The State Food and Drug Administration issued two guidelines for registration and review of medical device animal testing research

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However, not all medical devices require animal testing to verify the safety and effectiveness of their products

This guideline is the first part of the series of guidelines for the technical review of medical device animal testing research.

This guiding principle is a technical guidance document for applicants and technical reviewers.

This guiding principle is formulated under the current system of regulations and standards and the current level of awareness.

1.

This guideline applies to the decision of whether medical devices need to be tested in vivo on live animals, excluding research conducted on non-living animals, isolated tissues or organs

The following situations can refer to this guideline:

(1) When the medical device applicant determines whether it needs to carry out animal testing during the design and development stage;

(2) When the medical device regulatory agency evaluates the necessity of conducting animal tests in the technical review process

This guideline does not replace the technical documents related to the biological evaluation of medical devices such as GB/T 16886 series standards

If there are guidelines issued for a specific product, follow the guidelines for the corresponding product

This guideline does not apply to in vitro diagnostic reagents managed in accordance with medical device management

During the ethical review of clinical trials of medical devices, the applicable part of this guideline can be referred to to assess the necessity of pre-clinical animal testing

2.

In the design and development stage of medical devices, when deciding whether to conduct animal testing, it is recommended to consider the ethical principles of animal welfare and the principles of risk management
.

(1) Ethical principles of animal welfare

Applicants are required to follow the "Replacement, Reduction and Refinement" principles of animal testing, namely the 3R principles
.

Before deciding whether to conduct animal testing, applicants need to consider animal welfare ethics and fully carry out laboratory research.
It is not appropriate to use animal testing instead of laboratory research
.

If there are confirmed/verified methods such as non-living studies and computer simulations, the above methods shall be used in preference to animal experiments
.

Applicants should make full use of existing information to obtain relevant evidence of product safety, effectiveness, and feasibility.
For example, they can use existing animal test data of similar products or verify the product through performance comparison with similar products on the market.
Safety, effectiveness and feasibility
.
If the relevant evidence is sufficient, animal testing can be exempted
.

(2) Principles of risk management

The applicant shall carry out adequate risk management activities during the design and development of 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 confirmation activities)
.
Laboratory studies or animal tests are all means to verify the effectiveness of risk control measures.
Applicants should try their best to verify the effectiveness of control measures for identified risks through preliminary research (such as laboratory research, etc.
).
When the research is insufficient, further verification through animal experiments is considered
.
Animal test data can be used as supporting data for risk/benefit analysis
.

If it is necessary to verify the effectiveness of risk control measures through animal testing, combined with the purpose of animal testing, it is generally considered from three aspects: feasibility, effectiveness, and safety:

1.
Feasibility

Feasibility study refers to the research carried out in the product design and development stage to confirm/verify the working principle, mechanism of action, design, operability, functionality, safety, etc.
of the product, or to identify new unexpected risks, such as biological research.
screening platform absorbable stent material, the design possibilities conduit valve replacement device, updated iterative design verification, and the like
.

2.
Effectiveness

Although there may be certain differences in the effectiveness of some medical devices between animals and humans, well-designed animal tests can support the effectiveness of the product (including performance and operation), such as the anti-adhesion performance of absorbable anti-adhesion medical devices evaluation, evaluate the effectiveness of tissue repair material guiding tissue reconstruction, a porous coating or joint products 3D porous structure of the print product osseointegration effect evaluation
.

3.
Security

After the applicant adopts risk control measures, the safety of some products can be evaluated by animal test studies as appropriate, such as research on the safety scope of drugs in medical devices containing medicines, toxicological evaluation through histopathology, etc.
, and product damage to organisms evaluation of vascular thermal damage, the anti-calcification properties of materials of animal origin, surgical vessel sealing devices, adhesion prevention evaluation instrument and tissue adhesion and other related complications
.

The purpose of the test is sometimes not strictly defined.
Therefore, an animal test may simultaneously evaluate the feasibility, effectiveness, and safety of the product
.

If the product adopts a new mechanism of action, working principle, design, main material/formulation, application method (such as surgical operation), intended use, new scope of application, improvement of certain aspects of performance, etc.
, the applicant should focus on the risks related to product innovation Carry out an assessment and consider using animal tests to verify the effectiveness of risk control measures
.

Applicants can refer to the following decision flow chart to make a decision on whether to carry out animal testing
.

