Provisions for In-vitro Diagnostic Reagent Registration and Filing
Provisions for In-vitro Diagnostic Reagent Registration and Filing
(Promulgated by SAMR Decree No. 48, issued on August 26, 2021 and shall go into effect as of October 1, 2021)
Chapter I General Provisions
Article 1 The Provisions are formulated in accordance with the Regulations on Supervision and Administration of Medical Devices for the purpose of standardizing the administration on registration and filing of in-vitro diagnostic (IVD) reagents and ensuring the safety, effectiveness, and quality management of in-vitro diagnostic reagents.
Article 2 The Provisions shall apply to the registration and filing of in-vitro diagnostic reagents, and the supervision and administration thereof within the territory of the People's Republic of China.
Article 3 The in-vitro diagnostic reagents mentioned herein refer to those administered as medical devices, including reagents, reagent kits, calibrators, control materials, etc. for in-vitro examination of specimens derived from human body in the course of disease forecast, prevention, diagnosis, treatment monitoring, prognosis observation, health status evaluation, which can be used independently or in combination with instrument, devices, equipment, or systems.
The in-vitro diagnostic reagents used for blood screening and those labeled by radionuclide, which are subjected to drug administration, do not belong to the administration scope of the Provisions.
Article 4 In-vitro diagnostic reagent registration is a process that the registration applicant of in-vitro diagnostic reagents (hereinafter referred to as the "applicant") submits an application for in-vitro diagnostic reagent registration in accordance with the legal procedures and relevant requirements, and the drug regulatory department reviews the safety, efficacy, and quality management based on laws and regulations as well as the scientific cognition, and decides whether or not to approve such an application.
In-vitro diagnostic reagent filing is a process that the filing entity of in-vitro diagnostic reagents (hereinafter referred to as the "filing entity") submits the filing documents to the drug regulatory department in accordance with the legal procedures and relevant requirements, and the drug regulatory department files such submitted filing documents for future reference.
Article 5 The National Medical Products Administration (NMPA) shall take charge of the administration of in-vitro diagnostic reagent registration and filing nationwide. It is responsible for establishing the administration system for in-vitro diagnostic reagent registration and filing, and organizing the review and approval of domestic Class III and imported Class II and Class III in-vitro diagnostic reagents. Additionally, the NMPA shall be responsible for the filing of imported Class I in-vitro diagnostic reagents as well as the supervision and administration thereof according to law. It shall also supervise and guide the registration and filing activities of in-vitro diagnostic reagent conducted by local drug regulatory departments.
Article 6 The Center for Medical Device Evaluation of NMPA (CMDE) shall be responsible for the technical evaluation of the registration application, change registration application, and registration renewal application of domestic Class III and import Class II and Class III in-vitro diagnostic reagents.
The Center for Medical Device Standards Management, National Institutes for Food and Drug Control (NIFDC), Center for Food and Drug Inspection (CFDI), Center for Drug Reevaluation (CDR), Center for Administrative Services and Complaints & Reports and Information Center of NMPA and other specialized technical institutions shall be responsible for the administration of in-vitro diagnostic reagent standards, classification and definition, testing, inspection, monitoring and evaluation, certificate making and serving, and other work related to informatization and administration, and other necessary work related to supervision and administration of in-vitro diagnostic reagents according to their responsibilities.
Article 7 The drug regulatory department of the people's government of the province, autonomous region, or municipality directly under the central government shall be responsible for administration of the registration of the following in-vitro diagnostic reagents within their administrative areas:
(I) Review and approval of the registration of domestic Class II in-vitro diagnostic reagents;
(II) Inspection of the quality management system of domestic Class II and Class III in-vitro diagnostic reagents;
(III) Supervision and administration of medical device clinical trial institutions and clinical trial projects according to law;
(IV) Supervision and guidance of the filing of domestic Class I in-vitro diagnostic reagents for the department in charge of drug supervision and administration of the local people's government at the level of a city divided into districts.
Specialized technical institutions for medical devices established or designated by the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall undertake the technical evaluation, testing, inspection, monitoring, and evaluation, as well as other tasks required for the supervision and administration of in-vitro diagnostic reagents.
The department in charge of drug supervision and administration of the local people’s government at the level of a city divided into districts shall be responsible for filing management of domestic Class I in-vitro diagnostic reagents.
Article 8 The in-vitro diagnostic reagent registration and filing shall follow the principles of legality, scientificity, publicity, fairness, and justice.
Article 9 Class I in-vitro diagnostic reagents shall be subject to product filing management. Class II and Class III in-vitro diagnostic reagents shall be subject to product registration administration.
To apply for filing of domestic Class I in-vitro diagnostic reagents, the filing entity shall submit the filing documents to the department in charge of drug supervision and administration of the local people’s government at the level of a city divided into districts.
Domestic Class II in-vitro diagnostic reagents shall be reviewed by the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government, and the Medical Device Registration Certificate shall be issued after approval.
Domestic Class III in-vitro diagnostic reagents shall be reviewed by the NMPA, and the Medical Device Registration Certificate shall be issued after approval.
To apply for filing of imported Class I in-vitro diagnostic reagents, the filing entity shall submit the filing documents to the NMPA.
imported Class II and Class III in-vitro diagnostic reagents shall be reviewed by the NMPA, and the Medical Device Registration Certificate shall be issued after approval.
Article 10 The in-vitro diagnostic reagent registrant and filing entity shall strengthen the quality management over the whole life cycle of in-vitro diagnostic reagents, and bear responsibilities for the safety, efficacy, and quality management of in-vitro diagnostic reagents in the process of research and development (R&D), manufacture, distribution, and use according to law.
Article 11 The NMPA shall implement priority review and approval for in-vitro diagnostic reagents in urgent clinical need and special review and approval for innovative in-vitro diagnostic reagents, so as to encourage the research and innovation of in-vitro diagnostic reagents and promote the high-quality development of medical device industry.
