In vitro diagnostic reagents refer to reagent products used for in vitro testing of human samples. Except for in vitro diagnostic reagents used for blood source screening and radionuclide labeling, all of them belong to the supervision of medical devices. It includes reagents, kits, calibrators, quality control products, etc., with the ability to predict diseases, diagnose diseases and prognosis observation and health status evaluation, which plays an important role in improving the quality of medical care and reducing medical costs. Therefore, it is very important to establish a sound regulatory system to ensure the standardization of in vitro diagnostic reagent filing and registration and product safety and effectiveness.

In order to implement the regulatory requirements of the Administrative Measures for the Registration and Filing of In Vitro Diagnostic Reagents and the Regulations on the Supervision and Administration of Medical Devices, continuously promote the scientific nature of supervision, ensure the perfection of regulatory means and effectively improve the efficiency of supervision, this paper summarizes and analyzes the policies and regulations, classification rules, implementation standards, review guidelines and special procedures related to the registration of in vitro diagnostic reagents, it is beneficial for practitioners and supervisors to fully grasp the key links and supporting requirements of the registration system, improve the scientificity and accuracy of in vitro diagnostic reagent product supervision, and improve the efficiency and quality of enterprises to carry out related product registration.

Overview of 1. product classification rules and implementation standards

The classification of medical devices in China implements the classification catalogue system under the guidance of the classification rules, the classification rules and the classification catalogue coexist, and the classification catalogue is given priority. The current "Classification Subdirectory of 6840 in Vitro Diagnostic Reagents (2013 Edition)" (hereinafter referred to as the 2013 Edition directory) was released in 2013, and the "Notice on Product Attribute and Category Adjustment of Allergen, Flow Cytometer Matching, Immunohistochemistry and In Situ Hybridization in Vitro Diagnostic Reagents" (China Food and Drug Administration Notice No. 226, 2017, circular No. 226) and the Announcement on Adjusting the Contents of the <6840 In Vitro Diagnostic Reagent Classification Subdirectory (2013 Edition)> (SDA Announcement No. 112 of 2020, referred to as Announcement No. 112), to clarify the management categories of in vitro diagnostic reagent products. The above documents have played a positive role in promoting the regulation and industry development of in vitro diagnostic reagents. In the past 10 years, the in vitro diagnostic industry has ushered in a period of rapid growth, new technologies, new methods, new targets continue to emerge, and the number and types of products have risen sharply. The 2013 version of the catalogue, Circular No. 226 and Circular No. 112 cannot fully meet the regulatory and industrial needs, and some product management categories are not completely consistent with the "Classification Rules for In Vitro Diagnostic Reagents" [hereinafter referred to as "Classification Rules" (SDA No. 129)] issued in October 2021, and the classification of some products and their risk classification are easily blurred.

The Classification Rules, with reference to the classification rules of the International Medical Device Regulators Forum (IMDRF), add the main factors influencing the degree of product risk and clarify the rules for determining the classification, dividing in vitro diagnostic reagents into three broad categories and 23 sub-categories. Among the 23 sub-categories, the first category of in vitro diagnostic reagents is divided into 3 items, the second category 12 items, and the third category 7 items. At the same time, the State Drug Administration (hereinafter referred to as the "State Drug Administration") organized and initiated the revision of the "Classification Catalog of In Vitro Diagnostic Reagents", and continued to use 6840 in terms of classification codes to avoid changes in registered in vitro diagnostic reagent products due to classification code adjustments. Registration, change of production licenses, etc., reduce the impact on the industry.

Standards are the technical support for economic activities and social development, and are an important aspect of the national basic system. As of December 2022, my country has 26 medical device standardization technical committees and sub-technical committees, and 10 medical device standardization technology centralized units. The formulation and revision of in vitro diagnostic reagent standards are determined by the national medical clinical laboratory and in vitro diagnostic system standardization Technical Committee SAT/TC136 to complete. Based on the particularity of medical device standards, the state retains the mandatory national standards for medical devices and the mandatory industry standards for medical devices. The newly revised Regulations on the Supervision and Administration of Medical Devices further clarify the legal status of mandatory industry standards for medical devices-equivalent to mandatory national standards. The technical requirements for medical device products shall not be lower than the mandatory national standards and mandatory industry standards applicable to the products.

