Background
Theoretical framework
-
Function 1: Entrepreneurial activitiesEntrepreneurs are of prime importance; without entrepreneurs, no innovation system would take place. What the entrepreneurs do is turn the potential of a new technology into concrete action and take full advantage of business opportunities [30].
-
Function 2: Knowledge development (learning)If solutions to identified problems are to be provided, new technologies must be developed. Research and development (R&D), search and experimentation, learning-by-doing/using and imitation are regarded as possible sources of new technologies. They may combine old and new technologies in innovative ways and reuse old knowledge by imitation [31].
-
Function 3: Knowledge diffusion through networksExchanging information is the essential characteristic of networks, such as changing norms and values. The diffusion may lead to a change in R&D agendas [32].
-
Function 4: Guidance of the searchActivities can positively affect the visibility and clarity of specific needs [30]. Expectations are also included.
-
Function 5: Market formationIt is difficult for emerging technologies to compete with embedded ones. Therefore, it is important to create protected markets for new technologies by formation of temporary niche markets and tax regimes of minimal consumption quotas [33].
-
Function 6: Resource mobilizationBoth finance and human capital are necessary for all the activities within innovation systems [21]. They may determine the success or failure of a project.
-
Function 7: Advocacy coalition (creation of legitimacy/counteract resistance to change)In order to become a well-developed technology, emerging technologies must be part of an incumbent regime. Parties with vested interests will often oppose the force of ‘creative destruction’. Thus, advocacy coalitions can function as a catalyst to place a new technology on the agenda. If successful, advocacy coalitions grow in terms of size and influence and can become powerful enough to brisk up the spirit of creative destruction [22].
Methods
-
Product registryDatabase in China Food and Drug Administration was searched to confirm the exact number of domestic mAb products approved in China. “Biopharmaceutical drugs” as a category was selected in “domestic products”, and “monoclonal antibody” was used as a keyword; diagnostic antibodies and diagnostic agents were excluded.
-
PatentThe search strategy was defined as the mAb patents applied by Chinese Applicants in recent decades in the United States Patent and Trademark Office. Patent information with satisfactory purposes was searched using the following strategies: Topic = (monoclonal antibod*) AND Title = (monoclonal antibod*) AND Assignee = (CHINA). There was no limit to the year.
-
PublicationAcademic publications related to mAbs in China were extracted from the Thomson Reuters’ Web of Science database. Studies and research about mAbs in China began in the 21st century [37]. Publications related to mAbs between 2000 and 2013 were searched using the following strategies: Topic = (monoclonal antibod*) AND Title = (monoclonal antibod*) AND Address = (China not Hong Kong not Taiwan not Macau). “mAbs” was used as the keyword in the same way. In the query above, the asterisk (*) represents any group of characters or no character and the literature type was limited in “Article”. Given a better understanding about the position of China’s mAbs in the world, publication status of anti-tumour mAbs in China was chosen as an example and compared with “Top 5” countries with respect to mAbs. While keeping the database updated, all the data used were as recent as until March 21, 2014. Selected documents included “monoclonal antibod* or mab*” in the title or “monoclonal antibod* or mAb*” in the topic, and “cancer or tumor or anti-cancer or anti-tumor” in the topic. “Address” searched for the selected countries and regions, including China (excluding Hong Kong, Taiwan and Macau), United States, Japan, Germany, United Kingdom, Italy, France, the Netherlands, and Canada. The document type was limited in “Article” as well. The publication years covered were from 1980 to 2013, since commercially sponsored mAbs began entering clinical study in 1980 [38].
-
Clinical trials registryThe Chinese Clinical Trial Registry database was the source used to present situations about assignees and funding of clinical trials applied in China on mAbs. Both Chinese and English databases were used to search and sort records. “mAb” and “monoclonal antibody*” were used as keywords; the year was not limited.
-
Research projectsThe National Science and Technology Report Service database, which offers open access, was searched to ascertain and narrow down the list of targeted key mAb institutions.
mAb innovation systems in China
Stages of mAb technology development in China
-
Absorbing stageTracking the cutting-edge technology from foreign countries was the objective at this stage, with the advent of its own publications on the existing foreign mAb agents as well as the local R&D processes. China was preparing the first domestic mAb products for introduction into the market.
-
Exploratory stageBy buying and the introducing the technology, domestic products were listed on the market. By the year 2006, four local agents had been developed, including “me-too” and “me-better”. The number of publications concerned was accumulating. Literature types not only included reviews but also new-phased research results. At this stage, China started performing joint research with developed countries such as the United States to explore the path to independent studies.