Article 12 The NMPA shall establish and improve the technical specification system including standards and technical guidance, standardize the technical evaluation of in-vitro diagnostic reagents and the inspection of quality management system, and guide and serve the R&D and registration application of in-vitro diagnostic reagents.
Article 13 The drug regulatory department shall publicize relevant information on in-vitro diagnostic reagent registration and filing promptly according to law. The applicant can look up the approval progress and relevant results, and the public can look up the results of approval.
Without the consent of the applicant, the drug regulatory department, specialized technical institutions and staff members thereof, and experts involved in review shall not disclose business secrets, undisclosed information, or confidential business information submitted by the applicant or the filing entity, unless otherwise provided by law, or national security or the material social and public interest are involved.
Chapter II Essential Requirements
Article 14 The registration and filing of in-vitro diagnostic reagents shall comply with relevant laws, regulations, rules, and mandatory standards, follow basic principles for the safety and performance of in-vitro diagnostic reagents, and refer to the relevant technical guidance. It shall be proved that in-vitro diagnostic reagents under application for registration and filing are safe, effective, and manageable, and shall be ensured that the information is authentic, accurate, complete, and traceable.
Article 15 The applicant and the filing entity shall be enterprises or R&D institutions capable of assuming corresponding legal liabilities
The overseas applicant and filing entity shall designate a domestic enterprise legal person to act as the agent and to carry out the registration and filing of in-vitro diagnostic reagents. The agents shall assist registrants and filing entities to fulfill the obligations prescribed in Paragraph I, Article 20 of the Regulations on Supervision and Administration of Medical Devices, and assist overseas registrants and filing entities to implement corresponding legal liabilities.
Article 16 The applicant and the filling entity shall establish the quality management system related to product research, development, and manufacture, and shall keep its effective operation.
Article 17 The persons undertaking the registration and filing of in-vitro diagnostic reagents shall have corresponding expertise and be familiar with the laws, regulations, and rules related to the registration and filing management of in-vitro diagnostic reagents and the provisions related to registration management.
Article 18 For registration or filing application, applicants or filing entities shall submit relevant materials according to the requirements related to registration or filing of the NMPA, and be responsible for the authenticity of materials submitted.
The documents for registration or filing application shall be in Chinese, where they are translated from a foreign language, the original documents shall also be provided at the same time. When referring to unpublished literature, it is required to provide documents proving the owner's permission to use the information.
Article 19 Where applying for the registration or filing of imported in-vitro diagnostic reagents, it is required to submit the marketing certificate issued by the competent authority of the country (region) where the registrant or filing entity is registered or where the manufacturing site is located.
If the product is not managed as a medical device in the country (region) where the applicant or filing entity is registered or where the manufacturing site is located, the applicant or filing entity shall provide relevant proof documents, including the permission for distribution of sold product in the country (region) where the applicant or filing entity is registered or where the manufacturing site is located.
For any in-vitro diagnostic reagent that has not been marketed in the country (region) where the applicant or filing entity is registered or where the manufacturing site is located but subject to the review and approval as per the procedures for the registration of innovative products, relevant documents are not required.
Article 20 In-vitro diagnostic reagents shall conform to applicable mandatory standards. When a product deviates from the requirements outlined in a mandatory standard regarding its structural characteristics, technical principles, intended use, and method of application, the applicant or filing entity shall propose a statement on the non-applicability to the mandatory standards, with relevant data attached.
In the absence of mandatory standards, applicants or filing entities are encouraged to adopt recommended standards.
Article 21 The registration and filing of in-vitro diagnostic reagents shall follow the Classification Rules and Classification Catalogue for In-vitro Diagnostic Reagents.
Article 22 The drug regulatory department shall continue to accelerate the reform of review and approval system, strengthen the scientific research on in-vitro diagnostic reagent supervision, establish a registration management system for in-vitro diagnostic reagents dominated by technical evaluation and supported by inspection, testing, monitoring and evaluation, optimize the review and approval processes, enhance the review and approval capacity, and improve the quality and efficiency of review and approval.
Article 23 Specialized technical institutions of medical devices shall establish and improve a communication system, clarify the forms and contents of communication, and organize communication with applicants as needed.
Article 24 Specialized technical institutions of medical devices shall establish an expert consulting system as needed, through which they may collect advice from experts on major issues in the process of review, inspection and testing, etc. and take full advantage of the technical support of experts.
Chapter III In-vitro Diagnostic Reagent Registration
Section I Product Research & Development
Article 25 The R&D of in-vitro diagnostic reagents shall follow the risk management principle and take into account the state-of-the-art techniques so as to ensure that all known and foreseeable risks and unintended impacts of the products are minimized and acceptable, and that the benefits of the products outweigh the risks during normal use.
Article 26 For the engagement in R&D activities of in-vitro diagnostic reagents, the requirements of relevant laws, regulations, and mandatory standards of China shall be met.
Article 27 The applicant or filing entity shall prepare the product technical requirements for the in-vitro diagnostic reagents to be registered or filed.
Product technical requirements mainly include the functional and safety indicators and test methods that can be objectively determined for the finished in-vitro diagnostic reagents.
In the technical requirements for Class III in-vitro diagnostic reagents, it is required to clarify the requirements for main raw materials and manufacturing process in the form of an annex.
The in-vitro diagnostic reagents shall comply with the product technical requirements that have been approved through registration or filing.
Article 28 The applicant or filing entity shall prepare the Instructions for Use (IFU) and labels for the in-vitro diagnostic reagents to be registered or filed.
The IFU and product labels shall conform to the requirements specified in Article 39 of the Regulations on Supervision and Administration of Medical Devices and relevant provisions.
Article 29 For the R&D of in-vitro diagnostic reagents, the non-clinical study shall be carried out based on the intended use and technical characteristics of the products.
Non-clinical studies involve testing or evaluating in-vitro diagnostic reagents under laboratory conditions, including the study on selection and preparation of main raw materials, product manufacturing process, product analytical performance, cut-off value or reference interval, and product stability, etc.
