence rate is 13.2% … It can be seen that the current status of chronic disease management in China is far from the 70% normative management rate for hypertension and diabetes patients set in the

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Diseases of the heart

1286.9

Cerebrovascular diseases

1121.4

Malignant neoplasms

784.1

Pneumonia and influenza

227.4

Infectious diseases

125.0

Malignant neoplasms

265.9

Cerebrovascular diseases

171.5

Diseases of the heart

159.1

Accidents

32.9

Infectious diseases

32.6 0

Age ≥65 yr Age