-
Innovation stageAt this stage of China’s mAb evolution, a total of eight domestic products were available, some of which had reached the stages of humanized technology. The mAb agents were gradually expanding with abundant indications in the process. The R&D institutes attempted to push for United States Patent and Trademark Office approval of their domestic products and succeeded in 2006. The content of the patents in general was concentrated on the diagnosis of major diseases such as cancer and also on mAb preparation and production methods. The number of clinical trials for second and third generation anti-cancer products increased rapidly. Moreover, it was found that enterprises whose products had been put into the market had invested more effort and funding in clinical trials, hence becoming the main sponsors in China.
mAb firms in China
Company | Year | Ownership | Registered capital (Million) | Primary products | Indications | Medical insurance | R&D | Market | Position | Strategy |
---|---|---|---|---|---|---|---|---|---|---|
Bio-tech | 2000 | Private | 115.38 | Taixinsheng | Nasopharyngeal cancer | No | Me-better | Export, domestic market | Hospitals | Academic promotion |
Shanghai CP Guojian pharmaceuticals | 2002 | Private | 686 | Jiannipai | Kidney transplants | No | Me-better | Export, domestic market | Comprehensive and specialized hospitals | Academic promotion |
Yisaipu | Rheumatoid arthritis, psoriasis and Ankylosing spondylitis | Yes | ||||||||
Huasun | 2005 | Private | 127.98 | Licartin | Liver cancer | No | Me-too | Domestic market | Therapeutic centre | Academic promotion |
-
Taixinsheng, produced by Bio-tech pharmaceuticals and approved in 2008 had been the first outcome of national-level projects among developing countries. Substantial support was provided by the government program between China and Cuba, thus Bio-tech performed as an important cooperative carrier of R&D technology on nasopharyngeal cancer.
-
Based in east Shanghai, Shanghai CPGJ, was founded in 2002 and was jointly invested by China International Trust and Investment Corporation and Shanghai Lansheng Guojian pharmaceutical company limited. CPGJ made a joint R&D effort with the Second Military Medical University, one of earliest Chinese military universities. CPGJ’s products include mAb (Jiannipai, developed for kidney transplantation) and fusion protein (Yisaipu, developed for rheumatoid arthritis, etc.). Yisaipu has been successfully listed in the National Medical Insurance of numerous provinces and has consequently earned large-scale government orders. Further, CPGJ owns the intellectual property rights solely.
-
Huasun Biotech, established in 2005, is a subsidiary of the Chengdu Huasun Biological Technology Company Limited with listing in Shenzhen since 1998. Huasun Steel Structure, another Huasun subsidiary, provided a steady and stable inflow of cash. Moreover, Huasun Biotech seized the chance to enter the biopharmaceutical market by technology transfer from the Fourth Military Medical University. The product, Licartin, is the first domestic mAb for hepatocellular carcinoma.
Research institutes and their networking with firms
Project | Institution of first author | Keywords |
---|---|---|
Humanized and human mAbs structure and antibody optimization techniques | Academy of Military Medical Science | Antibody humanized, human antibody, expression system, analysis system |
Final report of tumour and autoimmune disease of certain target antibody drug design | Academy of Military Medical Science | Molecular simulation, molecular docking, target, BLyS, DR5, TNF |
Antibody engineering drugs and synergistic technology | Chinese Academy of Medical Sciences | Antibody engineering drugs, immune coupling objects, antibody fusion protein, synergistic technology |
Tumour marker optimization and clinical research and protein chip development | Second Military Medical University | Tumour marker, detection, protein chip, breast cancer, pancreatic cancer, primary liver cancer, colorectal cancer |
Targeted complement inhibitor for systemic lupus erythematosus (SLE) | The People’s Liberation Army Institute for Disease Control and Prevention | SLE, alexin, CR2, targeted inhibition, physiology of immune defence |
Studies on the novel technologies and approaches for tumour immunotherapy | Fourth Military Medical University | Tumour, immunotherapy, tumour vaccine, erbB2/HER2, apoptosis, exosome |
Novel antibodies in the therapy of autoimmune disease | Second Military Medical University | Auto-immune disease, antibody drug, clinical therapy, mechanism investigation |
Study on the new methods for diagnosing nasopharyngeal carcinoma in early stage | Sun Yat-Sen University | Nasopharyngeal carcinoma, Epstein-Barr virus, tumour biomarker, Bmi-1, CNEPF, LMP2A, IFI27 |
Immunological recognition, immune regulation and basic research of related immune diseases | Second Military Medical University | Immunological recognition, immune tolerance, related immune diseases |
Common malignant tumour prevention, early detection and comprehensive treatment research | Sun Yat-Sen University | nasopharynx cancer, screening, early detection, Epstein-Barr virus, pathogenesis |
Research and development of novel tri-specific single chain antibody drug for the treatment of ovarian cancer | Tianjin International Biomedical Research Joint Research Institute | Ovarian, tumour, antibody drug, specific |
Passing report of 973 project “personalized immunosuppression plan of transplant patients” | Huazhong University of Science and Technology | Galectin-7, galectin-9, SNP, MDR1, IL-6, rejection, immune tolerance, proteomics |
Acceptance report of basic research on organ transplantation immunology & application | Zhejiang University | Organ transplantation, transplantation immunology, chronic dysfunction, transplant infections, immunosuppression |
Institutions
Year | Title | Institute | Content | Aims | Influence/mAb |
---|---|---|---|---|---|
1987 | Development Plan for Biological Products Career | Ministry of Health | Biopharmaceutical industry is given priority to develop the vaccine | To lay a foundation for further technology development | Focus on vaccine, mAb industry in China has not developed well |