In the event of registration or filing application, non-clinical evidence generated in the R&D activities shall be submitted.
Article 30 The functional and safety indicators and test methods determined in the non-clinical study of in-vitro diagnostic reagents shall be adapted to the intended use conditions and purposes of the product, and the samples shall be representative and typical. When necessary, methodological validation and statistical analysis shall be carried out.
Article 31 In the event of registration or filing application, testing shall be performed in accordance with the product technical requirements, with the test report submitted. The clinical trials, registration, or filing application can only be carried out for those qualified in the test.
Article 32 When different packaging specifications are included in the same registration application, only one packaging specification can be tested. The products used in the testing shall represent the safety and efficacy of the product to be registered or filed, and the production thereof shall conform to relevant requirements of the Good Manufacturing Practice (GMP) for Medical Devices.
Article 33 The test report submitted for registration or filing application may be the self-test report of the applicant or filing entity, or the test report issued by a qualified medical device testing institution entrusted thereby.
For Class III in-vitro diagnostic reagents, it is necessary to provide the test reports of products from 3 different batches.
Article 34 For in-vitro diagnostic reagents with applicable national reference standards, it is required to use national reference standards for testing of the reagents. The NIFDC shall be responsible for organizing the preparation and calibration of national standard substances.
Section II Clinical Evaluation
Article 35 The clinical evaluation of in-vitro diagnostic reagents refers to the process of analyzing and evaluating the clinical data using scientific and reasonable methods and confirming whether the product meets the requirements for use or intended use, so as to prove the safety and efficacy of in-vitro diagnostic reagents.
Article 36 The clinical trial of in-vitro diagnostic reagents refers to the systematic study on the clinical performance of in-vitro diagnostic reagents in the corresponding clinical environment.
The technical guidance for clinical trials of in-vitro diagnostic reagents shall be formulated by the NMPA, and the requirements for conducting clinical trials and for drafting the clinical trial report are clarified.
Article 37 During the clinical evaluation of in-vitro diagnostic reagents, clinical trials shall be conducted to prove the safety and efficacy of in-vitro diagnostic reagents.
A clinical trial may be exempt under any of the following conditions:
(I) Where the reaction principle is definite, the design is finalized, the manufacturing process is well-established, and the marketed in-vitro diagnostic reagent of the same variety has been in clinical use for years without serious adverse events being recorded, and its conventional purposes of use are not changed;
(II) Where the safety and efficacy of the in-vitro diagnostic reagent can be proven through comparison with the predicate device.
The catalogue of Class II and Class III in-vitro diagnostic reagents that are exempted from clinical trial shall be compiled, adjusted, and published by the NMPA.
Article 38 For in-vitro diagnostic reagents that are exempted from clinical trials, applicants shall prove the safety and efficacy of the product through the methodological comparison of clinical specimens that meet the intended use with the predicate device.
The NMPA formulates the relevant guidance for clinical evaluation of in-vitro diagnostic reagents exempted from clinical trials.
Article 39 Clinical evaluation materials refer to the documents developed through clinical evaluation by the applicant.
Where the clinical trial is conducted, the clinical trial documents shall include the clinical trial protocol, EC comments, informed consent form (ICF), the clinical trial report, and relevant data, etc.
For in-vitro diagnostic reagents listed in the Catalogue of In-vitro Diagnostic Reagents Exempted from Clinical Trials, the clinical evaluation documents include comparative analysis with similar marketed products, methodological comparison data, and analysis of relevant literature data and empirical data, etc.
Article 40 When different packaging specifications are included in the same registration application, only one packaging specification can be used for clinical evaluation. The product used in the evaluation shall represent the safety and efficacy of the product to be registered or filed.
When registration applications of calibrators and control materials are submitted separately, it is not necessary to submit the clinical evaluation documents.
Article 41 The clinical trial of in-vitro diagnostic reagents shall be conducted according to the requirements of Good Clinical Practice (GCP) within a qualified clinical trial institution which has been filed as required. Before the clinical trial, the clinical trial sponsor shall file the clinical trial project to the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government where it is located. The production of in-vitro diagnostic reagents used in the clinical trial shall comply with relevant requirements of the GMP.
Article 42 For the information of SAEs related to in-vitro diagnostic reagents used in the clinical trials or other serious safety risks occurring during the clinical trials of in-vitro diagnostic reagents, the clinical trial sponsor shall report them to the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government where it is located and where the clinical trial institutions are located, respectively in accordance with relevant requirements, and moreover, risk control measures shall be taken. Where risk control measures are not taken, the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall order the sponsor to take corresponding risk control measures according to law.
Article 43 In the event of large-scale SAEs related to in-vitro diagnostic reagents used in clinical trials or other major safety issues occurring during the clinical trials of in-vitro diagnostic reagents, the sponsor shall suspend or terminate the in-vitro diagnostic reagent clinical trials and report it to the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government where it is located and where the clinical trial institutions are located, respectively. Where the medical device clinical trials are not suspended or terminated, the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall order the sponsor to take corresponding risk control measures according to law.
Article 44 When conducting a clinical evaluation for in-vitro diagnostic reagents intended to be used by consumers on their own, the registrants shall also evaluate the cognitive competence of IFU by consumers without medical background.
Article 45 For in-vitro diagnostic reagents under clinical trials, which are intended for diagnosing diseases that severely endanger life and have no effective diagnosis means yet, and which are deemed to benefit patients through medical observation, they may be used free of charge on other patients with similar diseases in the institution carrying out the in-vitro diagnostic reagent clinical trial after ethical review and obtaining the informed consent, and the safety data may be used for in-vitro diagnostic reagent registration application.
Section III Registration System Inspection
Article 46 The applicant shall submit quality management system materials related to product R&D or production at the time of registration application. Where a drug regulatory department accepting the registration application deems it necessary to conduct an inspection on the quality management system at the time of technical evaluation, the drug regulatory department shall organize the inspection on the quality management system and may access the original data as needed.
