On Aug. 26, China's State Administration for Market Regulation (SAMR) promulgated the Administrative Measures for In Vitro Diagnostic Reagent Registration and Filing1 (hereafter referred to as the Measures)
SAMR released the Administrative Measures for Medical Device Registration and Filing on the same day. The two measures resemble each other in their contents. The implementation dates are both on Oct. 1, 2021.
However, there are still noteworthy rules particular to IVD reagent registration and filing. This article is meant to help stakeholders grasp them.
This article's content is as follows:
The Measures' Application Scope;
Definition of IVD Reagents in China;
IVD Reagent Classification in China;
Definition and Application Scope of IVD Reagent Registration/Filing in China;
Qualification of Registration/Filing Applicant and Local Agent;
Competent Authority to Submit Application/Documentation to;
Documentation for IVD Reagent Registration Application/Filing;
Special Approval for IVD Reagents;
Product Change and Certificate Validity Extension;
Adjusting the Class of Registered IVD Reagents.
1. Application Scope of the Measures
The Measures applies to the registration, filing, supervision and administration of IVD reagents in China.
The Measures does NOT apply to two categories of IVD reagents that are administered as drug products. The two categories are (1) IVD reagents intended for blood screening and (2) IVD reagents labeled by radionuclide.
2. Introduction to IVD Reagents in China
The definition of IVD reagent in China is slightly different from overseas counterparts.
According to the Measures, IVD reagents refer to those administered as medical devices including reagents, reagent test kits, calibrators, samples for quality control, and products intended for disease prediction, prevention, diagnosis, treatment & monitoring, prognosis observation, and determination of the state of health. IVD reagents can be used alone or in combination with instruments, apparatuses, devices, or systems.
3. IVD Reagent Classification in China
IVD reagents are divided into three classes based on risk levels, says Administrative Measures for IVD Reagent Registration2 released by the former China Food and Drug Administration (CFDA) in 2014.
IVD Reagent Classification in China
Source: In Vitro Reagent Classification Rules effective since Oct. 29, 2021
1. Microbiological culture medium NOT for identifying microbes or testing drug allergies;
Cell culture medium ONLY for culturing microbes WITHOUT functions of selecting, inducing and differentiating cells, and the cultured microbes are for in vitro diagnosis.
2. Products for processing samples, e.g., hemolysis reagents, dilution solutions, stain solutions, nucleic acid extraction reagents.
3. General reagents for the reaction system, e.g., buffer solution, substrate solution.
IVD reagents, except for the Class I and Class III ones, are defined as Class II products, which mainly includes the following products:
1. Reagents for testing proteins;
2. Reagents for testing saccharide;
3. Reagents for testing hormones;
4. Reagents for testing enzymes;
5. Reagents for testing esters;
6. Reagents for testing vitamins;
7. Regents for testing inorganic ions;
8. Reagents for testing drugs and drug metabolites;
9. Reagents for testing autoantibodies;
10. Reagents for identifying microbes or testing drug allergies; cell culture medium for identifying microbes, with functions of selecting, inducing and differentiating cells, and the cultured microbes are for in vitro diagnosis;
11. Reagents for testing allergic reactions (allergens);
12. Reagents for testing other physiological, biochemical and immune function indicators.
1. Reagents for testing pathogenic antigens, antibodies and nucleic acids;
2. Reagents relevant to blood matching and tissue typing;
3. Reagents relevant to human genetic testing;
4. Reagents relevant to hereditary diseases;
5. Reagents relevant to testing anesthetic, psychiatric drugs and toxic drugs for medical use;
6. Reagents relevant to testing the targets of therapeutic drugs; companion diagnostics (CDx);
*CDx are tools for evaluating the safety and effectiveness of corresponding medical products. CDx are mainly used before and/or during treatment. They identify patients who are most likely to benefit from the corresponding medical product or at increased risk of severe adverse reactions as the result of treatment with the corresponding medical product.
