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In vitro diagnostic reagents refer to reagents, kits, calibrators, quality control products and other products used for in vitro detection of human samples in the process of disease prediction, prevention, diagnosis, treatment monitoring, prognosis observation and health status evaluation. With the development of medicine, the variety, functions and scope of application of in vitro diagnostic reagents are also constantly expanding, and they have attracted increasing social attention. In vitro diagnostic reagents play an irreplaceable role in the modern medical system and can be called the "doctor's eyes". Their safety is directly related to the vital interests of the people. National standards and industry standards for in vitro diagnostic reagents (hereinafter referred to as "national standards") are unified technical requirements that should be followed in the production and clinical testing of in vitro diagnostic reagents.
As my country's medical level continues to improve, the demand for clinical diagnosis continues to grow, and the standardization construction of in vitro diagnostic reagents and the reform of the standard system structure have also received wider attention. Building a scientific and reasonable in vitro diagnostic reagent standard system and assisting in the scientific supervision of the in vitro diagnostic industry are important guarantees for improving the quality of my country's in vitro diagnostic reagents. This article combines the current situation of my country's in vitro diagnostic reagent market and standards and puts forward relevant suggestions on how to effectively and appropriately promote the standardization of in vitro diagnostic reagents.
1 Current status of the development of in vitro diagnostic reagents in China
1.1 The quality of in vitro diagnostic reagent products varies, and industry competition is becoming increasingly fierce.
According to different in vitro diagnostic methodologies, in vitro diagnostic reagents can be mainly divided into biochemical reagents (mainly biochemical reactions) and immunological reagents (antigen and antibody analysis). immune response), molecular reagents (molecular biology technology, mainly nucleic acid amplification and gene chip technology) and point-of-care testing (POCT; corresponding detection principles are used according to different monitoring projects). At present, the majority of in vitro diagnostic reagents in my country are biochemical reagents and immunological reagents. my country's in vitro diagnostic reagent industry started late but is developing rapidly. At the same time, there are many types of reagent products but low quality and lack of core technology. In particular, many companies only develop diagnostic reagents, while diagnostic equipment and reagent raw materials still rely on imports, especially The development of core raw materials such as enzyme raw materials, antigens and antibodies is still in its infancy. It is urgent for the government to increase investment in R&D and supervision from the perspective of national security to provide continued guarantee for the prosperity of in vitro diagnostic reagents.
1.2 There is huge room for development of in vitro diagnostic reagents
With the advancement of science and technology and the deepening of the reform of China's medical system, the classification of diseases, diagnostic methods and treatment methods have undergone tremendous changes. Clinical treatment is also changing from the traditional "one size fits all" era to one based on individualized medicine. The era of high-level "medical care" changes. Medical care is a high-level technology that is based on a deep understanding of people, diseases and drugs, and provides personalized diagnosis and treatment of diseases and specific patients. Medical treatment provides broad space for the development of in vitro diagnostic reagents. In the future, in vitro diagnostic products will develop in the directions of individualization, automation, simplicity, high-throughput, and bedside. Among them, molecular diagnosis and point-of-care diagnosis will be the two major areas of potential. In addition, our country has a large population and a significant aging trend. At the same time, our country is implementing the two-child policy and medical insurance reform, which will drive the growth of diagnosis and treatment visits and per capita examination expenses, becoming an invisible driver of the development of the in vitro diagnostic reagent industry. With the implementation of the Healthy China Strategy and "Healthy China 2030", in vitro diagnostic reagents will also face tremendous changes and play a greater role.
2 The regulatory process of in vitro diagnostic reagents in China
is based on the international definition of medical devices. Except for blood screening diagnostic reagents, in vitro diagnostic reagents are medical devices, but their products are between drugs and medical devices and have special characteristics. China’s in vitro diagnostic reagents The reagent product supervision system has been continuously improved. On April 19, 2007, the "Registration and Management Measures for In Vitro Diagnostic Reagents (Trial)" (State Food and Drug Administration [2007] No. 229) was released, which for the first time clarified the use of in vitro diagnostic reagents for blood source screening and the use of radionuclides Labeled in vitro diagnostic reagents are managed as drugs, while other in vitro diagnostic reagents are managed as medical devices. In vitro diagnostic reagents managed as medical devices are divided into three categories and managed separately according to the risk level of the product.