Article 47 In case of the inspection on quality management system of domestic Class III in-vitro diagnostic reagents, the CMDE shall inform the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government where the applicants are located to carry out the inspection.
In case of the inspection on quality management system of domestic Class II in-vitro diagnostic reagents, the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government where the applicants are located shall organize to carry out the inspection.
Article 48 The drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall conduct an inspection on quality management system in accordance with the GMP, focusing on whether the applicant has established the quality management system adapted to the product in accordance with the GMP, and also on the contents related to product R&D and production such as the design and development, production management, and quality control.
In the process of inspection, the authenticity of products used in the testing and clinical trial shall be inspected at the same time. Emphasis shall be placed on consulting the relevant records of the process of design and development, as well as the relevant records of the production of such products.
Where a self-test report is submitted, the inspection will focus on the test qualification of the applicant, filing entity, or entrusted institution during the development, as well as the test results.
Article 49 The drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government may carry out quality management system inspection by means of data review or on-site inspection. The decision on whether to carry out an on-site inspection or not, as well as the inspection contents, shall be made according to the specific situation of the applicant, the information on supervision and inspection, as well as the comparison in terms of production conditions and processes between the product under registration application and that passing the previous inspection, so as to avoid repeated inspection.
Article 50 Where the CMDE deems it necessary to conduct an inspection on the quality management system for imported Class II or Class III in-vitro diagnostic reagents at the time of technical evaluation, it shall notify the CFDI to carry out the inspection according to relevant requirements.
Section IV Product Registration
Article 51 After completing the safety and efficacy study supporting in-vitro diagnostic reagent registration, and being ready for the inspection on the quality management system, the applicant shall apply for in-vitro diagnostic reagent registration and submit the following documents to the drug regulatory department through online registration application:
(I) Product risk analysis materials;
(II) Product technical requirements;
(III) Product test report;
(IV) Clinical evaluation documents;
(V) Product IFU and label sample;
(VI) Documents of quality management system related to product development and production;
(VII) Other materials necessary for demonstrating the safety and efficacy of products.
Article 52 The drug regulatory department shall conduct a review on application materials after accepting an application, and handle according to the following circumstances respectively:
(I) Where the application is within the scope of functions and duties of the administrative authority, and the application materials are complete and meet the formal review requirements;
(II) Where the application materials contain errors that may be corrected on the spot, the applicant shall be allowed to correct them on the spot.
(III) Where the application materials are incomplete or do not meet the legal form requirements, the applicant shall be informed one-off of all the supplements or corrections required on the spot or within 5 workdays. If failing to inform the registrant within the specified time limit, the application is regarded as accepted from the date the application materials are received;
(IV) Where the application is not within the scope of functions and duties of the administrative authority, the decision of rejection shall be made immediately and the applicant shall be informed to apply to the relevant administrative authority.
The drug regulatory department shall issue a dated acceptance or rejection notice affixed with its special seal to indicate its acceptance or rejection of the in-vitro diagnostic reagent registration application.
Once the in-vitro diagnostic reagent registration application is accepted, the applicant shall make payment, if required, according to the regulations. Where the applicant fails to make payment within the specified time limit, the applicant will be deemed to have voluntarily withdrawn the application, and the drug regulatory department shall terminate the registration procedure.
Article 53 Where supplementary and correction materials are required during technical evaluation, the institution for technical evaluation shall inform the applicant one-off of all the supplements or corrections required. The applicant shall provide required supplementary materials in a single delivery within 1 year upon receipt of the notice on supplements or corrections, and the institution for technical evaluation shall, within the specified time limit, complete the technical evaluation upon receipt of required supplementary materials.
Where the applicant has an objection to the content of the notice, it may submit its written opinions to the corresponding institution for technical evaluation, stating reasons and providing corresponding technical supporting materials.
Where the applicant fails to submit the required supplementary materials within the specified time limit, the technical evaluation shall be terminated, and the drug regulatory department will reject the registration application.
Article 54 For an accepted registration application, the applicant may, prior to the administrative licensing decision being made, withdraw the registration application and relevant materials, and state reasons to the drug regulatory department which accepted the application. Where the withdrawal of the application is approved, the drug regulatory department shall terminate the registration procedure.
If the review, inspection or approval is suspected of any circumstance under which the real situation is concealed or false information is provided or other illegal acts emerge, it shall be handled according to law, and the applicant shall not withdraw the registration application.
Article 55 For an accepted registration application, where there are signs of evidence indicating that the registration dossier may be spurious, the drug regulatory department shall suspend the review and approval process. After investigation, the drug regulatory department shall determine whether to continue the process or to reject the registration application in accordance with the investigation conclusion.
Article 56 During the review of in-vitro diagnostic reagent registration application, for those to be rejected, the institution for technical evaluation shall inform the applicant of the reasons for rejection, and the applicant can raise an objection to the institution for technical evaluation within 15 days with the contents concerned only limited to the original application items and original application materials. The institution for technical evaluation shall conduct a comprehensive evaluation taking the objection of the applicant into consideration and provide feedback to the applicant. The time taken for handling the objection shall not be counted into the time limit for the review.
Article 57 The drug regulatory department accepting the registration application shall make the decision of whether to approve or not upon the conclusion of technical evaluation. For those that meet the safety, efficacy, and quality management requirements, the registration shall be approved, and a Medical Device Registration Certificate shall be issued, and the approved product technical requirements and IFU shall be issued as an attachment to the applicant. For those disapproved, reasons shall be given in writing, and the applicant shall be informed of its right to apply for an administrative reconsideration or administrative litigation according to law.
The valid term of the Medical Device Registration Certificate is five years.