7. Reagents relevant to cancer screening, diagnosis, companion diagnostics, staging, etc.
4. Definition and Application Scope of IVD Reagent Registration/Filing in China
IVD reagent registration:
IVD reagent registration refers to the applicant applies for IVD reagent registration in accordance with legal procedures to a medical products administration. The administration reviews the safety, effectiveness and quality controllability, then decides whether to approve the application.
For Class II and Class III IVD reagents.
IVD reagent filing:
IVD reagent filing refers to the applicant submits the documentation of an IVD reagent to a medical products administration. The administration puts the documents on file for future reference.
For Class I IVD reagents.
5. Qualification of Registration/Filing Applicant and Local Agent
An IVD reagent registration/filing applicant shall be a company or research institute that is capable for shouldering legal responsibilities. An overseas registration/filing applicant shall appoint a corporate legal entity in China as the agent for carrying out registration/filing affairs.
6. Competent Authority to Submit Application/Documentation to
IVD Reagent Registration/Filing in China
Submission Items to the Authority
File the documentation to the municipal medical products administration of a city with subordinate districts.
Submit the application to the medical products administration of a province/autonomous region/municipality directly under the Central Government;
Medical Device Registration Certificate will be issued after approval.
Submit the application to the National Medical Products Administration (NMPA);
Medical Device Registration Certificate will be issued after approval.
File the documentation to NMPA.
Submit the application to NMPA;
Medical Device Registration Certificate will be issued after approval.
7. Documentation for IVD Reagent Registration Application/Filing
7.1 A general list of required documents
The documentation for submission, whether for IVD reagent registration or filing4, shall include the following documents.
Product risk analysis documents;
Technical requirements of the product;
Product test report;
Clinical evaluation (can be exempted in certain situations);
Sample manuscripts of the product's instructions and labels.
Documents that are relevant to the quality management system (QMS) of product development and manufacturing.
Other necessary documents to prove the safety and efficacy of the product.
7.2 Two noteworthy requirements for importing IVD reagents to China:
All submitted documents shall be in Chinese. If the documents are initially in a foreign language, a Chinese translation shall be submitted together.
7.2.2 Marketing authorization certificate outside China
Both registration and filing of imported medical devices to China shall comply with the submission rules below.
Sold as a medical device in the country/region of the registration applicant/filing applicant/manufacturer
Marketing authorization certificate issued by the authority of the corresponding country/region
Not sold as a medical device but still sold in the country/region of the registration applicant/filing applicant/manufacturer
Documentary evidence showing that the authority of the corresponding country/region has given marketing authorization to the medical device
Not sold in the country/region of the registration applicant
No need to submit any document relevant to marketing authorization; the application submission shall comply with procedures and requirements for innovative new products.
7.3 Explanation of significant documents
The following documents are covered by the general list mentioned above, but they are so significant that the Measures further explains them.
7.3.1 Product's technical requirements
During the product development, registration/filing applicants shall compile product's technical requirements, whose contents shall mainly include finished IVD reagent product's functions, safety indicators, and test methods, and all of which shall be available for objective judgement.
For Class III IVD reagents, their technical requirement documents shall include an appendix clarifying main raw materials and manufacturing technique requirements.
A new IVD reagent shall comply with the product technical requirement documents of the previously approved or on-file IVD reagents.
7.3.2 Non-clinical evidence
During the product development stage, the applicant shall conduct non-clinical research according to the expected uses and technical characteristics of the product.
Non-clinical research refers to IVD reagent trials or evaluations carried out in laboratories. The research topics include choosing and preparing the raw materials, product manufacturing technique, product performance analysis, positive judgment value or reference range determination, product stability, etc.
The non-clinical evidence generated during product development shall be submitted as part of the registration application/filing documentation.
7.3.3 Test report
A test shall be completed and the test report shall be submitted. Only after the applicant gets a qualified test result can the clinical trial/registration/filing begin.
In the case of an application for the same IVD reagent with different packaging specifications, the applicant is permitted to conduct tests for only one specification. The tested product shall be qualified to represent other products with different specifications in safety and effectiveness; and shall be manufactured in compliance with GMP for medical devices.
For a Class III IVD reagent, the applicant shall submit test reports of products manufactured from three different batches.
