Question and Answer for Registration of Medical Devices,IVDs

Q: What materials are included in the annex to the clinical trial report of in vitro diagnostic reagents? What are your requirements?

According to the “Announcement on Publishing the Requirements for Registration Application Materials of In Vitro Diagnostic Reagents and the Format of Approval Documents” (formerly China Food and Drug Administration Announcement No. 44 in 2014), the attachments of the clinical trial report include:

(1) Basic information on other test methods or other diagnostic reagent products used in clinical trials, such as test methods, sources of diagnostic reagent products, product instructions, and registration and approval status.

(2) All test data in the clinical trial (need to be signed by the clinical trial operator and reviewer, and the clinical trial institution will stamp the front page and stamp).

(3) Main references.

(4) The resume of the main researcher.

(5) Other circumstances that the applicant needs to explain, etc.

The above materials should be submitted as an attachment to the clinical trial report and confirmed by the signature of the clinical trial institution. Article (1) should include the instructions of comparative reagents and third-party reagents (if involved). If a clinical reference method/gold standard is used, the operation process and judgment standards of the specific method should be submitted. The data sheet in Article (2) shall at least include sample number, basic information (such as gender, age, sample type), test results of all parties, and clinical background information. Among them, the clinical background information should come from the clinical case information of the subjects and meet the inclusion criteria of the scheme. Article (4) The resume of the main researcher should be submitted, and other participants do not need to submit. Articles (3) and (5) should be submitted together if involved.

Q: What is the detection system of in vitro diagnostic reagents?

The detection system of in vitro diagnostic reagents is a combination of sample processing products, detection reagents, calibrators, quality control products, applicable instruments, etc. The entire detection system has been fully evaluated for safety and effectiveness and has been approved.

During the product registration process of in vitro diagnostic reagents, no matter whether it includes other products that have been tested, the supporting products should be specified in the instructions to ensure that the testing process is carried out in accordance with the detection system composed of all supporting products. For example, for nucleic acid detection reagents that do not include extraction reagents, in the process of performance evaluation and clinical evaluation, the matching extraction reagents claimed in the instructions should be used.

Similarly, if the application materials involve contrast reagents, they should also be operated according to the approved detection system. If nucleic acid is extracted with a matching extraction reagent that is not claimed in the instructions of the comparative reagent, and subsequent testing is performed, the test results obtained have not been fully verified and confirmed, and cannot be used as the basis for evaluating the reagents.

Q: What are the requirements for anticoagulants used in samples in clinical trials of in vitro diagnostic reagents?

When the test samples of in vitro diagnostic reagents involve different anticoagulants, different anticoagulants should be studied in the preclinical research stage to verify the applicability of the anticoagulants and their impact on detection. In general, if the pre-research finds that the available anticoagulants claimed in the instructions have no differential impact on sample detection, there is no need to group samples using different anticoagulants during the clinical trial, and all applicable anticoagulants can be found in the It is used in clinical trial samples; under special circumstances, when different anticoagulants have a significant impact on the test results, resulting in different reference values for the judgment of clinical test results, sample collection and research should be carried out separately in clinical trials.

The type of sample and the anticoagulant used in the sample should be clearly stated in the clinical trial protocol and report.

Q: When the manufacturer of the main raw material changes, when can it not be reported as a registration change?

In July 2019, how should suppliers of main raw materials fill in the “Technical Requirements for In Vitro Diagnostic Reagent Products” appendix of the WeChat public account of “China Device Review”? “Emphasis that the supplier should be the raw material manufacturer , not the distributor or agent. In the corresponding registration change, the change of the main raw material supplier refers to the change of the raw material manufacturer. It should be pointed out that not all changes of major raw material manufacturers can be reported as registration changes. For example, changes in manufacturers leading to substantial changes in antigens and antibodies, changes in primer and probe sequences, etc., are major changes in product design, and the above changes should be registered. Register for the first time to declare.

Q: Are pyrogens and bacterial endotoxins included in product technical requirements for medical devices that come into contact with circulating blood?

For medical devices in contact with circulating blood, bacterial endotoxins need to be formulated in the technical requirements according to the requirements in the “Guiding Principles for Compiling Technical Requirements for Medical Device Products”. Pyrogen items are available in the Biocompatibility Research Profile. Both bacterial endotoxins and pyrogens need to be studied for product registration.

Q: If it is inconsistent with the description in the clinical exemption catalogue, can it still be exempt from clinical practice?

Products in the free clinical catalog, such as interleukin detection reagents, are described in the catalog as “used to detect interleukin in human samples, mainly used to monitor the body’s immune status, inflammatory response, etc..” There are many types of interleukin, and the products claim to meet the above Various interleukin detection items for different purposes can be declared as clinical-free products. If the product has a new intended use, such as auxiliary diagnosis for specific pathogen infection, it is not a clinical-free product.