2. Clinical Evaluation Management

In order to improve the clinical evaluation management of in vitro diagnostic reagents and ensure the safety and effectiveness of medical devices, the State Food and Drug Administration and the National Health Commission jointly revised the "Medical Device Clinical Trial Quality Management Practice". The document will be implemented on May 1, 2022, providing applicable regulations and guidelines for clinical trial management, regulatory audit and clinical safety. In order to cooperate with the implementation of the "Medical Device Clinical Trial Quality Management Standard" and achieve the purpose of better clinical trials, on March 31, 2022, the State Food and Drug Administration issued the "Medical Device Clinical Trial Program Model" and "Medical Device Clinical Trial Report Model" and other 6 documents were implemented together with the "Standard" to provide a basis for the accuracy and scientificity of clinical trial results.

With the continuous improvement of medical device laws and regulations, in order to ensure the high quality and standardized management of in vitro diagnostic reagents, the State Food and Drug Administration issued the Notice on Publishing the Newly Revised Catalogue of Medical Devices Exempt from Clinical Trials (No. 94 of 2018) in September 2018, revising the previously published catalogue of in vitro diagnostic reagents exempt from clinical trials, and issuing the catalogue of in vitro diagnostic reagents exempt from clinical trials. And on this basis, another revision of the catalogue was made on December 13, 2019, with 23 new items and 4 amendments. Since then, the State Food and Drug Administration issued a notice on January 19, 2021 to exempt the catalogue of medical devices from clinical trials (the second batch of amendments), and revised a total of 7 products. So far, the catalogue of in vitro diagnostic reagents exempted from clinical trials has been continuously improved. On September 16, 2021, the SFDA issued the latest edition of the Catalogue of In Vitro Diagnostic Reagents Exempt from Clinical Trials (2021) (SFDA Circular No. 70), which will summarize in vitro diagnostic reagents that can be exempted from clinical trials, totaling 14 categories and 423 species. This edition of the catalogue clearly points out that in vitro diagnostic reagents for patient self-testing or neonatal testing cannot be exempted from clinical trials, while Class II products such as test condition setting reagents and general counting reagents for flow cytometric analysis should be classified as products exempted from clinical trials. The continuous improvement of the catalog of in vitro diagnostic reagents that are free from clinical trials is conducive to saving resources, improving efficiency, and better managing the evaluation of in vitro diagnostic reagents.

In order to guide the management of clinical trials of in vitro diagnostic reagents, in 2016, the former State Food and Drug Administration issued the Notice on Carrying out Supervision and Spot Check of Clinical Trials of Medical Devices (No. 98 of 2016), which clarified the key points and procedures of supervision and spot check, and put forward the key points and procedures of on-site inspection of clinical trials of medical devices, it is stipulated that only clinical trial institutions that have the necessary conditions for the test and have completed the filing in accordance with the relevant procedures can carry out the test to evaluate in vitro diagnostic products. As of February 2023, 1191 institutions nationwide have completed the filing of medical device clinical trial institutions. In November 2017, the former State Food and Drug Administration issued the ''Administrative Measures for the Conditions and Filing of Medical Device Clinical Trial Institutions'' (Announcement No. 145 of 2017), which put forward specific requirements for the conditions that clinical trial institutions should have, and for medical institutions Make specific regulations on qualifications, professional and technical levels, organization and management capabilities, ethics committees, etc.

3. review guidelines
As a national regulatory agency, the State Food and Drug Administration has formulated relevant guidelines in the guidance document "Guiding Principles for Technical Review of Medical Devices", which is applicable to the supervision and guidance of medical device registration and helps to improve the quality of registration review. Review guidelines are not mandatory guidance documents, but are a reference for risk management, review, registration and clinical evaluation. As of the end of May 2021, the State Food and Drug Administration has issued 399 guidelines, of which 140 are related to in vitro diagnostic reagents. In order to further clarify the technical requirements for the performance evaluation of in vitro diagnostic reagents, the National Medical Device Technology Review Center drafted and issued the Guiding Principles for the Performance Evaluation of Quantitative in vitro Diagnostic Reagents to clarify the technical requirements for the performance evaluation of in vitro diagnostic reagents.