Article 58 For accepted registration applications, where one of the following circumstances exists, the drug regulatory department shall decide to reject the application and notify the applicant:
(I) The study conducted by the applicant and its result cannot prove the safety, efficacy, and quality management of the in-vitro diagnostic reagent to be sold on the market;
(II) Where the quality management system inspection failed, and the applicant refuses to accept on-site inspection on the quality management system;
(III) The registration dossiers are spurious;
(IV) Where the application materials contain confused or contradictory contents, or those obviously inconsistent with the application items, which cannot prove the safety, efficacy, and quality management of the product;
(V) Other circumstances under which the registration application shall not be approved.
Article 59 For the item of implementing administrative licensing that shall be subject to hearing as specified in the laws, regulations, and rules, or other major administrative licensing items involving public interests that need to hold a hearing as deemed by the drug regulatory department, the drug regulatory department shall announce to the public and hold a hearing. For medical device registration applications that have a direct bearing on the vital interests between the applicant and the other party, the drug regulatory department shall, prior to making the decision of administrative licensing, inform the applicant and the interested party of their rights of requesting for hearing.
Article 60 The drug regulatory department may conditionally approve the registration of in-vitro diagnostic reagents for diagnosing rare diseases and diseases that severely endanger life and have no effective diagnosis means yet, as well as those under urgent need for dealing with public health emergencies. The department shall specify such relevant matters as valid term, post-marketing studies to be completed, and the completion time limit, etc. in the Medical Device Registration Certificate.
Article 61 For the in-vitro diagnostic reagent with conditional approval, the registrant shall collect the data on benefits and risks after the in-vitro diagnostic reagent marketing, as well as continuously monitor and evaluate the benefits and risks of the product, take effective measures to actively manage and control risks, and complete the studies and submit relevant materials as required within the specified time limit.
Article 62 For the in-vitro diagnostic reagent with conditional approval, if the registrant fails to complete the study as required within the time limit or fails to prove that its benefits outweigh the risks, the registrant shall apply for the cancellation of the Medical Device Registration Certificate in a timely manner, and the drug regulatory department may cancel the Medical Device Registration Certificate according to law.
Article 63 For a newly developed in-vitro diagnostic reagent not yet listed in the classification catalogue, the applicant may directly apply for a Class III in-vitro diagnostic reagent registration, or, after determining the class of the product in accordance with the classification rules and applying for class confirmation to the NMPA, apply for registration or filing.
Where a Class III in-vitro diagnostic reagent registration is directly applied for, the NMPA shall determine the class based on its degree of risks. Where a domestic in-vitro diagnostic reagent is determined as a Class II or Class I product, the applicant shall be informed to apply for registration or conduct filing at the corresponding drug regulatory department.
Article 64 Where, for a registered in-vitro diagnostic reagent, the management category is adjusted from a higher class to a lower one, the Medical Device Registration Certificate within its valid term shall remain valid. Where a renewal is needed, the registrant shall apply for registration renewal or filing on the changed classification to the corresponding drug regulatory department six months prior to the expiration of valid term of the Medical Device Registration Certificate.
Where, the in-vitro diagnostic reagent management category is adjusted from a lower class to a higher one, the registrant shall apply for registration on the changed category to the corresponding drug regulatory department. The NMPA shall specify a time limit for completing the adjustment in the notice on adjusting management category.
Article 65 In case of the loss or damage of Medical Device Registration Certificate and attachments thereto, the registrant shall apply for certificate re-issuance to the authority issued former license. The authority issued former license shall re-issue the certificate upon review.
Article 66 Where a patent dispute arises during the registration application review or after approval, it shall be dealt with according to relevant laws and regulations.
Chapter IV Special Registration Procedures
Section I Registration Procedures for Innovative Products
Article 67 For in-vitro diagnostic reagents that comply with the following requirements, the applicant may apply for the applicability to the registration procedures for innovative products:
(I) The applicant legally owns the patent for invention of core technology of the product through its dominant technical innovation activities in China, or obtains the patent for invention in China or the right of use through legal transfer, and the date to apply for the applicability to the registration procedures for innovative products shall be within 5 years from the date of authorization announcement for patent; or the application of the patent for core technology invention has been made public by the patent administrative department directly under the State Council and the Patent Search and Consultation Center of CNIPA has issued the search report, in which the core technology protocol of the product shall be specified to be novel and creative;
(II) The applicant has completed the preliminary study on the product and owns the basically finalized product, the study process is true and controlled, and the study data is complete and traceable;
(III) The primary working principle/action mechanism of the product is the first of its kind in China, the product performance or safety has been substantially improved compared with the equivalent products, and the technology of the product reaches the international advanced level, and has significant value in clinical application.
Article 68 In case of applying for the applicability to the registration procedures for innovative products, the applicant shall submit an application for the review of innovative medical devices to the NMPA after the product is basically finalized. The NMPA shall organize experts to conduct the review and include those meeting the requirements of the registration procedures for innovative products.
Article 69 For the in-vitro diagnostic reagent registration application applicable to the registration procedures for innovative products, the NMPA and institutions that undertake the relevant technical work shall designate special personnel to take charge according to their responsibilities, communicate in a timely manner, and provide guidance.
For the in-vitro diagnostic reagent subject to the registration procedures for innovative products, the CMDE can communicate with the applicant on major technical issues, major safety issues, clinical trial protocol, summary and evaluation of the results of phased clinical trials, and other issues in product R&D before the acceptance of registration application and during the process of technical evaluation.
Article 70 For the in-vitro diagnostic reagent subject to the registration procedures for innovative products, if the applicant voluntarily requires to terminate the procedure, or the NMPA identifies that the in-vitro diagnostic reagent no longer meets the requirements of the registration procedures for innovative products, the NMPA shall terminate the registration procedure for the relevant product and inform the applicant.
Article 71 For the in-vitro diagnostic reagent subject to the registration procedures for innovative products, if the applicant fails to apply for registration within the specified time limit, the registration procedures for innovative products shall be no longer applicable.