3.
Decision-making cases on whether to carry out animal testing

The attached page lists some examples of products that may need to carry out animal testing.
It should be noted that in different specific situations, different judgment results may be obtained for the same product according to the decision-making principle; in addition, it is not listed in the table.
For medical device products, animal testing may also be required under certain specific circumstances
.
It is recommended that the applicant refer to the decision flow chart to make a judgment based on the actual situation of the product
.

In order to facilitate the understanding of decision-making principles, this chapter lists the following practical cases
.
Relevant cases are only for the decision-making and determination of specific products in specific situations, such as the improvement or update of the product function by the same applicant based on the previous generation of implantable cardiac pacemakers, and the intestinal stapler made of new materials, etc.

.

(1) Porous coating bio-type hip prosthesis

The main risks of porous coated biological hip prostheses include poor osseointegration of the product or failure of prosthesis fixation caused by peeling of the coating.
Animal tests can be used to evaluate the osseointegration effect of the coating
.
If the coating composition, morphology and stereological data (thickness, porosity, pore size, etc.
), coating mechanical performance evaluation (coating and substrate bonding strength, etc.
), coating stability and corrosion resistance are evaluated , Biocompatibility evaluation and other studies have proved that it is equivalent to the coatings of similar products on the market, so animal tests are not required to evaluate the osseointegration effect and stability of the porous coating
.

(B) Electrocardiograph

One of the main risks of the electrocardiograph is the inaccuracy of working data, including the inaccuracy of the automatic measurement of the electrocardiogram and the inaccuracy of the automatic diagnosis of the electrocardiogram
.
Laboratory research can be conducted to verify the accuracy of automatic ECG measurement through the ECG standard database, and the accuracy of public morphological interpretation and the accuracy of public rhythm diagnosis can be confirmed through the ECG database for morphological diagnosis and the ECG database for rhythm diagnosis.
Animal testing
.

(3) Cross-linked sodium hyaluronate gel for injection

Cross-linked sodium hyaluronate gel can be used for facial injection to correct nasolabial fold wrinkles, and the correction effect can generally reach 6 months
.
In view of the fact that the improvement of human facial wrinkles cannot be investigated through animal tests, animal test 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 of product injection in the human clinical evaluation data.
(Such as WSRS) Curative effect evaluation indicators such as the degree of improvement compared to preoperative
.

(4) Absorbable biological hernia repair patch

The absorbable biological hernia repair patch mentioned in this case is used to repair abdominal wall hernias and abdominal wall defects, and generally has a microstructure similar to extracellular matrix
.
After the product is implanted in the human body, the host cells grow in the material, and the abdominal wall tissue is finally reshaped to repair the defect
.

1.
One of the main risks of this type of product is the recurrence of hernias or abdominal wall defects.
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, only relying on routine laboratory research cannot verify the effectiveness of the control measures related to the risk of hernia recurrence.
It is appropriate to consider using animal test data such as histopathology to verify the effect of tissue reconstruction
.

2.
The applicant can collect animal test data or literature data of similar products before carrying out animal tests, and analyze whether these data can be used to support the evaluation of the organization reconstruction effect of the declared product.
If the existing data is sufficient, no animal test is required
.

(5) External defibrillation products

External defibrillation products are available for different users and operators to perform external electrical cardioversion treatment under different expected use environments
.

For this type of product, routine laboratory research cannot verify the effectiveness of the risk-related control measures of external electrical cardioversion technology.
Therefore, 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 vascular closure products.
The heat generated by friction causes the tissue to be coagulated and the blood vessel is cut and sealed (this example does not include special requirements for the cutting and closing function of blood vessels above 3mm)
.

1.
The main risks of this product include inadequate blood vessel cutting and closure and tissue thermal damage caused by unreasonable product design and other reasons
.
Laboratory studies alone cannot fully verify the effectiveness of these risk control measures.
Acute animal tests are required to observe the immediate blood vessel cutting and closure and tissue thermal damage of the product, and chronic animal tests are required to observe the healing of heat damage and subsequent bleeding.
Circumstance, and then verify the effectiveness of risk control measures
.

2.
If the applied product contains multiple similarly designed cutter heads, the in vitro burst pressure test can be used to screen out the worst-performing cutter head to carry out animal tests, so as to reduce some animal tests
.
For new cutter heads similar to existing cutter heads (similar design and similar performance), the results of in vitro burst pressure test can be used to prove the equivalence with similar cutter heads, and no animal tests will be carried out
.

(7) Implantable cardiac pacemaker

1.
Implantable cardiac pacemakers are high-risk implantable devices, and animal testing can provide corresponding evidence support for product design and finalization
.
If the same applicant improves or updates the implantable cardiac pacemaker on the basis of the previous generation product, there is no need to carry out animal tests on the verified content of the previous generation product.
If necessary, the applicant only conducts corresponding animal experiments for the improved or updated part Experiment
.