7.3.4 Clinical evaluation
IVD reagent clinical evaluation refers to the process using scientific and reasonable methods to analyze and evaluate the clinical data to verify whether the IVD reagent product meets the needs for use or achieves expected functions, and finally to prove the safety and effectiveness of the product.
IVD reagent clinical trial refers to the systemic research on the clinical performance of the IVD reagent in a corresponding clinical setting.
Clinical evaluation documents refer to documents created when the applicant conducts clinical evaluation. The documents shall include clinical trial plan, opinions from the Ethics Committee, informed consent, clinical trial report, relevant data, etc.
Conditions for clinical trial exemption for IVD reagents
Registration/filing applicants can skip clinical trials only when the IVD reagent meets both of the following conditions:
The IVD reagent has a clear work mechanism and a fixed design, and is produced with mature technologies. There is a same type of previously approved product that has been clinically used for years with no record of severe adverse events. Also, the new IVD reagent's functions are kept the same as the normal ones of this type of IVD reagents.
The new IVD reagents can be proved to be safe and effective by comparison with the same type of products.
For IVD reagents meeting the conditions for exemption, clinical trial evaluation documents are still required to be submitted. The documents include the analysis of the comparison between the new IVD product and the same type of approved product, methodology comparison data, the analysis of relevant literature and data, the analysis of empirical data, etc.
About the exemption lists: China to Exempt Eligible Medical Devices and IVD Reagents from Clinical Evaluation or Trials
7.3.5 Quality management system (QMS) documents
Applicants shall establish quality management systems for product development and production, and keep them operating effectively. When apply for registration, applicants shall submit the QMS documents, whose original data will possibly be verified by the authority during the technical review.
8. Special Approval for IVD Reagents
There are three types of programs for special approval for IVD reagents:
(1) Innovative Product Registration for IVD reagents meeting all the following three requirements:
① - The applicant has a registered patent of the innovative technology,
- or the applicant got the authorization to use the technology in China within the past five years;
- or the applicant's innovative technology patent application has been made public by the patent department of the State Council, and it has a retrieval report issued by China National Intellectual Property Administration (CNIPA) proving the technology is innovative and creative.
② The applicant has completed early-stage research and decided on the fixed pattern of the product, with authentic and traceable research data;
③ The product has a trailblazing work/function mechanism in China. It has essential advantage over the same type of products in the aspects of functions and safety. It is embedded with world-leading technology and distinct clinical value.
(2) Priority Registration for IVD reagents meeting all the following three requirements:
① - For the diagnosis or treatment of rare diseases or malignant tumors and with distinct clinical advantage;
- or for the diagnosis or treatment of diseases special to or prevalent in elder people but currently without effective diagnosis or treatment methods;
- or exclusively used in children and with distinct clinical advantage;
- or urgently needed in China's clinical settings, and no same type of medical device has been approved.
② Listed in China's national science and technology major projects or major research & development plans;
③ Other medical devices considered to be qualified by NMPA.
(3) Emergency Registration for IVD reagents meeting one of the following two requirements:
① Urgently needed in public health events and no same type of products approved in China;
② There are other products of the same type that have acquired marketing authorization, but the supply is insufficient to meet the needs during the public health event.
9. Product Change and Certificate Validity Extension
Changes to registered Class II and Class III IVD reagents:
If the registrant plans to make changes to the design, raw materials, manufacturing techniques, application scope and methods of usage and thus bring potential change to the product's safety and efficacy, it shall submit a change application to the authority which previously issued the registration certificate.
For other changes, the registrant shall file a document stating the change to the authority where the registration certificate was from.
Changes to on-file Class I IVD reagents:
If the filing person intends to make changes to the product's technical requirements recorded in the on-file information form, the person shall file a change statement and relevant documents to the authority which previously put the product on file.
Registration certificate validity extension
The valid period of every medical device registration certificate is five years. If the applicant wants to extend the validity, it shall submit an registration extension application to the original registration authority six months before the certificate expires.
10. Adjusting the Class of a Registered IVD Reagents
Registrants shall take corresponding measures if NMPA adjusts the class of registered IVD reagents.