Language
动物实验,实验器材,医疗器械
z-bo
2020-07-17
701
Guiding Principles for Technical Review of Medical Device Animal Experimental Research Part 1: Decision Principles
I. Introduction
Medical device safety and effectiveness evaluation research should use scientific and reasonable evaluation methods, of which animal experiment is one of the important means, which is an important research in product design and development, and can provide corresponding evidence support for product design stereotypes; if needed Carrying out clinical trials can provide support for whether medical devices can be used in human research, reduce the risks of clinical trial subjects and users, and provide references for clinical trial design.
But not all medical devices need to be verified by animal experiments for product safety and effectiveness. In order to provide guidance for the determination of the necessity of conducting animal experiments, this principle is specially formulated.
This principle is the first in a series of guidelines for the technical review of medical device animal experiment research. To determine whether to conduct medical device animal experiment decision-making principles, please refer to other guidelines for other aspects of animal experiment design.
This principle is a technical guidance document for applicants and technical reviewers. It does not involve administrative matters such as registration approval, nor is it enforced as a regulation. Any other method that can meet the requirements of the regulation can also be used, but should be provided. Full research data and verification data. This principle should be used in compliance with relevant regulations.
This principle is formulated under the current laws and standards system and current level of awareness. With the continuous improvement of laws and standards and the continuous development of science and technology, the relevant content of this principle will also be adjusted in a timely manner.
2. Scope of application
This principle applies to the decision whether medical devices need to be tested in vivo on live animals, excluding research conducted on non-live animals, isolated tissues or organs.
The following conditions can refer to this principle:
(1) When the applicant of the medical device determines whether it is necessary to carry out animal experiments in the design and development stage;
(2) When the medical device regulatory agency evaluates the necessity of conducting animal experiments during the technical review.
This principle does not replace the technical documents related to the biological evaluation of medical devices such as GB/T 16886 series of standards. If the biocompatibility of medical devices is evaluated through animal experiments, it should also comply with relevant technical documents for biological evaluation such as GB/T 16886 series of standards.
If the guidelines for specific products are released, follow the guidelines for the corresponding products.
This principle does not apply to in vitro diagnostic reagents managed in accordance with medical devices.
In the ethical review of clinical trials of medical devices, you can refer to the applicable parts of this principle to assess the necessity of preclinical animal experiments.
3. Basic decision-making principles
In the stage of medical device design and development, it is recommended to consider animal welfare ethical principles and risk management principles when deciding whether to conduct animal experiments.
(1) Animal welfare ethical principles
Applicants must follow the “Replacement, Reduction and Refinement” principles of animal experiments, that is, the 3R principle.
Before deciding whether to conduct animal experiments, the applicant needs to give special consideration to animal welfare ethics, fully carry out laboratory research, and it is not appropriate to use animal experiments to replace laboratory research.
If there are confirmed/validated in vivo research, computer simulation and other methods, the above methods are preferred to replace animal experiments.
Applicants should make full use of the existing information to obtain relevant evidence of product safety, effectiveness and feasibility. For example, the existing animal test data of similar products can be used or the performance of the product can be verified through performance comparison with similar products on the market. Safety, effectiveness and feasibility. If the relevant evidence is sufficient, it can be exempted from animal experiments.
(2) Risk management principles
Applicants should carry out adequate risk management activities when designing and developing medical devices. As an important part of risk management, risk control is the process of reducing and maintaining risks at a prescribed level. After implementing each risk control measure, its effectiveness should be verified (including validation activities). Laboratory research or animal experiments are all means to verify the effectiveness of risk control measures. Applicants should try to verify the effectiveness of identified risk control measures through preliminary research (such as laboratory research, etc.) as much as possible. When the research is insufficient, it is considered to carry out further verification through animal experiments. Animal experiment data can be used as supporting data for risk/benefit analysis.
If the effectiveness of risk control measures needs to be verified through animal experiments, combined with the purpose of animal experiments, it is generally considered from the aspects of feasibility, effectiveness, and safety:
1. Feasibility
The feasibility study refers to the research conducted on the product design and development stage to confirm/verify the product working principle, mechanism of action, design, operability, functionality, safety, etc., or to identify new unexpected risks, such as biological research Screening of absorbable stent platform materials, design feasibility of transcatheter valve replacement devices, verification of iterative design updates, etc.
2. Effectiveness
Although there may be some differences in the effectiveness of some medical devices between animals and humans, properly designed animal experiments can support the effectiveness (including performance and operation) of products, such as the anti-adhesion performance of absorbable anti-adhesion medical devices Evaluation, evaluation of the effectiveness of tissue repair materials to guide tissue reconstruction, evaluation of the osseointegration effect of porous coated joint products or 3D printed porous structure products.