2006 | National Program for Long- and Medium-term Scientific and Technological Development (2006–2020) | The State Council | Reaffirm a fact that biotechnology is an emerging technology and the focus of the future high technology industry tool of catching up is very important | To make enterprises to be innovators, cultivate a group of world-class scientists and endeavour to turn out a batch of influential breakthroughs | Middle and small enterprises cannot become the main body of innovations |
2007 | Biological Industry Development of the “Eleventh Five-Year Plan” | The Development and Reform Commission | The overall planning and deployment of biological industry. Four out of nine companies involved in biomedical field | To form a cluster and have local advantages | Strengthen the technical innovation ability construction, promote the achievements of transformation and the development of industrial agglomeration, advance cooperation with developed countries |
2009 | Several Policies to Speed-up the Development of the Biological Industry | The State Council | Biotech drugs should be developed for the treatment of common and serious diseases | To accelerate realization of the aim of fostering biopharmaceutical industry into a strategic pillar in industry | Promote the cooperation and restructure between business-to-business, enterprises and academies, expand the scale of the enterprises |
2010 | Decision about speeding up of cultivating and developing strategic emerging industries | The State Council | From the aspects of the fiscal and taxation financial policies to speed up the cultivation and development of strategic emerging industries | To take in a new round of economic and technology development commanding heights | Clearly fefine the position of antibody drugs and support the industry |
2012 | National Basic Medicine Catalogue | SFDA | Drugs in the list of essential medicines are to meet the needs of basic medical and health care The dosage form is appropriate, the price is reasonable, and can guarantee the supply, the public can have equitable access to medicine | To protect people’s health, to meet people's needs, and to make the country resources get the most reasonable use | mAbs gradually listed on the catalogue, expanded the market |
2012 | “Twelfth – five” Plan | The State Council | Discovery of new target, construction of humanized antibodies, development of therapeutic antibodies for major non-infectious diseases (malignancy, metabolic disease and autoimmune disease) | To carry out the innovation-driven development strategy, get output of major landmark achievements | Emerging industries were supported and advanced rapidly; enterprises are guided to speed up R&D of “Me-better” drugs |
2013 | The “Twelfth – Five Plan” of biological industry development | The State Council | Emphasize R&D of new drugs for major diseases, speed up the process of therapeutic antibody innovation, give support to develop antibody production industrialization | To get significant results in the field of antibody and reach world-class levels in a decade | Get special funds to support R&D, mAbs for anti-tumour advanced rapidly |
Functions of mAb innovation system in China
-
Entrepreneurial activity (F1) is prospering, with a value chain clearly dominated by foreign players since the last century. However, China’s mAb supply chain is growing rapidly and expected to become one of the top 10 largest in the near future.
-
Knowledge development (F2) is being driven by incentives such as the R&D subsidies from the State and corporate R&D efforts, and innovation pressure such as fierce price competition from the leading countries and the need to improve antibody expression performance.
-
Knowledge diffusion (F3) has been best served over the last 10 years through information exchange in networks and technology transfer between developed countries and China. Clearly, the mAbs leading enterprises like CPGJ were driving this growth and the national policies were channelling much of this demand towards domestic suppliers.
-
Guidance of search (F4) has improved. The early transfer successes helped to highlight the need for independent innovation and competitive designs. As operators of mAbs, the enterprises had experienced a downside and had access to first-information of the strengths and weaknesses of their technologies.
-
Market formation (F5) is not strong enough and there are many replacement drugs to share the market. However, high potential niche markets (export and globalization) have been explored.
-
Resource mobilisation (F6) or resource supply situation has improved in that some resource categories are supported by the State (financial and industrial resources); however, for others there are still obstacles on the path to professional industrialization (human and infrastructural resources).
-
Advocacy coalition or legitimacy (F7) has gained momentum due to the government policies of The Eleventh Five-year Plan in 2007 and the national projects named as the “973 Program” and the “863 Program”. The successes in building a domestic mAbs industry and the increase of the targets have reinforced the legitimacy of the technology furthermore.
Discussion
Comparison of mAb development between the United States and China
Comparison of mAb development between India and China
Comparison between mAbs and pharmaceuticals in China
mAbs | Pharmaceuticals | |
---|---|---|
Specificity | High | Very low |
Side effect | Big (early products) | Very big |
Scope of indications | Wide range | Wide range |
Potential of drug transformation | Large | Large |
Year | 1980s | 1950s |
Objective | Prevention and control of major diseases | People’s basic life safety |
Technology source | Transfer of key technology | All generic |
Cross-disciplines | Biology: proteomics, genetic engineering | Combining with biology, traditional Chinese medicine |
Level | Starting period | Mature period |
Industry threshold | High investment threshold, high barriers of entry | Low investment threshold, low barriers of entry |
Actor scale | Individual leading enterprise | Most of enterprises in China |
Actor | Academies | Enterprises |
Market strategy | Academic promotion | Hospital, pharmacy |
Bottleneck | Large scale production | Hard to R&D, price controls strict, over capacity |