2.
Patients generally cannot undergo MRI after implantation of 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 on the product To conduct MRI compatibility related research
.
MRI compatibility studies usually require the use of animal computer modeling to verify the safety and effectiveness of MRI compatibility.
After the accuracy of computer modeling is verified, the MRI compatibility of other implantable cardiac pacemakers from the same applicant Research, it is no longer necessary to repeat animal experiments
.

3.
Compared with the traditional implantable cardiac pacemaker, the leadless pacemaker adopts new structural design and surgical operation method, and does not require the implantation of traditional implantable cardiac electrode leads.
Applicants should focus on innovations Assess relevant risks and verify or confirm the effectiveness of risk control measures.
Applicants should conduct animal tests on leadless pacemakers to verify the safety, effectiveness and feasibility of the product
.

(8) Drug-eluting stent

1.
Although the drugs contained in drug-eluting stent products such as paclitaxel and rapamycin have a long history of clinical application as drugs, their application in devices is quite different from when they are used as drugs alone, such as drug-eluting stents.
After implantation, the local tissue drug concentration in the target blood 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 sufficient to support its safety, and it should be further adopted Animal experiments Carry out toxicological safety studies of local tissues such as target blood vessels and distal myocardium, and obtain necessary histopathological data
.
For two drug-eluting stents containing the same drug, if the drug carrier material of the stent is different, there are also big differences in clinical application.
For example, the rate of drug release and absorption from different carrier materials is different.
Some literature data are used to confirm the drug dose density and safety range
.

2.
For drug-eluting stent products coated with a degradable coating, its degradation performance is an important factor in the screening of carrier polymer materials
.
It is necessary to study the degradation performance of drug-eluting stent coatings in vivo through animal tests.
However, if the degradation performance of carrier polymers (such as polylactic acid-glycolic acid copolymer, PLGA) can be obtained through similar product information, literature data information, and materials Database information and regulatory agency filing information are supported, and applicants do not need to carry out animal tests on the degradation performance of the declared products again
.

(9) Degradable metal screws for bone internal fixation

Degradable metal screws for bone internal fixation.
This type of product provides initial stable fixation at the initial stage of bone healing, and gradually degrades after the bone is healed, avoiding secondary surgical removal
.

The main risks of this type of product include the premature failure of the 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, only relying on routine laboratory research cannot verify the effectiveness of the failure risk-related control measures.
It is necessary to prepare fracture or bone defect models through the corresponding parts of the appropriate animal model to evaluate the degradable metal products in the appropriate animal body.
The degradation performance of the product and the safety and effectiveness of the product
.
Specific tests may include X-ray project evaluation, blood elemental analysis, pathological analysis, micro-CT analysis, evaluation biomechanical implant, surrounding bone tissue analysis
.

(10) Stapler

The stapler is mainly used for the resection and closure of tissues/organs
.

1.
For stapler products used for the cutting/anastomosis of solid organs or blood vessels, animal experiments should be carried out because routine laboratory research cannot fully verify the operational performance and anastomosis performance of the stapler for the human body
.

2.
For intestinal or skin stapler products that use new materials, if the product performance, staple material, etc.
are different from those on the market, it is not enough to rely on routine laboratory research and existing data to evaluate product safety And effectiveness, animal testing should be carried out
.
In addition, animal testing can determine the clinically relevant parameters of the product (such as tissue thickness, etc.
), and predict the safety issues that may occur when the product is used in the human body
.

(11) Absorbable surgical anti-adhesion products

For absorbable surgical anti-adhesion products, the expected anti-adhesion function of the product should be realized
.
This function should be studied on appropriate live animal models
.
In animal experiments, it is advisable to reflect as much as possible the surgical method, specific surgical site, adhesion type, evaluation method of adhesion, as well as the method of use of the product to be used in clinical application, and observe whether the product can effectively reduce the incidence, extent and extent of adhesion.
severity
.
In addition, animal experiments can also provide a better reference for the design of clinical research programs
.

Four, reference materials

[1] General Considerations for Animal Studies for Medical Devices [EB].
(Draft Guidance)

[2] EFS Guidance: Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical studies, Including Certain First in Human (FIH) Studies[EB].