The purpose of the blood gas detection reagent catalog is described as “used in conjunction with the blood gas analysis system to determine the pH value, partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), hematocrit, sodium, potassium and calcium ions in human samples Concentration and other electrolyte analysis. Clinically, it is mainly used to monitor acid-base balance imbalance, hypoxia and carbon dioxide retention, etc.”, in addition to the content described above, the declared product testing items also include chloride ion, oxyhemoglobin, blood oxygen saturation, etc. Some routine blood gas testing items can also be declared as clinical-free products.

Q: Selection of clinical comparative reagents/methods for bacterial drug resistance gene detection reagents?

Bacterial drug resistance gene detection reagent refers to the detection reagent that judges the drug resistance by detecting the specific drug resistance gene of the target bacteria. When conducting clinical research on such reagents, the results of clinical drug resistance phenotype should be selected as the clinical reference standard Conduct comparative studies to compare the results of genetic testing with clinical drug resistance testing results, so as to obtain the sensitivity and specificity of genetic testing reagents for the detection of drug-resistant bacteria. The detection performance of the reagents for relevant genes in clinical samples can be confirmed by means of comparative studies with gene sequencing or similar marketed products.

For detection reagents whose drug-resistant gene loci are relatively recognized in clinical application and similar products have been on the market for many years, clinical trials can mainly be carried out in the way of comparative research with similar marketed products, and some samples are compared with drug-resistant phenotypes. way to confirm further. Reference should be made to the relevant requirements, if applicable, for product class guidelines.

Q: How should the registration unit of titanium cage products for spine be divided?

Titanium cages for spine are mainly used for vertebral body replacement or spinal fusion. The common ones are titanium cage vertebral body replacement implants and titanium cage vertebral body implants, which should be divided into different registration units. Product composition materials (including material grades) are different and should be divided into different registration units. According to the commonly used materials for making titanium cages, it can be divided into registration units such as TA3 pure titanium, TC4 titanium alloy, and TC4 ELI titanium alloy.

Q: What factors should be considered when selecting or changing primary packaging materials for soft contact lens products?

The free substances in the primary packaging materials of soft contact lens products may be extracted by the solution, which may affect the performance and safety of contact lenses. Therefore, when selecting or changing the primary packaging materials, attention should be paid to:

1. Verify the performance of primary packaging materials, including physical and chemical properties, and recommend biological evaluation;

2. Sterilization applicability and sterilization verification;

3. Carry out stability tests according to “GB/T 11417.8-2012 Ophthalmic Optical Contact Lenses Part 8: Determination of Validity Period”, it is recommended to include lens performance, packaging integrity, sterility performance, etc., and it is recommended to conduct preservation solution performance research;

4. Transport stability verification;

5. If there are two or more packages, the final product should be tested for full performance and biological evaluation;

6. If primary packaging materials that have never been used in similar products are used, in the stability test, it is recommended to consider adequate evaluation and verification of the solution that may contain leachate, including but not limited to biological evaluation.

Q: How should dental light curing machine products be tested if they are equipped with light guide elements?

If the light curing machine must be equipped with a light guide element during clinical use, the light curing machine should be tested with the light guide element to evaluate whether it meets the requirements of the radiation clause 7.2 in YY 0055.1-2009 or YY 0055.2-2009 . The type or model of the light guide element selected during the test should be able to cover all the light guide elements in the composition of the declared product, or all the light guide elements that can be used together as specified in the accompanying documents. The type or model of the light guide element is reflected in the test report.

Curing lights that do not require light guide elements during clinical use should be tested under normal use conditions.

Q: What aspects should at least focus on in the performance research of PMMA bone cement products for spine?

The performance research of PMMA bone cement products for spine should not only focus on the performance research of powder and liquid, but also the performance research of the final product formed after powder and liquid are mixed. At least the following should be given attention:

(1) Research on the components and proportions of powder and liquid, the morphology and particle size distribution of powder components;

(2) Molecular weight, such as viscosity average molecular weight, number average molecular weight/weight average molecular weight;

(3) Polymer structure, such as graft, linear or copolymer;

(4) Physical properties, such as shrinkage, water absorption, etc.;

(5) Stability of components, such as aging due to liquid absorption and polymerization, change in liquid viscosity after heating, change in benzoyl peroxide level (aging);

(6) Carry out residual evaluation of polymer monomers, such as the amount of monomers precipitated during polymerization and after polymerization, and the amount of residual monomers after polymerization, and on this basis, conduct safety evaluations on the residual toxicity of monomers;

(7) Combined with the applicable parts of the product, research on the relevant dynamic and static mechanical properties;

(8) Research on the polymerization reaction process of mixing bone cement powder and liquid in the expected use mode.

Q: The reducing substances caused by the PVP coating exceed the standard. Is it necessary to formulate the requirements for reducing substances in the technical requirements?

