The registrations of IVD reagents and instruments follow different regulations and their applications should be submitted separately. However, the evaluation of the performance of reagents and their applicable instruments is an inseparable verification process. Therefore, when the design of the reagents and instruments has been settled down, the approval order of the reagent and its applicable instrument is not fixed.
It should be noted that, when applying for IVD reagent registration, it should be ensured that the applicable instruments are finalized, and its performance on the specified instruments is fully verified and confirmed.
Only after the IVD reagent and its applicable instruments are all approved for marketing in China, can the reagent be used clinically in China in accordance with the approved instruction.
For gene sequencing reagents using high-throughput sequencing methods, the sequencer should have been approved in China when registration is applied for, or the sequencer and the reagent should apply for registration at the same time. The gene sequencing reagents should not be used on a sequencer for research use only or unapproved in China.
When designing a multi-marker joint detection product, first of all, it should be considered that the multiple markers should have a collaborative diagnostic significance, target populations and proper indications, and the multi-marker joint detection is indeed necessary as a laboratory test. Multiple markers without collaborative diagnostic significance are not recommended to be designed as a joint detection reagent.
Different combinations of multiple markers can be of different specifications in the same registration unit. But it should be noticed that it is only limited to the situation where the reaction systems of different markers are relatively independent and not mixed.
For example, there are five test strips for different drug abuse tests (colloidal gold method), of which five test strips and three or four of them can be of different specifications in the same registration unit. Here each test is relatively independent and does not interfere with each other. In the case of different combinations, there is no difference in the performance of each testing item. When applying for registration with different combinations in the same registration unit, submitting evaluation data of the five-strip joint detection kit, as one of the specifications, can cover the verification and confirmation of all packaging specifications.
The changes of the IVD reagent instructions for use include two kinds of conditions: textual changes in information content and other content changes.
Textual changes in informational content. In accordance with the Notice of the General Office of NMPA on Issues Concerning the textual Changes of the In-vitro Diagnostic Reagents Instructions, the textual changes in the informational content can be modified by the registrants themselves. Including: The changes about the information under the item of [Basic information] in the instructions, such as the contact details of the registrant or the manufacturer of the IVD reagents, the name and contact details of the after-sales service company, the production license number or the production filling certificate number, the contact details of the agent for imported products, can be modified by the registrant himself. Among them, the production license number or the production filling certificate number should be revised after being issued by the corresponding provincial authorities. The changes about the information under the item of [Medical Device Registration Certificate Number/Product Technical Requirement Number] can be modified by the registrant itself, if the changes are because of the corresponding issuing of the medical device by NMPA. The changes about the information under the item of [Explanat
Article 58 of Chapter VH of the Provisions for In-vitro Diagnostic Reagent Registration provides that, "If the following changes occur in the contents of the registration certificate and attachment, the applicant should apply to the original registration department for changes of permission items: 1. Changes in suppliers of major materials such as antigens and antibodies/5 The implementation of this clause is explained as follows:
The change of permission items mentioned in this article is only for the situation where the main raw material suppliers explicitly stated in the appendix to the product technical requirements attached to the registration certificate are changed. Regarding the changes of other raw material suppliers that are not specified in the registration certificate and its attachments (including the case that the products technical requirements for the second category of IVD reagents have no attachments), the registrant may conduct research and verification on the changes, and perform the management and quality control through the quality management system, without applying for changes of permission items.
This Article is only for the situation where the supplier of major materials such as antigens and antibodies is changed. If the major raw materials themselves change, for example, antibo
For the IVD reagents that do not contain calibrators and controls in the original registration unit, you can apply for the addition of calibrators and/or controls by applying for change of permission items under the following conditions:
The added calibrators and/or controls are indeed the ones having been used with the approved reagent in the product evaluation, type examination and clinical application of the approved reagent.
After adding calibrators and/or controls, the value traceability of the approved reagent and the quality control method will not change.
The manufacturing quality management system at the time of registration of the approved reagents should be able to cover the calibrators and controls to be added.
Relevant supporting documents may include, but are not limited to: evidence that the calibrators and controls are used during reaction system research, performance evaluation, and type examination of the approved reagent; evidence that the manufacturing quality management system of the approved reagent covers the proposed calibrators and controls at the time of original reagent registration; evidence in the original registration dossiers of the IVD reagent th
To prepare the product research documents, attention should be paid to the following aspects:
Documents for the product performance research: mainly about the research of product technical requirements and preparation instructions, which should include performance study and safety study (electrical safety and electromagnetic compatibility) specified in product technical requirements.
Documents for the research of each clinical functional module: such as temperature control module, optical detection module, sample addition module, circuit control module, etc.