[3] Recommended Content and Format of Test Reports for Complete Non-Clinical Bench Performance Testing in Premarket Submissions [EB].
(Draft Guidance)

[4] "Guidelines for Technical Review of Ultrasonic Soft Tissue Cutting Hemostasis System" (Announcement No.
37 of 2018)

[5] "Guidelines for Technical Review of Registration of Endoscopic Stapler Products" (Notice No.
44 of 2017)

[6] "Guidelines for the Technical Review of the Registration of Absorbable Anti-adhesion Products for Abdominal and Pelvic Surgery" (Announcement No.
7 of 2016)

[7] "Guiding Principles for Preclinical Research of Coronary Artery Drug-Eluting Stents" (Announcement No.
21 of 2018)

[8] "Technical Guidelines for the Registration of External Defibrillation Products" (Announcement No.
6 of 2017)

[9] "Guidelines for the Technical Review of Animal Experiments on Intra-abdominal Hernia Repair Patches" (Announcement No.
18, 2019)

[10] "Guidelines for the Technical Review of the Registration of Calcium Phosphorus/Silicon Bone Filling Materials" (Announcement No.
14 of 2017)

[11] "Guidelines for Technical Review of Clinical Trial Approval of Passive Implantable Medical Devices" (Announcement No.
40 of 2018)

[12] YY/T 0316-2016 "Application of Medical Device Risk Management to Medical Devices"

[13]ISO 14971:2007 Medical devices—Application of risk management to medical devices[S].

[14] "Non-Animal Approaches-The Way Forward", European Commission Scientific Conference summary report, Mark Cronin, March 2017

[15] Directive 2010/63/EU of The European Parliament And of The Council on the protection of animals used for scientific purposes[EB]

5.
Drafting unit:

Medical Device Technology Evaluation Center of the State Drug Administration

Annex 2

Guiding Principles for Registration and Review of Medical Device Animal Test Research Part 2: Test Design and Implementation Quality Assurance

Medical device safety and effectiveness evaluation research should use scientific and reasonable evaluation methods, among which animal testing is one of the important methods, which is an important research in product design and development, and can provide corresponding evidence support for product design finalization; if necessary Carrying out clinical trials can provide supporting information 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
.

This guideline is the second part of the series of guidelines for technical review of medical device animal test research, which aims to further guide applicants to carry out medical device animal test research with higher quality with minimal burden
.
Applicants should refer to the "Guiding Principles for Medical Device Animal Test Research Technical Review Part I: Decision Principles" to avoid unnecessary animal testing; when the applicant decides to conduct animal testing, they can refer to this guideline for research plan design and implementation quality Guarantee related work
.

This guiding principle is a technical guidance document for applicants and technical reviewers.
It does not involve administrative matters such as registration and approval, nor is it enforced as a law.
If there are other methods that can meet the requirements of the law, it can also be used, but it should Provide sufficient research data and verification data
.
This guideline should be used under the premise of following relevant laws and regulations
.

This guiding principle is formulated under the current system of regulations and standards and the current level of awareness.
With the continuous improvement of regulations and standards, as well as the continuous development of science and technology, the relevant content of this guiding principle will also be adjusted in due course
.

1.
Scope of application

This guideline applies to the design and implementation of animal experiments related to medical device products, and does not apply to research conducted on non-living animals, isolated tissues or organs
.

This guideline does not replace the technical documents related to the biological evaluation of medical devices such as GB/T 16886 series standards
.
If the biocompatibility of medical devices is evaluated through animal testing, it should also comply with the technical documents related to biological evaluation such as the GB/T 16886 series of standards
.

If there are guidelines issued for a specific product, follow the guidelines for the corresponding product
.

This guideline does not apply to in vitro diagnostic reagents managed in accordance with medical device management
.

2.
Research plan design

Medical device animal testing is based on the purpose of the test, selecting animals that meet the test requirements, conducting product feasibility and/or safety and/or effectiveness studies under the pre-designed research plan, and observing and recording the reaction process and results of the animals.
To confirm the role and influence of medical devices on life activities
.
The feasibility, safety and effectiveness data obtained from animal experiments should consider repeatability and reproducibility
.

When designing a research plan, it is advisable to follow the principle of "Replacement, Reduction and Refinement (3R)", and consider factors such as science, ethics, and economy
.
Prior to the design of the research plan, it is advisable to combine the expected benefits and risks of medical devices to summarize and analyze the existing animal test data, including literature data, animal test evidence of similar products and other information
.

A good animal experiment design can not only ensure that as few animals as possible are used for scientific data analysis, but also can scientifically and reasonably evaluate the feasibility, safety and effectiveness of medical device products
.
The applicant should design the research plan in combination with the product's function mechanism, working principle, and design features
.