For PVP-coated products, if the coating material causes abnormal reducing substance test results, it is recommended to test the uncoated product to confirm whether the chemical performance test results are interfered by the coating, and at the same time combine the clinical results of the coating material Application history and biocompatibility data, comprehensive evaluation, no need to formulate reducing substance requirements in product technical requirements.

Q: Should the connection method between the implant and the abutment be specified in the product structure and composition?

The connection between the implant and the abutment is mainly divided into two types: external connection and internal connection. According to the geometric shape, it can be divided into internal square connection, external hexagonal connection, external octagonal connection, spline connection, Morse taper connection, etc. The connection method between the implant and the abutment belongs to the content that should be specified in the structure and composition of the product. For different connection methods, the connection taper fit in the implant, the fit clearance between the implant and the implant abutment, torsion resistance, tightening torque, fatigue Relevant research on system compatibility verification such as limits.

Q: What are the issues that should be paid attention to in the disinfection and sterilization data of reusable accessories in active medical devices?

Reusable accessories should be disinfected or sterilized before use. The instructions should specify the specific disinfection/sterilization method (such as the disinfectant used, disinfection or sterilization equipment), and the important parameters of the disinfection/sterilization cycle (such as time, temperature and pressure, etc.). The research data should provide the basis for determining the disinfection/sterilization method, the confirmation data of the disinfection/sterilization effect, and the research data on the tolerance of the recommended disinfection/sterilization method.

Q: General-purpose computers and tablet computers do not belong to medical devices. What standards apply when they are part of the product structure of medical devices?

If the general information equipment is used as part of the product structure of the declared medical device, the product as a whole shall apply to the GB9706.1-2007 and YY0505-2012 standards.

Q: How should the product registration unit of the posterior spinal elastic fusion fixation system be divided?

The elastic posterior spinal fusion fixation system is used for posterior spinal fusion fixation, which is different from the posterior spinal rigid internal fixation system used for fusion, and should be divided into different registration units. Products with different structural designs and different mechanical properties should be divided into different registration units. The materials that play the main function of the product are different, and should be divided into different registration units. If the components of the product are made of different materials, but the product is assembled or used as a whole, it can be declared as the same registration unit.

Q: How to carry out the cytotoxicity evaluation of drug-eluting stents?

The cytotoxicity evaluation should be carried out separately for the stent part and the delivery system. If the cytotoxicity of the drug-containing stent is high, the cause should be analyzed and a comprehensive evaluation should be carried out. For example, when the cytotoxicity is considered to be caused by drugs, the cytotoxicity tests of the bare stent and the drug-containing stent should be carried out separately, and the risk analysis of the cytotoxicity of the drug-containing stent should be carried out to comprehensively evaluate the impact of the contained drugs.

Q: Is the electronic nose and throat endoscope with built-in light source an exempt catalog product?

In the “Catalogue of Medical Devices Exempted from Clinical Trials (Revised)” (referred to as the Exemption Catalog), the structure and composition of electronic nose and throat endoscopes are described as “generally consisting of a head end, a bending part, an insertion part, an operating part, and electrical and light source connections. The photoelectric conversion device at the head end converts the received optical signal into an electrical signal, and observes it on the display through the camera system. The video monitor provides images for observation, diagnosis, and photography of the nose and throat.”

The products in the exemption catalog refer to common electronic nose and throat endoscopes that connect traditional external endoscope cold light sources and image processing devices (i.e. camera systems). connected. The electronic nose and throat endoscope with a built-in light source already includes a light source and does not need an external cold light source. It is different from the product structure in the exemption catalog and does not belong to the exemption catalog products.

Q: Under the premise of complying with the license change, if it is planned to increase the online use of sodium bicarbonate B dry powder, under what circumstances does it not need to provide clinical evaluation documents?

1. The product that has obtained the medical device registration certificate contains the model of sodium bicarbonate B powder.

2. The model of sodium bicarbonate B dry powder to be added online is the same as the original formula. It is only prepared to replace the original sodium bicarbonate B powder and A agent, and the ion type and concentration of the formed dialysis concentrate remain unchanged.

When the above two conditions are met at the same time, there is no need to provide clinical evaluation documents.

Q: If the medical X-ray diagnostic equipment is applicable to the pediatric population, how should the research materials be submitted?

Since children or newborns are very sensitive to X-rays, if the applicant claims that the device is suitable for the pediatric population, it should provide the measures to be taken to reduce the radiation dose of children or newborns. For example, the automatic exposure control is designed and calibrated for pediatric patients; it has a low radiation dose protocol suitable for infants and young children; special filtering; the radiation incident dose is lower than that of adults, and the exposure limit prompts; display and record patient dose information or dose index and Additional patient information such as age, height and weight (manual input or automatic calculation); with tool-free detachable grid, etc.