On June 27, 2014, the former State Food and Drug Administration (hereinafter referred to as the "former State Food and Drug Administration") issued the "Measures for the Registration and Management of In Vitro Diagnostic Reagents" (General Administration Order No. 5), further detailing the requirements for in vitro diagnostic reagents. The registration management categories and registration processes have added new contents such as clinical trials, quality management system assessment, registration change process and time limit, and product filing process. In recent years, in order to further support and rectify the development of the in vitro diagnostic reagent industry, the country has increased investment in formulating specifications for in vitro diagnostic reagents and introduced a series of policies.
According to General Administration Order No. 5, the former State Food and Drug Administration issued the "Technical Guiding Principles for Clinical Trials of In Vitro Diagnostic Reagents" on September 11, 2014 to guide the clinical trial work of in vitro diagnostic reagents; in order to fully understand the quality and safety status of in vitro diagnostic reagents , to further standardize the order of production, operation and use of in vitro diagnostic reagents, effectively strengthen supervision, and severely crack down on violations of laws and regulations. The former State Food and Drug Administration issued the "In vitro Diagnostic Reagents Quality Assessment and Comprehensive Management Plan" on April 7, 2015; for To standardize the production quality management of in vitro diagnostic reagents, on
July 10, 2015, the former State Food and Drug Administration issued the "Appendix to the Good Manufacturing Practice for Medical Devices In Vitro Diagnostic Reagents", which clearly stated that the production quality management system for in vitro diagnostic reagents should comply with the "Medical Device Production Quality Management System." Quality Management Specifications" and the special requirements of this appendix. These policies standardize the management of manufacturing enterprises and promote the development of the in vitro diagnostic reagent industry, which has positive and far-reaching significance. However, it should be noted that the domestic regulatory system is not perfect enough. For example, the most widely used immunodiagnostic reagent in my country is the five-item enzyme immunoassay hepatitis B test product. One of the products is classified as a drug, and the other four are classified as medical devices. The standards for in vitro diagnostic reagents under drug management fall under the scope of the "Pharmacopoeia of the People's Republic of China" (hereinafter referred to as the "Chinese Pharmacopoeia"), and the standards for other products fall under the national standards for medical devices, the "Chinese Pharmacopoeia" and the national standards for medical devices. Standard systems are separated from each other.
3 The evolution and current status of in vitro diagnostic reagent standardization construction
A standard is a document that is formulated through consensus through standardization activities and in accordance with prescribed procedures, providing rules, guidelines or characteristics for various activities or their results for common use and reuse. According to the implementation effectiveness, standards can be divided into mandatory standards, recommended standards and guiding technical documents; according to the scope of use, they are divided into national standards and industry standards; according to the different objects of specification, standards can be divided into basic standards, management standards and methods. standards and product standards. In order to meet the development and regulatory needs of the in vitro diagnostic industry, my country is also accelerating the formulation and revision of relevant standards and the reform of the standard management system. Currently, there are about 20 national standards for in vitro diagnostic products and more than 200 industry standards. Since my country's in vitro diagnostic reagents fall into two categories: drugs and medical devices, the corresponding standard system is also divided into two parts.
3.1 Standardization construction of in vitro diagnostic reagents according to drug management
These in vitro diagnostic reagents are biological products, and the relevant standards have long been seen in the "Chinese Biological Products Regulations" (2000 edition), which stipulates the manufacturing and testing procedures for some in vitro diagnostic reagents. Later, the "Chinese Biological Products Regulations" (2000 edition) was incorporated into the three volumes of the "Chinese Pharmacopoeia" 2005 edition. The 2010 edition of the three volumes of the Chinese Pharmacopoeia, which came into effect on October 1, 2010, contains hepatitis B virus surface antigen diagnostic kit (enzyme-linked immunoassay), hepatitis C virus antibody diagnostic kit (enzyme-linked immunoassay), human immunoassay Defective virus antibody diagnostic kit (enzyme-linked immunoassay), Treponema pallidum antibody diagnostic kit (enzyme-linked immunoassay), syphilis rapid plasma reagin diagnostic reagent, syphilis toluidine red non-heated serum test diagnostic reagent and anti-A anti-B blood group Typing reagents (monoclonal antibodies), anti-A and anti-B blood group typing reagents (human serum), a total of 8 in vitro diagnostic reagent standards for drug management. Compared with the standards included in the 2005 edition, they have better technical requirements and normativeness. Improvements to varying degrees. The 2015 edition of the third volume of the "Chinese Pharmacopoeia" has eliminated the standards for anti-A and anti-B blood group typing reagents (human serum). The 2020 version of the "Chinese Pharmacopoeia Compilation Outline" [in the principle of variety collection] clearly states that blood screening in vitro diagnostic reagents and other products should be included in priority, indicating that the country attaches more importance to in vitro diagnostic reagents managed as drugs. As of the end of 2018, my country has formulated a total of 10 standards related to in vitro diagnostic reagents regulated by drugs, all of which are recommended standards.