Appropriate pre-tests can help optimize the experimental design
.
There is evidence that test methods or operations have a significant impact on research results, such as learning curve effects.
Pre-tests should be conducted before safety and effectiveness studies
.

The applicant should put forward a clear test purpose (that is, the problem to be solved), and according to the test purpose, a scientific and reasonable research plan should be formulated by personnel with corresponding professional knowledge and practical experience
.

All test methods or operating steps in the research plan should be specified in detail through relevant operating specifications and other documents.
If there is a deviation from the research plan and/or test methods or operating steps, the deviation should be explained in detail and the deviation should be analyzed to the research results Impact
.

If the product adopts a new mechanism of action, working principle, design, main materials/formulations, application methods (such as surgical operations), adds a new scope of application, improves certain aspects of performance, etc.
, relevant additions should be introduced for product innovations/changes Risks, and design the research plan in combination with the intended use
.

(1) Test purpose

Animal experiment research is generally divided into feasibility study, safety study and effectiveness study according to the purpose, but sometimes the boundaries cannot be strictly divided.
In an animal experiment, the feasibility, effectiveness, and safety of the product can be evaluated at the same time
.

1.
Feasibility study

Feasibility study refers to the research carried out in the product design and development stage to confirm the product's mechanism, working principle, design, operability, functionality, preliminary safety, etc.
, or to identify new unexpected risks
.

Feasibility studies can be used to evaluate the variability of the results of different research indicators in animal experiments, and provide design basis for the experimental design elements of safety and effectiveness studies, such as the number of animals
.

For some products, such as innovative medical devices, applicants can identify new risks introduced in product design through feasibility studies, carry out corresponding risk management activities, and improve and improve the products
.

The applicant may provide evidence of feasibility animal test research as supporting data for the basis of product design
.
Feasibility studies are not necessary.
For some medical devices with more research background information, safety and effectiveness studies can be carried out directly
.

2.
Safety research

Medical device safety research is generally the main research purpose of animal testing.
The evaluation of the impact of design and finalized products on the safety of the body when fulfilling their functions can include short-term (such as immediate research to evaluate operational safety), medium/long-term (such as based on plant (Incoming material degradation cycle) safety test
.

When applicable, the applicant should provide safety animal test research data as supporting data for evaluating product safety
.

3.
Effectiveness research

Although there may be some differences in effectiveness evaluation between animals and humans, in some cases, a well-designed animal test can support the effectiveness of the product
.
Such as the evaluation of the anti-adhesion performance of absorbable anti-adhesion medical devices, the evaluation of the effectiveness of tissue repair materials in guiding tissue regeneration and remodeling, and the evaluation of the osseointegration effect of porous coated joint products or 3D printed porous structure products
.

Use animal tests to evaluate the effectiveness of products, and if necessary, analyze the correlation between animals and evaluation indicators and the human body in advance, such as using existing literature information, database information, and animal test research data of previous products
.

When applicable, the applicant should provide validity animal test research data as supporting data for evaluating the validity of the product
.

(2) Tested devices and controls

1.
Tested device

The applicant should describe in detail the tested device used in the research plan, including the name, structure and composition (including accessories and product illustrations for use), model specifications, batch number, shelf life, storage conditions, and the number of individual animals used , frequency of use (if applicable), and other information if reused
.

In the process of animal testing and research, if product design changes occur, the applicant should describe the changes in detail and analyze the impact of the changes on the process of animal testing, test results, and conclusions
.
Redesign and implement animal tests when necessary
.

In the feasibility study, the unfinished design product can be used as the tested device, but in the final evaluation of the safety and effectiveness of the animal test research, the tested device should generally be the final product of the design
.

The device under test in animal testing should be able to represent the safety and effectiveness of other products in the registration unit
.

If the final product is not used due to the influence of animal anatomy and other factors, it is necessary to provide a rational analysis to confirm that it does not affect the test results and conclusions
.

The operation method of the device under test in the animal experiment should be consistent with the expected clinical operation method
.
If a different operation method is used, it should be confirmed that it has no influence on the test results and conclusions
.

2.
Control

Applicants should analyze and demonstrate whether to establish a control group
.

If a control group needs to be set up, control devices and/or control materials can be selected according to the characteristics of evaluation indicators
.
It is advisable to give priority to the selection of similar devices that have been marketed as a comparison.
If a non-domestic marketed product is selected, it is necessary to provide reasonable reasons and evidence that it can be used as a comparison device
.

When appropriate, other appropriate control groups can be established in animal experiments, such as other interventions
.