Section II Priority Registration Procedures
Article 72 For in-vitro diagnostic reagents that meet any of the following circumstances, an application may be submitted for the applicability to the priority registration procedures:
(I) Medical devices that are used to diagnose rare diseases or malignant tumors with significant clinical advantages, or those used to diagnose the diseases that are specific to or more prevalent among the elderly with no effective diagnostic means currently, or those intended for children with significant clinical advantages, or those which are in urgent clinical need and for which there is currently no predicate device approved to be registered in China;
(II) Medical devices that have been listed in the National Science and Technology Major Project or National Key Research and Development Project;
(III) Other medical devices that may be applicable to the priority registration procedures as specified by the NMPA.
Article 73 In case of applying for the applicability to the priority registration procedures, the applicant shall submit an application for the applicability to the priority registration procedures to the NMPA at the time of applying for in-vitro diagnostic reagent registration. For the circumstances specified in Paragraph I of Article 72, the NMPA shall organize experts to review the application, and include those meeting the requirements of the priority registration procedures; for the circumstances specified in Paragraph II of Article 72, the CMDE shall review the application, and include those meeting the requirements of the priority registration procedures; for the circumstances specified in Paragraph III of Article 72, the NMPA shall solicit opinions widely and organize experts to conduct demonstration to determine whether to include in the priority registration procedures or not.
Article 74 For in-vitro diagnostic reagent registration applications included in the priority registration procedures, the NMPA shall conduct the review and approval with priority, and the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall arrange the quality management system inspection for in-vitro diagnostic reagent registration with priority.
In the process of technical evaluation for medical devices included in the priority registration procedures, the CMDE shall actively communicate with the applicant in accordance with relevant regulations, and if necessary, may arrange for special communication.
Section III Emergency Registration Procedures
Article 75 The NMPA may carry out emergency registration procedures for in-vitro diagnostic reagents which are in urgent need for handling public health emergencies and there is no equivalent product marketed in China, or those having equivalent products marketed in China but insufficient product supply cannot meet the urgent need for handling public health emergencies.
Article 76 In case of applying for the applicability to the emergency registration procedures, the applicant shall submit an application for emergency registration to the NMPA. Those complying with the requirements shall be included in the emergency registration procedures.
Article 77 For in-vitro diagnostic reagent registration applications subject to emergency registration procedures, the NMPA shall handle them in accordance with the requirements of unified command, early intervention, on-demand review, and scientific approval, and carry out the testing and technical evaluation of in-vitro diagnostic reagents as well as system inspection in parallel.
Chapter V Change Registration and Registration Renewal
Section I Change Registration
Article 78 The registrant shall take the initiative to conduct a post-marketing study of in-vitro diagnostic reagents, carry out further validation for the safety, efficacy, and quality management of in-vitro diagnostic reagents, and strengthen continuous management of marketed in-vitro diagnostic reagents.
Where there is any substantial change in the design, raw materials, manufacturing process, scope of application and method of application of Class II and Class Ⅲ in-vitro diagnostic reagents that have been registered, which may affect the safety and efficacy of in-vitro diagnostic reagents, the registrant shall apply to the former registration department for the change registration procedures. Any other changes shall be filed to the former registration department within 30 days from the date of change.
The product name, packaging specification, main components, intended use, product technical requirements, IFU, and the address of manufacturing site of imported in-vitro diagnostic reagents, etc. indicated in the Medical Device Registration Certificate are the items requiring change registration as specified in the preceding paragraph. The name and domicile of the registrant and the agent, etc. are the items requiring filing as specified in the preceding paragraph. In case of any change in the address of manufacturing site of domestic in-vitro diagnostic reagents, the registrant shall conduct filing after the corresponding change of manufacturing licensing.
In case of any other changes, the registrant shall complete relevant work in accordance with the requirements of quality management system and report to the drug regulatory department as required.
Article 79 Where there is any substantial change in the core technical principle, etc. or other major changes of Class II and Class III in-vitro diagnostic reagents that have been registered, which may significantly affect the safety and efficacy of the products and actually make them new products, such changes do not fall within the scope of change application specified in this chapter and shall be handled as registration applications.
Article 80 For the application for change registration, the institution for technical evaluation shall focus on evaluating the changes and give comments on product safety, efficacy, and quality management after the change.
During the technical evaluation of the application for change registration, the drug regulatory department may conduct an inspection on quality management system if it deems necessary.
Article 81 The medical device change registration document shall be used in conjunction with the original Medical Device Registration Certificate, and its valid term shall be the same as that of the original Medical Device Registration Certificate.
Section II Registration Renewal
Article 82 Where it is required to extend the valid term of the Medical Device Registration Certificate, the registrant shall apply for registration renewal to the former registration department six months before the expiration of valid term and submit application materials according to the corresponding requirements.
Except for the situations specified in Article 83, the drug regulatory department receiving the application for registration renewal shall make a decision for the renewal before the expiration of valid term of the Medical Device Registration Certificate. If the decision is not made within the specified time limit, the renewal is considered approved.
Article 83 The registration renewal shall not be approved in any of the following circumstances:
(I) The applicant fails to apply for registration renewal within the specified time limit;
(II) The in-vitro diagnostic reagent under application for registration renewal cannot meet new requirements as new mandatory standards for in-vitro diagnostic reagents and new national reference standards have been issued and implemented;
(III) The in-vitro diagnostic reagents approved conditionally fail to finish the items as specified in the Medical Device Registration Certificate within the specified time limit.
Article 84 Where the approval time of registration renewal is within the valid term of the original Registration Certificate, the valid term of the Certificate for registration renewal shall start from the next day after the expiration of the original Registration Certificate. If the approval time is not within the valid term of the original Registration Certificate, the valid term of the Certificate for registration renewal shall start from the approval date of registration renewal.
Article 85 Where provisions concerning acceptance and approval procedures of applications for change registration and registration renewal of in-vitro diagnostic reagents are not outlined in this Chapter, Chapter Ⅲ hereof shall prevail.