3.2 Standardization construction of in vitro diagnostic reagents managed by medical devices
As of the end of 2018, my country has formulated 199 industry standards for in vitro diagnostic products (instruments and reagents) managed by medical devices and 16 national standards, including about 130 industry standards for in vitro diagnostic reagents, involving about 100 specific reagent products, only Covering 13% of the total number of products in the in vitro diagnostic reagent product category sub-category. On March 7, 2014, the State Council issued the "Regulations on the Supervision and Administration of Medical Devices" (State Council Order No. 650), which included product technical requirements in the registration of Class I medical device products and the application for Class II and Class III medical device products. Information that should be submitted when registering. Article 58 of the "Good Manufacturing Practice for Medical Devices" (General Administration Order No. 7) stipulates that enterprises should formulate product inspection procedures based on mandatory standards and registered or filed product technical requirements, and issue corresponding inspection reports or Certificate. It can be seen that the medical device product inspection regulations include mandatory standards and registered or filed product technical requirements, which clarify the legal status of product technical requirements. As one of the registration materials, product technical requirements are given the same status as standards. According to the "Measures for the Administration of Medical Device Standards" (General Administration Order No. 33) implemented on July 1, 2017, my country's medical device standards management organizational structure consists of the former State Food and Drug Administration and the Medical Device Standards Management Center (hereinafter referred to as "Standard Management Center"), Medical Device Standardization (Sub) Technical Committee (focal point unit), local food and drug supervision and administration departments, medical device research and development, production and operation enterprises and user units. Currently, the National Standardization Technical Committee for Medical Clinical Laboratory and In Vitro Diagnostic Systems (SAC/TC136) is responsible for the organization and drafting of medical device standards in the field of in vitro diagnostic reagents. The Standards Control Center coordinates the formulation, revision, management and implementation of standards. In order to further strengthen the standardized and refined management of the formulation and revision of medical device standards, the former State Food and Drug Administration organized and revised the "Management Specifications for the Formulation and Revision of Medical Device Standards", marking the improvement of my country's medical device standards and regulations system.
4 Thoughts on China’s in vitro diagnostic reagent standards work
In our country, standards, as one of the basic systems for the modernization of the national governance system and governance capabilities, have been elevated to a national strategy. However, at present, the standard coverage rate and compliance rate of China's in vitro diagnostic reagent products are relatively low, and the standard system needs to be improved. This is mainly reflected in:
4.1 The lack of unified standards for in vitro diagnostic reagents
The in vitro diagnostic reagent industry has strong innovation capabilities, but for some emerging technology products such as high-throughput sequencing technology and molecular companion diagnostic reagents, there are still no unified standards in terms of product quality evaluation, technology development, and test result analysis and utilization. In addition, among the many standards for in vitro diagnostic reagents, there are relatively few product standards. Many mature products do not yet have mature national standards due to restrictions on standard establishment. For example, there are no national standards for the four enzyme-labeled reagents and gold-labeled reagents for hepatitis B. Four enzyme-labeled reagents for hepatitis B have been included in the 1995 version of "Chinese Biological Products Regulations". The lack of standards leads to different measurement results of the same marker for products from different manufacturers. The test results between product users cannot recognize each other and require repeated testing.
4.2 Lack of mandatory standards for in vitro diagnostic reagents
Mandatory standards refer to standards to protect human health, personal and property safety, and standards that are enforced by laws and administrative laws. The connotation is that mandatory standards can be formulated for product standards related to personal health. At present, the relevant standards for in vitro diagnostic reagents are basically recommended standards, resulting in the lack of legal basis for implementation in supervision and inspection, production system assessment and product registration renewal. Whether mandatory standards should be formulated for diagnostic reagent standards for major infectious diseases related to public health requires further in-depth study by the standards department.
4.3 The standard formulation and revision process is too long and lacks a regular revision mechanism.
The standard formulation and revision process includes project establishment, drafting, solicitation of opinions, technical review, approval and release, review and abolition. In order to enhance the openness and transparency of the standard formulation and revision process, the new version of the "Management Specifications for the Development and Revision of Medical Device Standards" has extended the period for soliciting opinions [17]. It takes more than 3 years for a mature product to go from standard establishment to approval to release, and The technology of in vitro diagnostic reagents is developing rapidly, and standards are facing the problem of lagging behind. In addition, each medical device standard is issued individually, and the number of publications is limited. It is difficult for numerous inspection agencies and manufacturing companies to obtain more product standards. In addition, after several years of national supervision and inspection, it was found that although the qualification rate of in vitro diagnostic reagent products is very high, the compliance rate is relatively low. How to promote the implementation of recommended standards by enterprises requires further research.