(3) Experimental animals

The selection of experimental animals is very important for the feasibility, safety and effectiveness evaluation of medical devices
.
It is recommended to choose experimental animals first
.

When selecting experimental animals, it is recommended to comprehensively consider the following aspects (including but not limited to):

1.
The purpose of animal testing

Experimental animals usually include conventional experimental animals, spontaneous mutation experimental animals, genetic engineering experimental animals, etc.
; experimental animal species can include rodents such as rats and mice, non-human primates such as macaques, and other mammals such as rabbits and dogs.
, Pigs, etc.
Applicants should select suitable experimental animals according to different test purposes
.

For example, calcium, phosphorous and silicon-like bone filling materials, when studying the effect of bone formation in the defect, the influence of the self-repairing ability of animal bones on the test results should be considered.
In order to better complete the research purpose of the animal test, bone development should be selected.
Mature animals
.

For example, for bioabsorbable coronary artery drug-eluting stent products, small animals (such as rabbits) can be selected for research in the early development of product degradation cycle, mechanical properties, compatibility of degradation products with tissues, and tissue response
.
Pigs can be used as experimental animals in animal experiment research after product design and finalization
.

2.
Standardized laboratory animals should be used

Standardized laboratory animals mainly refer to animals that have a clear genetic background or a clear source and meet the relevant standards that control the microorganisms they carry
.
In medical device animal testing and research, it is advisable to use this type of laboratory animal as much as possible.
If there is no standard laboratory animal, the reason for the selection should be explained and the impact on the test result should be analyzed
.

3.
The similarity with the human body,

Priority should be given to the similarity of structure (such as anatomical structure, size), function, metabolism and disease characteristics, biological response to the human body and the impact on the test results.
The higher the similarity between the animal and the human body, the feasibility and safety of animal testing.
When the results of sex and validity analysis are extrapolated to the human level, the higher the level of supporting evidence
.

Different animal species and breeds/strains may have different anatomical structures and physiological characteristics, resulting in different biological responses.
Therefore, applicants should select suitable species and breeds/strains of animals for animal experiments according to the purpose of the experiment
.

For example, for intra-abdominal hernia repair patches, considering the comparability of the anatomical structure of the abdominal wall and the degree of neoperitonization between animals and humans, it is advisable to choose miniature pigs and beagle dogs for animal experiment research
.

For example, for in vitro defibrillation animal experiments, considering that the pig's heart is most similar to humans in anatomy, histopathology, hemodynamics, and distribution of myocardial collateral circulation, healthy pigs should be selected for in vitro defibrillation animal experiments.

.

4.
Evaluation index sensitivity

When selecting experimental animals, the sensitivity relationship between animals and evaluation indicators should be fully considered
.
Such as biological artificial heart valve products, in the animal experiment of calcification level research, it is advisable to select young animals as experimental animals for calcification level research
.

5.
Basic Elements of Animals

Animal sex, size (age, weight), health and disease status, pathogen infection, etc.
may affect the results and conclusions of animal experiments.
Therefore, the above factors should be fully considered when selecting experimental animals
.

For example, for the animal test of external defibrillation equipment, the weight of pigs in the animal test of medical devices for adults needs to be between 30kg and 80kg, and the weight of pigs in the animal test of medical devices for children needs to be between 4kg and 25kg
.

6.
Establishment of disease model

Appropriate animal disease models should be established for research in animal experiments.
If no disease model has been established, a reasonable argument must be provided
.

For example, when evaluating the repair effect of dural repair materials through animal experiments, it is necessary to establish a dural defect model according to the intended use
.

For in vitro defibrillation animal experiments, it is advisable to establish experimental pig models of induced ventricular fibrillation
.

7.
Other

When selecting experimental animals, it is also necessary to consider the impact of factors such as environment, nutrition, animal work and rest, anesthesia methods, surgical techniques, and disease model preparation methods on the experimental conclusions
.

(4) Number of animals

In the early feasibility study of product design and development, due to lack of more mature experience, the number of animals may be estimated, but the data obtained can provide a design basis for the number of animals for safety and effectiveness studies
.

The safety and effectiveness research carried out after the product design is finalized can generally be combined with clear research purposes, corresponding research hypotheses (if applicable), literature information, experience of similar products, feasibility studies or pre-test results, etc.
to estimate the number of animals
.
Although statistical principles can be directly used to estimate the sample size, it is also possible to increase the number of animals required for animal experiments
.
It is recommended that the number of animals should be sufficient to ensure that the test results are reliable and conform to the 3R principle, and statistical methods may not be used to estimate the number
.
If under the same test conditions, the evaluation results presented between individual animals have greater variability, the reasons for the variability, such as operation methods, product quality, etc.
, should be analyzed, and the number of animals should be increased when appropriate to obtain more scientific and objective conclusions.