4. Discussion

At present, in vitro diagnostic reagents have entered a new stage of rapid development, the domestic market continues to expand, the number of listed companies, product research and development investment, equipment exports and investment in product research and development are showing an upward trend. With the increasing incidence of malignant tumors, individualized precision medicine has become the mainstream of development. In addition, in vitro diagnostic reagents play an irreplaceable role in the health management of residents, and are a powerful tool for early screening, prognosis and treatment of diseases. While the industry is booming, it also exposes the regulatory problems in China's in vitro diagnostic reagent industry, which brings us the following enlightenment:

Laws and regulations are the source power to ensure the orderly development of the industry.. Strengthening and maintaining the safety of medical devices is the main problem currently facing. Laws and regulations are the key to ensuring the sustainable development of the industry and protecting the rights and interests of the industry. Medical device laws and regulations must keep pace with the times according to the development of the industry to ensure the safety of consumers. For new problems, it is necessary to innovate supervision methods in time according to the characteristics of industry development. On the one hand, it is necessary to strengthen prior supervision, make unremitting efforts on issues such as product, service quality, and advertising, and reduce the space for implementing infringements; on the other hand, it is necessary to strengthen social supervision and unblock rights protection channels. In the future, the safety of medical devices should be strengthened and the law enforcement should be strict. At the same time, the publicity of medical device safety knowledge should be further strengthened, the relevant system should be implemented, and the awareness of medical device safety responsibility should be improved.

Accelerate the development of medical device standards in emerging industries and give full play to the technical support role of standards.. The State Food and Drug Administration may, according to regulatory needs, determine the centralized unit of medical device standardization technology according to procedures, sort out and collect some group standards, supplement and improve the group standards, and further promote the application. At the same time, the management of enterprise registration standards should be strengthened, and the national standard management department should strengthen the training of theoretical knowledge of enterprise implementation standards, and effectively improve the quality of product implementation standards. In addition, in view of the long revision cycle and incomplete contents of the standards, it is suggested that the relevant departments should timely change the product implementation standards and revise the loopholes in the relevant standards in combination with the data and results collected by the national supervision and sampling inspection, provincial and municipal supervision and sampling inspection, etc.

Strengthen the main responsibility consciousness of enterprises, promote enterprises to improve the quality management system. Medical device registrants and filers are the first responsible persons for product quality assurance. Implementing the main responsibility of enterprise quality and safety is the fundamental way to improve product quality. Strictly grasp responsibility interviews and daily supervision, enhance the sense of corporate responsibility, take responsibility interviews as an important measure to urge enterprises to fully implement the main responsibility, prevent and eliminate hidden quality and safety hazards in a timely manner, and build a solid bottom line for product quality and safety. In addition, the regulatory authorities can carry out system inspections on enterprises to guide and promote production enterprises to establish and improve quality management systems. On the basis of system inspection, we will implement quality management risk investigation and capacity improvement projects for existing quality management problems, and provide targeted assistance and guidance to production enterprises to improve the quality and safety management system.

Strengthen all aspects of supervision, strengthen the regulatory professional capacity to ensure the high-quality development of the in vitro diagnostic reagent industry.. In the task of supervision and sampling of in vitro diagnostic reagents, the sampling situation is generally good, but there are still some problems such as unqualified inspection of individual products and low compliance rate, which expose the problems such as insufficient supervision and lack of supervision professional ability. In the future, the regulatory authorities should strengthen the supervision of product research and development, production, operation and other aspects, adjust and improve the clinical trial management scheme for problematic products, and ensure the high-quality development of the in vitro diagnostic reagent industry by strengthening the implementation of standards, reasonably formulating sampling plans and improving sampling modes. For products without standard support, the national standardization technology centralized unit should ensure the applicability and feasibility, part of the group standards will be tested on a trial basis, and the standards will be improved after accumulating experience, further promoted and revised regularly.