3. Security
After the applicant takes risk control measures, the safety of some products can be appropriately evaluated using animal experiments, such as the study of the scope of drug safety in medical devices containing drugs, toxicological evaluation through histopathology, etc., and product damage to organisms. Evaluation, anti-calcification performance of animal-derived materials, research on vascular thermal injury of surgical vascular closure equipment, evaluation of complications related to anti-adhesion devices and tissue adhesion, etc.
Sometimes the purpose of the experiment cannot be strictly delineated, so an animal experiment may simultaneously evaluate the feasibility, effectiveness, and safety of the product.
If the product adopts a new mechanism of action, working principle, design, main materials/formulations, application methods (such as surgical operations), intended use, new application scope, performance improvement, etc., the applicant should address the risks associated with product innovation Evaluate and consider validating the effectiveness of risk control measures through animal experiments.
Fourth, the decision case of whether to carry out animal experiments
The attached page lists some examples of products that may require animal experiments. It should be noted that in different specific situations, different judgment results may be obtained for the same product according to the decision-making principles; Of medical device products may also require animal experiments under certain circumstances. Applicants are advised to make decisions based on the actual product situation with reference to the decision flowchart.
To facilitate understanding of decision-making principles, this chapter lists the following practical cases. Related cases are only for specific product decision-making under specific circumstances, such as the same applicant's improvement or update of the product function based on the previous generation implantable cardiac pacemaker, and for example, an intestinal stapler made of new materials, etc. .
(1) Porous coated biological hip joint prosthesis
The main risks of porous-coated bioprosthetic hip prosthesis include poor bone bonding of the product or failure of fixation of the prosthesis caused by the peeling of the coating. The bone bonding effect of the coating can be evaluated through animal experiments. If through the coating composition characterization, morphology and stereology data (thickness, porosity, pore size, etc.), coating mechanical performance evaluation (coating and substrate bonding strength, etc.), coating stability and corrosion resistance evaluation , Biocompatibility evaluation and other studies have proved that it is equivalent to the coatings of similar products on the market, so there is no need to evaluate the bone binding effect of the porous coating and the stability of the coating through animal experiments.
(2) Electrocardiograph
One of the main risks of ECG machine is the inaccuracy of working data, including the inaccuracy of automatic measurement of electrocardiogram and the inaccuracy of automatic diagnosis of electrocardiogram. Laboratory research can be conducted to verify the accuracy of ECG automatic measurement through the ECG standard database, and the accuracy of public morphological interpretation and public rhythm diagnosis can be confirmed through ECG database for morphological diagnosis and ECG database for rhythmic diagnosis, without the need to carry out Animal experiment.
(3) Cross-linked sodium hyaluronate gel for injection
Crosslinked sodium hyaluronate gel can be used for facial injections to correct wrinkles in the nasolabial fold. The correction effect can generally reach 6 months. In view of the fact that it is impossible to investigate the improvement of facial wrinkles in animals, animal data is generally not used to support the effectiveness of such products. It is recommended to pay attention to the severity of nasolabial fold wrinkles at 6 months after product injection in human clinical evaluation data (Such as WSRS) compared with preoperative improvement and other evaluation indicators of efficacy.
(four) absorbable biological hernia repair patch
The absorbable biohernia repair patch mentioned in this case is used to repair abdominal wall hernia and abdominal wall defects, and generally has a microstructure similar to the extracellular matrix. After the product is implanted in the human body, the host cells grow in the material, and finally the abdominal wall tissue is reshaped to repair the defect.
1. One of the main risks of this type of product is the recurrence of hernia or abdominal wall defect. A series of risk control measures should be taken to ensure the effectiveness of product tissue reconstruction to reduce the risk of hernia recurrence. For such products, relying on routine laboratory research alone cannot verify the effectiveness of control measures related to the risk of hernia recurrence. It should be considered to use histopathology and other animal experimental data to verify the effect of tissue reconstruction.
2. The applicant can collect animal experiment data or literature data of similar products before conducting animal experiments, and analyze whether these data can be used to support the evaluation of the organizational reconstruction effect of the declared product. If the existing information is sufficient, no animal experiment is required. .
(5) External defibrillation products
Extracorporeal defibrillation products are used by different users and operators to perform extracorporeal cardioversion therapy in different intended use environments.
For this type of product, routine laboratory studies cannot verify the effectiveness of in vitro electrocardioversion technology-related risk control measures, so it is advisable to use live animals to conduct experiments to obtain defibrillation research data for verification.
