The State Food and Drug Administration issued the “Guidelines for the Registration and Review of Animal Experimental Research on Medical Devices Part I: Decision-Making Principles (2021 Revision)” and “The Second Part of the Guidelines for the Registration Review of Medical Device Animal Experimental Research: Experimental Design and Implementation Quality Assurance” (Notice No. 75 of 2021) (hereinafter referred to as the “Guiding Principles”). The background and key issues of the formulation of the Guiding Principles are explained as follows:
1. Formulation background
Medical device animal testing is to select animals that meet the test requirements according to the purpose of the test, conduct product feasibility and/or safety and/or effectiveness research under the pre-designed research plan, observe and record the reaction process and results of the animals, To confirm the role and impact of medical devices on life activities. In the risk management activities of design and development, after the implementation of risk reduction control measures, the effectiveness of risk control measures needs to be verified/confirmed. Animal testing is one of the means to confirm the effectiveness of risk control measures. Important Evidence Module for Effectiveness.
In order to implement the general requirements of the “Opinions on Deepening the Reform of the Review and Approval System and Encouraging the Innovation of Drugs and Medical Devices” (Ting Zi [2017] No. 42), the Medical Device Technology Evaluation Center of the State Drug Administration has established a special work on animal experiments After extensive solicitation of opinions, discussions among experts and enterprises, a series of guiding principles for the registration and review of medical device animal test research have been compiled, aiming at reducing the number of unnecessary animal tests and guiding applicants to carry out medical treatment with a higher quality and with minimal burden. Device animal testing research.
2. Description of key issues
(1) Scope of application of the Guiding Principles
The “Guiding Principles” do not apply to research conducted on non-living animals, isolated tissues or organs, and do not apply to in vitro diagnostic reagents managed as medical devices.
(2) General Principles of Animal Experimental Research
Animal test research for medical devices must comply with the 3R+DQ principles. The 3R principle (Replacement, Reduction and Refinement) is the protection of animal welfare, the scientific program design (Design) is the software and scientific basis for the realization of the 3R principle, and the implementation under the effective operation of the quality management system (Quality) is the hardware and engineering basis. The 3R+DQ principle is the principle guarantee for avoiding excessive animal experiments and obtaining scientific, reasonable, objective and credible animal experiment data and evidence.
(3) Regarding whether it is necessary to carry out animal test research
There are many types of medical devices, and not all products need to be tested on animals. Applicants should make reasonable use of decision-making principles in the design and development stage, give priority to non-in vivo research, computer simulation and other methods to replace animal tests, and make full use of existing similar products. Experimental data or evidence such as performance comparison with commercially available similar products to reduce the number of animal experiments.
(4) About the purpose of animal experiment research
The purpose of animal test research is generally divided into feasibility study, safety study and effectiveness study. In one animal test, the feasibility, effectiveness and safety of the product can be evaluated at the same time. When there is no clear test purpose, animal test research should be avoided.
(5) About the relationship between animal experiments and research on biological characteristics
The “Guiding Principles” do not replace GB/T 16886 series standards and other technical documents related to the biological evaluation of medical devices. Some biological risks can be assessed in animal experiments, but the content of the assessment must meet the requirements of technical documents related to biological assessment such as GB/T 16886 series standards.
(6) Regarding the additional pages in the Guiding Principles
The attached page of the “Guiding Principles” lists “examples of products that may require animal testing”, not a list of products that must be tested on animals. Research scientific decision-making.
(7) Regarding the design of animal experiment protocols
The applicant should design the plan scientifically based on the purpose, and then follow the plan to strictly control the quality to implement the test, record the test results truthfully, and have the results systematically evaluated by professionals.
A. Test device
The device under test should be a sample produced under the effective operation of the quality management system, generally the final product of the design, and an alternative sample can be used due to factors such as animal anatomy.
The design of the product can be changed during the animal test research process. It is necessary to analyze the impact of the changes on the animal test process, test results and conclusions, and re-conduct the animal test research if necessary.
B. Experimental animals
Experimental animals are crucial to the evaluation of the feasibility, safety and effectiveness of medical devices, and it is recommended to give priority to the selection of experimental animals. When selecting experimental animals, the following factors should be considered (including but not limited to):
(a) Meet the requirements of the test purpose;
(b) The structure (such as anatomical structure, size), function, metabolism and disease characteristics, biological response and other aspects are similar to the human body;
(c) Sensitive to evaluation indicators;
(d) The basic elements of animals, such as gender and specifications, will not affect the results and conclusions of animal experiments.
C. Number of animals
The number of animals should be sufficient to ensure the reliability of the test results and comply with the 3R principle, and statistical methods may not be used to estimate the number. If under the same experimental conditions, the evaluation results presented by individual animals have large variability, it is necessary to analyze the reasons for the variability, such as operating methods, product quality, etc., and increase the number of animals when appropriate to obtain more scientific and objective conclusions .
D. Observation time
The applicant should set up sufficient and different observation time points based on factors such as product test purpose, working principle, expected contact mode and time with the human body, time required to reach a steady state of biological response, and generally include preoperative, intraoperative, and postoperative time points. Immediately, short-term postoperatively, medium/long-term postoperatively, etc.
E. Evaluation indicators
The specific evaluation method of the evaluation index, the observation time point and frequency of the specific evaluation index need to be clarified in the research plan. Evaluation indicators should have scientific and objective evaluation criteria.
(8) Implementation of animal experiments and quality assurance
Animal experiments need to be carried out under an effectively operating quality management system, and the supervisory department will inspect the system when necessary.
Animal welfare protection should be ensured during the whole process of animal experiments, and the research protocol must be approved by the Animal Ethics Committee before implementation.
All data generated by the experiment shall be recorded in strict accordance with the research protocol and corresponding operating specification documents, and the data records shall be timely, direct, accurate, clear and difficult to delete. As the first responsible person, the applicant should ensure that the test data is complete, authentic, reliable, traceable, and the results credible.
According to the requirements of the established quality management system, sufficient quality assurance personnel shall be assigned to be responsible for the quality assurance work, and the independence of the quality assurance work shall be ensured. 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. They should confirm that the test meets the requirements of the “Guiding Principles” .