Chapter VI In-vitro Diagnostic Reagent Filing
Article 86 Filing for a Class I in-vitro diagnostic reagent shall be conducted prior to production.
Article 87 While conducting the in-vitro diagnostic reagent filing, the filing entity shall submit filing documents to the drug regulatory department in accordance with the Regulations on Supervision and Administration of Medical Devices, so as to obtain the filing number.
Article 88 For filed in-vitro diagnostic reagents, where the contents set forth in the filing information table of the in-vitro diagnostic reagent and filed product technical requirements have been changed, the filing entity shall apply for change of filing and submit a description of changes and related supporting documents to the original filing department. The drug regulatory department shall record the changes in filing information.
Article 89 For any filed in-vitro diagnostic reagent, if the management category is adjusted to Class II or Class III, the registration shall be applied in accordance with the relevant regulations of the Provisions.
Chapter VII Time Limit
Article 90 The time limit specified in the Provisions is the maximum time for acceptance, technical evaluation, inspection, and approval of in-vitro diagnostic reagent registration. The time limit for work related to special registration procedures shall be implemented in accordance with relevant provisions of special registration procedures.
The CMDE and other specialized technical institutions shall determine the work procedures and time limit of its authority and publicize them.
Article 91 After receiving the application for in-vitro diagnostic reagent registration, the drug regulatory department shall forward application materials to the institution for technical evaluation within 3 days from the date of acceptance.
Article 92 The time limit for technical evaluation of in-vitro diagnostic reagent registration shall comply with the following provisions:
(I) The time limit for technical evaluation of applications for registration, change registration and registration renewal of Class II in-vitro diagnostic reagents is 60 days, and that for technical evaluation after the supplement of application materials is 60 days;
(II) The time limit for technical evaluation of applications for registration, change registration, and registration renewal of Class III in-vitro diagnostic reagents is 90 days, and that for technical evaluation after the supplement of application materials is 60 days.
Article 93 The time limit for the inspection on quality management system of domestic Class III in-vitro diagnostic reagents shall comply with the following provisions:
(I) The CMDE shall notify the drug regulatory department of the people's government of the province, autonomous region, or municipality directly under the central government to initiate inspection within 10 days upon the acceptance of in-vitro diagnostic reagent registration applications;
(II) The drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall, in principle, complete the inspection and feedback the inspection situation and results thereof, as well as other relevant materials to the CMDE within 30 days upon the receipt of the notification of inspection.
Article 94 The drug regulatory department accepting registration application shall make a decision within 20 days after receiving the comments made after evaluation.
Article 95 The drug regulatory department shall issue and serve relevant certificate of administrative licensing within 10 days from the date when the decision of approval of in-vitro diagnostic reagent registration is made.
Article 96 Where the time limit needs to be extended due to characteristics of the product or special circumstances that occurred in technical evaluation and inspection, the extension shall not exceed 1/2 of the original time limit. Upon approval by the responsible person of relevant technical institutions involved in the review and inspection of medical devices, the technical institution extending the time limit shall inform the applicant in writing and notify other relevant technical institutions.
Article 97 The authority issued former license shall re-issue a new Medical Device Registration Certificate within 20 days upon the receipt of the application.
Article 98 The time taken for the following circumstances shall not be counted into the relevant time limit for work:
(I) The time taken by the applicant to supplement materials or perform rectification after inspection, etc.;
(II) The time taken for inspection delay attributable to the applicant;
(III) The time taken for hiring external experts for consultation, the time taken for expert consultation meetings, and the time taken for joint review with the drug evaluation institution;
(IV) The time taken during the suspension of review and approval as per regulations;
(V) The time taken for the quality management system inspection.
Article 99 The time limit specified in the Provisions is calculated by working days.
Chapter VIII Supervision and Administration
Article 100 The drug regulatory department shall enhance supervision and inspection on the R&D of in-vitro diagnostic reagents, and when necessary, it may conduct an extended inspection for units and individuals providing products or services for the R&D of in-vitro diagnostic reagents. Units and individuals concerned shall cooperate to provide relevant documents and dossiers, and shall not refuse, conceal, or obstruct.
Article 101 The NMPA shall establish and implement a system of unique device identification (UDI) of medical devices by steps. Applicants or filing entities shall submit the information related to UDI in accordance with relevant regulations to ensure that the data is authentic, accurate, and traceable.
Article 102 The NMPA shall promptly communicate the information of the agent to the drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government where the agent is located. The drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall organize routine supervision and administration of the agents within their administrative areas.
Article 103 The drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall, according to the filing of medical device clinical trial institutions, organize the post-filing supervision and inspection on clinical trial institutions that have been filed within their administrative areas. For the newly filed medical device clinical trial institutions, the supervision and inspection shall be carried out within 60 days after filing.
The drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government shall organize the routine supervision and inspection on the compliance with the GCP by medical device clinical trial institutions within their administrative areas to ensure the continuous compliance with requirements. The NMPA shall conduct supervision and inspection on medical device clinical trial institutions as required.
Article 104 The drug regulatory department may conduct on-site inspection on the authenticity, accuracy, completeness, standardization, and traceability of clinical trials as it deems necessary.
Article 105 In case of identifying that any filing document is non-standardized in the post-filing supervision, the drug regulatory department undertaking the filing of Class I in-vitro diagnostic reagents shall order the filing entity to make corrections within a time limit.
Article 106 Where a drug regulatory department fails to timely identify systematic or regional risks in the administration of in-vitro diagnostic reagent registration within its administrative areas, or fails to timely eliminate potential systematic or regional hazards in the administration of in-vitro diagnostic reagent registration within its administrative areas, the superior drug regulatory department may schedule a warning meeting with the principal responsible person of this drug regulatory department at a lower level.