.

If the animal experiment has multiple observation time points, the number of animals at each observation point should ensure the reliability of the test results
.
It is recommended that when estimating the number of animals, consider the premature death of animals due to various reasons
.

When appropriate, the device can be used on multiple tissues of the same animal
.

(5) Observation time

The observation time of animal experiments should be set according to the purpose of the experiment, product characteristics, and evaluation indicators.
At the same time, it should refer to the research situation of similar products
.
Animal experiments can be divided into acute studies and chronic studies according to the length of observation time.
Acute studies are generally immediate/short-term observation studies after surgery; chronic studies are generally mid/long-term observation studies after surgery
.
The applicant should determine which type of animal test research to carry out based on the mechanism of action of the medical device product, the existing background information and other materials
.

It is advisable to set sufficient and different observation time points in animal experiments to observe the evaluation indicators at specific time points to evaluate the impact of products on animals
.
In the study protocol should fully justify different observation points set time, before generally include surgery, postoperative immediate, short-term postoperative, postoperative medium / long term and so on
.

The setting of the observation time point should take into account factors such as the working principle of the medical device product, the expected way and time of contact with the human body, and the time required to reach a steady state of biological response
.
For example, the observation time point should be at least 28 days for the product with non-absorbable material on the abdominal cavity side of the intra-abdominal hernia repair patch; for the product with absorbable material on the abdominal cavity side, the product should be completely degraded according to the expected complete degradation or stable biological response.
The time determines the observation time point
.
The frequency of observation for different evaluation indicators may be different
.

When the animal test lasts for a long time, such as a bioabsorbable coronary artery drug-eluting stent, and the applicant can fully demonstrate the preliminary safety and feasibility of the product in combination with the existing animal test results, it may consider conducting human clinical trials.
At the same time, it is necessary to continue to complete animal tests
.

(6) Evaluation index

The evaluation index should be preset in the research plan, and the evaluation index should be observed at the preset observation time point
.

The specific evaluation methods of the evaluation indicators, such as imaging, gross anatomy, histopathology, performance testing, etc.
, need to be clarified in the research plan; the observation time point and frequency of the specific evaluation indicators need to be clarified
.
Evaluation indicators should have scientific and objective evaluation standards
.

In animal experiments and research, any safety events/abnormalities should be recorded and analyzed
.

If animal death occurs, the cause of death should be analyzed in detail, and the correlation with the device should be analyzed
.

3.
Implementation and Quality Assurance

The applicant is responsible for initiating, applying, organizing, and monitoring animal experiments, and is responsible for the animal welfare ethics, authenticity, and science of animal experiments.
The applicant shall ensure that the experimental data is complete, authentic, reliable, and traceable, and the results are credible
.

A corresponding quality management system for animal testing and research shall be established, and the system shall be maintained to maintain effective operation, and shall be inspected by the supervisory authority when necessary
.

General requirements for animal testing can refer to relevant national standards (such as GB/T 35823)
.

This guideline only recommends the basic elements of animal testing implementation and quality assurance
.

(1) Implementation of animal testing

For animal testing of medical devices, the test title or code shall be formulated, and the test title or code shall be uniformly used in the relevant quality management system documents and test records
.
All samples collected in the experiment should be marked with title or code, sample number and date of collection
.

It is necessary to ensure the protection of animal welfare during the whole process of the implementation of animal experiments.
When the animals have health, disease and other problems during the experiment, they shall be dealt with in a timely manner and the impact on the results of the experiment shall be evaluated
.
The research protocol needs to be approved by the animal ethics committee before implementation
.

The main content of the research plan should include but not limited to:

1.
Animal test title or code;

2.
The name, address and contact information of all research institutions/units and applicants participating in the research; animal production and/or use permit number (if applicable);

3.
The names and responsibilities of the person in charge of the animal experiment project and the main personnel participating in the experiment; if there is a multi-site study, the name of the research site responsible for each part of the experiment, the name of the main investigator and the content of the work undertaken;

4.
The test standards, guidelines or documents on which the animal test research is based;

5.
Animal test purpose and background information (including product change information);

6.
The tested device and control description, such as name, abbreviation, code, model specification, batch number, shelf life, and storage conditions
.
Providing a test instrument, a control, a reasonable model specifications and the like of the selected instructions
.
A statement of reasonableness without a comparison (if applicable);