Documents for the machine performance research: mainly about the analytical performance research data of the analytes to be detected on the machine. It is recommended that the applicants choose one or more representative items for every class of analytes to do the performance research using clinical samples. When choosing the representative items to do the research, it is recommended to consider the overall situation of the target analytes and the main functions of the product according to the principle of the most unfavorable condition for evaluation.
IVD equipment generally defines its environmental conditions for use in its instructions or labels. The verification data of the IVD equipment for environmental testing should be submitted to confirm the safety and efficacy under its claimed environmental conditions when applying for product registration, changes of permission items and change notification of instructions for environmental conditions, regardless of domestic or imported products.
If the product has applicable mandatory standards and GB/T 14710 is referred to in the standards, the environmental test should be part of the content of the product technical requirements and referred to according to the requirements of the mandatory standard. Generally, it is not necessary to specify the experimental conditions in detail, but only to indicate "comply with the content of applicable chapters of GB/T 14710". And the contents of the environmental test should be included in the test report.
For the product without applicable mandatory standards, one of the following documents can be submitted as verification data that environmental conditions have no interference on the decision about the safety and efficacy of the product, and there is no need to quote GB/T 14710 in product technical requirements: ①Test report including the environmental test;②Test report of environmental
The shelf-life of an IVD reagent should be determined based on the real-time stability research. The real-time stability research should be completed before registration, including the testing of at least three batches stored under actual storage conditions until the end of the expiry date.
At the same time, considerations should be given to the adverse conditions of the product during storage, transportation, and use in corresponding stability studies. If the real-time stability study is still ongoing at the time of application, the expiry date can be determined based on the available data.
After all the stability studies are completed, the expiry date can be extended by applying for change of permission items.
The suppliers of the main raw materials should be mentioned in the appendix to the product technical requirements. For external suppliers, they should be the manufacturers of raw materials which are mentioned in the product technical requirements, but not the distributors or agents. Correspondingly, the change of permission items for the suppliers of the main raw materials refers to the situation where the raw material itself has no change (for example, the clone of the antibody has no change) but only the manufacturer has changed.
It is required in Article 25 of the Provisions for In-vitro Diagnostic Reagent Registration that the products with national standards and reference materials should be registered for type examination with national standards and reference materials.
It is also required in the Annex 4 of the Announcement of the China Food and Drug Administration on Issuing the Requirements for the Registration of In-vitro Diagnostic Reagents and the Approved Document Format (2014 No. 44) that the type examination report of the product meeting the requirements of the new generation of national standards or reference materials should be provided, if there is any update issued about the standards and reference materials.
Based on the requirements above, when doing the registration or renewing of an IVD reagent, the reagent should meet the requirements of the current national standards and reference materials, if there are any applicable national standards or reference materials released or updated (the applicability of the product to be judged according to the published instructions of the national standards and reference materials). When submitting the application, if the national standards and reference materials have been released or updated before the date of sampling and examination, the product should be proved to meet the requirements of the current national sta
The content of the review information Part (V) in the IVD reagent application dossiers is often neglected. This part is a summary of the innovativeness of the product and the approval status of similar products in China and abroad.
If similar products have been approved in China or abroad, the applicant should give a brief introduction to the similar products, including the information about manufacturers, product name, approved country or region, etc. Compare the investigational reagent with the similar products in technical methods, product performance, result reporting methods, etc. Briefly describe the market application of similar products in China and abroad.
For newly developed IVD reagents, if there is no similar product approved, or the applied product changes its conventional intended use and has a new clinical significance, the sponsor should provide proof to support the new marker or the new intended use, such as literatures, guidance documents, expert consensus, etc., which can interpret the relationship between the test result and the clinical endpoint. How the kit will be used in the disease diagnosis and treatment, and how to interpret the test result should also be detailed.
Whether an IVD reagent is one of the products related to the prevention and treatment of rare diseases should be determined in accordance with documents of the Guideline for the Registration of Medical Devices for the Prevention and Treatment of Rare Diseases, Notice on the Publication of the First Catalogue of Rare Diseases, Notice of the General Office of the National Health Commission of the People's Republic of China on Printing and Distributing the Guideline for the Diagnosis and Treatment of Rare Diseases (2019 Edition) and other documents.
If the clinical indication of the investigational reagent is a disease in the first catalogue of rare diseases, and at the same time, according to the Rare Disease Diagnosis and Treatment Guidelines (2019 edition), this assay is one of the applied detection items in the diagnosis and treatment process of the disease, the investigational reagent can be identified as a product related to the prevention and treatment of rare diseases. For the registration of the product testing a new biomarker, the intended use of the product and its relationship with the diagnosis and treatment of related rare diseases should be clarified, with which it can be determined whether the product is for the prevention and treatment of rare diseases.
According to the Provisions for In-vitro Diagnostic Reagent Registration and the