Chapter IX Legal Liabilities
Article 107 The filing entity who fails to file changes according to the requirements and is in violation of Article 78 of the Provisions shall be ordered to make corrections within a time limit; where correction is not made within the prescribed period, the filing entity shall be imposed a fine of not less than RMB 10,000 but not more than RMB 30,000.
Article 108 Where the clinical trials of in-vitro diagnostic reagents fail to be complied with the GCP, the punishment shall be carried out according to Article 94 of the Regulations on Supervision and Administration of Medical Devices.
Article 109 Where the institution for technical evaluation of medical devices fails to perform its duties according to the Provisions, resulting in major mistakes in review, the drug regulatory department shall order the institution to make corrections, circulate a notice of criticism, or issue a warning; where serious consequences are caused, punishment shall be imposed on the legal representative, the principal responsible person, the person directly in charge, and other responsible persons from the unit concerned according to law.
Article 110 Any personnel of drug regulatory departments who abuses his/her power, neglects his/her duty, or engages in malpractices for personal gain in violation of the Provisions shall be punished according to law.
Chapter X Supplementary Provisions
Article 111 Naming for in-vitro diagnostic reagents shall comply with the following principles:
Product names of in-vitro diagnostic reagents are generally composed of three parts. The first part shall be the name of the substance to be tested; the second part shall be the usage, e.g., diagnostic reagent kits and control materials, etc.; the third part shall be the method or rationale, e.g., magnetic particles-based chemiluminescence enzyme immunoassay, fluorescence PCR, and fluorescence in situ hybridization, etc., and this part shall be listed in parentheses.
If the substance to be tested has many components or is under special circumstances, the substance can adopt the indication name related to the product or other substitute names.
Class I products, calibrators, and control materials shall be named according to their intended use.
Article 112 The registration or filing unit of in-vitro diagnostic reagents shall be a single reagent or a single reagent kit. One registration or filing unit may include different packaging specifications.
For the calibrators and control materials used in conjunction with in-vitro diagnostic reagents, the applicant may apply for registration of such calibrators and control materials together with the in-vitro diagnostic reagents or submit a separate application for registration.
Article 113 In-vitro diagnostic reagents approved for registration refer to in-vitro diagnostic reagents that are consistent with those specified in the Medical Device Registration Certificate and attachments thereto, and are manufactured within the valid term of the Registration Certificate.
Article 114 The independent reagent components in the column of “main components” of the Medical Device Registration Certificate may be sold individually if used for the original registered product.
Article 115 In case of applying for in-vitro diagnostic reagent registration and change registration, the applicant may refer to master files of registered medical devices upon authorization by the owner of medical device master files. The medical device master files shall be registered by its owner or an agency, and relevant procedures shall be specified separately.
Article 116 The format of the Medical Device Registration Certificate shall be prepared by the NMPA.
The registration certificate number shall be arranged in the following form:
×1械注×2××××3×4××5××××6, among which,
×1 shall be the abbreviation of the place where the registration department is located.
The character “国” shall refer to domestic Class III in-vitro diagnostic reagents and imported Class II and III in-vitro diagnostic reagents;
The abbreviation of the provinces, autonomous regions, or municipalities directly under the central government where the registration department is located shall be adopted for domestic Class II in-vitro diagnostic reagents;
×2 shall indicate the form of registration;
The character “准” applies to domestic in-vitro diagnostic reagents;
The character “进” applies to imported in-vitro diagnostic reagents;
The character “许” applies to in-vitro diagnostic reagents from Hong Kong SAR, Macao, and Chinese Taipei;
××××3 shall indicate the year of initial registration;
×4 shall indicate the management category;
××5 shall indicate the product classification code;
××××6 shall indicate the serial number of initial registration.
For the registration renewal, ××××3 and ××××6 shall remain the same. In case of the management category changes, a new registration number shall be issued.
Article 117 The filing number for Class I medical devices shall be arranged in the following form:
×1械备××××2××××3, among which,
×1 shall be the abbreviation of the place where the filing department is located.
The character “国” shall refer to imported Class I in-vitro diagnostic reagents;
The abbreviation of the provinces, autonomous regions, or municipalities directly under the central government combines the abbreviation of city divided into districts where filing department is located (if there is no corresponding city divided into districts, only use the abbreviation of province, autonomous region, or municipality directly under the central government) shall be adopted for domestic Class I in-vitro diagnostic reagents;
××××2 shall indicate the year of filing;
××××3 shall indicate the serial number of filing.
Article 118 The electronic Medical Device Registration Certificate and medical device change registration document issued by drug regulatory departments shall have the same legal force as paper materials.
Article 119 The NMPA may, if necessary, authorize the drug regulatory departments or technical institutions of provinces, autonomous regions, or municipalities directly under the central government and relevant social organizations to conduct the specific work.
Article 120 The drug regulatory department of the people’s government of the province, autonomous region, or municipality directly under the central government may formulate special registration procedures for Class II in-vitro diagnostic reagents within their administrative areas with reference to Chapter IV in the Provisions and report to the NMPA for filing.
Article 121 The charging items and the charging standards for in-vitro diagnostic reagent registration shall be determined in accordance with the relevant regulations formulated by the competent finance department and the competent pricing department of the State Council.
Article 122 The provisions related to the emergency use of in-vitro diagnostic reagents shall be formulated by the NMPA in conjunction with other authorities concerned.
Article 123 Where no predicate device has been marketed in China and the medical institution develops the in-vitro diagnostic reagent independently based on clinical needs of the institution and uses it within the institution under the guidance of medical practitioners, the relevant administrative regulations shall be formulated by the NMPA in conjunction with other authorities concerned.
Article 124 The in-vitro diagnostic reagents from Hong Kong SAR, Macao, and Chinese Taipei shall be registered and filed in reference to the imported medical devices.
Article 125 The Provisions shall go into effect as of October 1, 2021. The Provisions for In-vitro Diagnostic Reagent Registration promulgated on July 30, 2014 (Decree No. 5 of the former China Food and Drug Administration) is annulled simultaneously.