(6) Ultrasonic soft tissue cutting hemostasis system
Ultrasonic soft tissue cutting hemostasis system is used for soft tissue cutting and blood vessel closing products. The heat generated by friction causes tissue to be cut and closed after solidification (this example does not include the special requirements for the cutting and closing functions of blood vessels larger than 3mm).
1. The main risks of this product include inadequate cutting and closing of blood vessels and thermal damage to tissues due to unreasonable product design. Laboratory research alone cannot fully verify the effectiveness of the control measures for these risks. It is necessary to observe the immediate vascular cutting closure and tissue thermal damage of the product through acute animal experiments, and observe the thermal injury healing and secondary bleeding through chronic animal experiments. Situation, and then verify the effectiveness of risk control measures.
2. If the applied product contains multiple similarly designed cutter heads, the worst performing cutter head can be selected through the in vitro blast pressure test to carry out animal experiments before the animal test is carried out, in order to reduce the part of animal experiments. For newly added cutting heads with similar cutting heads (similar design and similar performance), the results of in vitro blasting pressure test can be used to prove their equivalence with similar cutting heads, and animal experiments are no longer carried out.
(seven) implantable cardiac pacemaker
1. Implantable cardiac pacemakers are high-risk implantable devices. Animal experiments can provide corresponding evidence support for product design and stereotypes. If the same applicant makes improvements or updates on implantable cardiac pacemakers on the basis of previous generation products, there is no need to carry out animal experiments on the content verified by the previous generation products. If necessary, the applicant only carries out corresponding animals for the improvement or update part. experiment.
2. Patients are generally unable to perform magnetic resonance imaging (MRI) after implanting a cardiac pacemaker. If the applicant designs and develops an MRI-compatible implantable cardiac pacemaker, it is necessary to evaluate the safety and effectiveness of the MRI environment for the product. To study the impact of MRI compatibility. MRI compatibility studies usually require the use of animals for computer modeling to verify the safety and effectiveness of MRI compatibility. After the accuracy of computer modeling is verified, the MRI compatibility for other implantable cardiac pacemaker products of the same applicant Research can no longer repeat animal experiments.
3. Compared with the traditional implantable cardiac pacemaker, the leadless pacemaker adopts a new structural design and surgical operation method, and does not need to implant the traditional implantable cardiac electrode lead. Applicants should focus on innovation Assess related risks and verify or confirm the effectiveness of risk control measures. Applicants should conduct animal tests on leadless pacemakers to verify product safety, effectiveness and feasibility.
(eight) drug eluting stent
1. Although drugs such as paclitaxel and rapamycin contained in drug-eluting stent products have a long history of clinical application as drugs, there is a big difference between the application in devices and their application as drugs alone, such as drug-eluting stents After implantation, the local tissue drug concentration in the target vessel wall will be much higher than the blood drug concentration after the drug system is used. The pharmacokinetic and toxicology research data used as a drug alone is not enough to support its safety, and it should be further passed Animal experiments carry out toxicological safety studies on target blood vessels, distal myocardium and other local tissues, and obtain necessary histopathological data. For two drug-eluting stents containing the same drug, if the drug carrier materials of the stent are different, there are also large differences in clinical application. For example, the rate of release and absorption of drug components from different carrier materials is different. There are literature data to confirm the drug dose density and safe range.
2. For drug-eluting stent products coated with a degradable coating, the degradation performance is an important factor in the screening of carrier polymer materials. It is necessary to study the degradation performance of the drug-eluting stent coating in vivo through animal experiments, but if the degradation performance of the carrier polymer (such as polylactic acid-glycolic acid copolymer, PLGA), similar product information, literature data information, materials Database information, regulatory agency filing information, etc. are supported, and applicants do not need to conduct animal experiments on the degraded properties of the declared product.
(9) Degradable metal screws for internal fixation
Degradable metal screws for internal fixation of bones. These products provide initial stable fixation in the early stage of bone healing, and gradually degrade after bone healing, avoiding secondary surgery.
The main risks of these products include premature failure of internal fixation caused by the mismatch of the degradation cycle and the bone healing cycle, and the safety problems caused by the degradation products to the body tissues and organs. For this kind of products, relying on routine laboratory research alone cannot verify the effectiveness of control measures related to failure risk. It is necessary to prepare fracture or bone defect models through appropriate parts of appropriate animal models to evaluate degradable metal products in suitable animals. The degradation performance and product safety and effectiveness. Specific test items may include X-ray evaluation, blood elemental analysis, histopathological analysis, micro-CT analysis, implant biomechanical evaluation, peripheral bone tissue analysis, etc.
(ten) stapler
Stapler is mainly used for tissue/visceral resection and closure.