7.
Relevant information about the experimental drugs and the equipment used, such as the name and dosage of the drugs, the name of the equipment used and the model specifications, etc.
;

8.
The species and breed/strain, gender, specification, source, animal grade (if applicable), grouping method and identification method, health status and other information of experimental animals;

9.
The use method, dosage (if applicable) and frequency of the tested device and the control;

10.
Animal test evaluation indicators and detection methods, frequency and duration;

11.
Data statistical processing method;

12.
Scheme deviation processing method;

13.
When and where the archives are kept
.

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Quality assurance personnel need to review the animal test items and issue a quality assurance statement to confirm whether the research methods, procedures, and results are accurately and completely described, and the original data of the research are truly and comprehensively reflected
.
The quality assurance statement shall include complete research identification information, related quality assurance inspection activities, and the date and stage of the report
.
Any amendments or additions to the completed summary report shall be re-reviewed and a quality assurance statement signed
.
Before signing the quality assurance statement, the quality assurance personnel should confirm that the test meets the requirements of this guideline, follow the research plan and operating procedures, and confirm that the summary report accurately and reliably reflects the original data
.

Four, terminology

1.
Institutional person in charge: the person who is fully responsible for the organization and operation and management of a research institution
.

2.
Project leader: the person who is fully responsible for organizing and implementing a certain experiment in animal experiment research
.

3.
Main investigator: In a multi-site study, the person who represents the project leader to implement the experiment at the sub-research site
.

4.
Multi-site research: research projects that are jointly implemented in different research institutions or in different places in the same research institution
.
This type of research project has only one research plan and project leader, and a summary report is formed.
The research institution or site where the project leader and the animal are located is the "main research site", and other research institutions or sites that are responsible for the implementation of the research work are "subjects".
Research site"
.

5.
Deviation: A situation that does not meet the requirements of the research plan or operating procedures unintentionally or caused by unforeseen factors
.

6.
Electronic data: Any text, graphics, data, sound, image and other information expressed in electronic form, which are created, modified, backed up, maintained, archived, retrieved or distributed by a computerized system
.

7.
Audit trail: Continuously record system activities in chronological order.
This record is sufficient to reconstruct, review, and inspect the process of system activities in order to grasp the activities that may affect the final results and changes in the operating environment
.

V.
References

[1] Qin Chuan, Wei Hong.
Experimental Zoology Second Edition [M].
Beijing: People's Medical Publishing House, 2015.

[2] "Technical Guidelines for the Registration of External Defibrillation Products" (Announcement No.
6 of 2017)

[3] "Guidelines for the Technical Review of the Registration of Calcium Phosphorus/Silicon Bone Filling Materials" (Announcement No.
14 of 2017)

[4] "Guiding Principles for Preclinical Research of Coronary Artery Drug-Eluting Stents" (Announcement No.
21 of 2018)

[5] "Guiding Principles for Technical Review of Ultrasonic Soft Tissue Cutting Hemostasis System" (Announcement No.
37, 2018)

[6] "Guiding Principles for Technical Review of Medical Device Animal Test Research Part One: Decision-Making Principles" (Announcement No.
18 of 2019)

[7] "Guidelines for the Technical Review of Animal Experiments on Intra-abdominal Hernia Repair Patches" (Announcement No.
18, 2019)

[8] "Non-clinical Drug Research Quality Management Standards" (State Food and Drug Administration Order No.
34)

[9] GB 12279-2008 "Cardiovascular Implants and Artificial Heart Valves"

[10]US Food and Drug Administration.
General Considerations for Animal Studies for Cardiovascular Devices[EB],2010.

[11]US Food and Drug Administration.
General Considerations for Animal Studies for Cardiovascular Devices (Draft) [EB], 2015.

[12]Munnelly A.
et al.
Biomaterial Calcification: Mechanisms and Prevention [M].
In: Eliaz N.
(eds) Degradation of Implant Materials.
Springer,2012.

[13]Office of Animal Care and Use.
Guidelines for Endpoints in Animal Study Proposals[EB],2019.

[14] B Voelkl et al.
Reproducibility of preclinical animal research improvement with heterogeneity of study samples[J].
PLoS Biol, 2018.

[15] Kilkenny C et al.
Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research[J].
PLoS Biol,2010.

[16] CR Hooijmans et al.
A Gold Standard Publication Checklist to Improve the Quality of Animal Studies, to Fully Integrate the Three Rs, and to Make Systematic Reviews More Feasible[J].
Altern Lab Anim,2010.

6.
Drafting unit

Medical Device Technology Evaluation Center of the State Drug Administration