5 Suggestions on the construction of in vitro diagnostic reagent standardization work
5.1 Improve the existing standard system and build more scientific and reasonable standards
The quantity and quality of my country's in vitro diagnostic reagent product standards have been greatly improved in recent years. In view of the fact that in vitro diagnostic reagents are closely related to public health, it is recommended to establish mandatory standards for diagnostic reagents for major infectious diseases, or to add mandatory provisions to recommended standards to improve the quality of diagnostic reagent products. In order to further ensure the accessibility and applicability of standards, it is recommended to refer to the issuance method of the "Chinese Pharmacopoeia" to collect in vitro diagnostic reagent standards, further refine the content and classification, and revise them regularly. The intersection and integration of multiple disciplines and technologies is an inevitable trend in the development of in vitro diagnostic reagents in the future. Traditional standards have gradually developed into standards based on a certain number of products. However, with the development of today's big data, intelligence, and multi-disciplinary interdisciplinary Under the current situation, the model of products first and then standards cannot meet the needs of technological development. Standards should be formed first based on multi-field and multi-disciplinary consensus to facilitate the transformation of new technologies. At the same time, the new situation also puts forward higher requirements for the specialization and knowledge structure of standardized talents. Therefore, the construction of standardized talent teams should also be strengthened.
5.2 Establish a more efficient standard management system.
With the development of China's medical and health industry, there are more and more types of in vitro diagnostic reagents in China. New technologies and new methods are emerging in an endless stream. There are professional and technical fields that cannot be covered by the existing standardization technical committee. my country should speed up the formulation and revision of national and industry standards for in vitro diagnostic reagent products to meet industry development and regulatory needs. Article 13 of the "Measures for the Administration of Medical Device Standards" (General Administration Order No. 33) stipulates that in professional and technical fields that cannot be covered by the existing Medical Device Standardization Technical Committee, the State Food and Drug Administration may determine the standardization of medical devices according to regulatory needs and procedures. Technical focal point. At present, in vitro diagnostic reagents are managed by two departments: drugs and medical devices. It is recommended that the State Food and Drug Administration set up special in vitro diagnostic reagent standards focal points in some departments with advantageous projects and technologies to better leverage their technical expertise. and characteristics, improve the efficiency of standard management, meet the standardization needs in new fields, and ensure the healthy development of the in vitro diagnostic industry. At the same time, we also hope that more opportunities for standardization projects for in vitro diagnostic reagents will be given in the future. In addition, in addition to the standard management department, the evaluation of standards and the assessment of the standardization technical committee should also introduce review and approval agencies and regulatory agencies, one for ex-ante use and the other for ex-post supervision. The two organizations should strengthen communication with the standard formulation and revision departments and the standardization technical committee to enhance understanding of the standards and promote the improvement of standardization work.
5.3 Effectively strengthen the ability to implement standards
. In order to increase the accessibility of standards, the Standards Management Center has set up a catalog of medical device standards and an inquiry portal for relevant standards in the medical device industry on its website for free inquiry by relevant departments. However, it should also be noted that some enterprises and management departments in my country do not fully understand the standards. There is an urgent need to strengthen the publicity and implementation of standards and practical training, and unify the understanding and use of standards by production enterprises, user departments and regulatory departments to improve standards. execution ability.
5.4 The construction of the standard system adheres to the national standardization strategy.
The "Measures for the Administration of Medical Device Standards" (General Administration Order No. 33) stipulates that the production of medical device products should comply with mandatory national standards. If there are no mandatory national standards, it should comply with mandatory industry standards. Standards are the basic control of product quality. They are technical documents that play a role in the supervision of the entire product life chain before and after. It is necessary to continue to be organized and formulated by the national standard management department for a long time. The country has listed standards and standard work as a national strategy and formulated national standards and industry standards for medical devices, which reflects the advantages of our country's national system. At the same time, we should also actively encourage and guide society and industry to research and formulate standards, and use mobilizable social resources to jointly promote the development of Healthy China and the industry. By establishing a medical device group standard recognition mechanism, we will prioritize the recognition of some medical device group standards as pilot projects. After accumulating experience, we will further promote this working system.