Summary of frequently asked questions about medical device clinical trials

1. When conducting clinical evaluation through the clinical data of the same type of medical device, if the products of other registrants are selected as the medical device of the same type for comparison, does the production process, clinical data and other data need to obtain the authorization of the registrant of the same type of medical device?

Answer: According to the "Technical Guiding Principles for Clinical Evaluation of Medical Devices" (General Administration Circular No. 14 of 2015), it is clear that the data should be legally obtained corresponding data in the requirements for analysis and evaluation of clinical data of medical devices of the same variety.

"Notice of the Food and Drug Administration on Relevant Issues Concerning the Implementation of the Administrative Measures for the Registration of Medical Devices and In Vitro Diagnostic Reagents" (Food and Drug Administration [2015] No. 247) should be legally obtained based on the data, stipulating that the clinical evaluation carried out according to Article 6 of the Guidelines If the production process and clinical data of medical devices of the same variety are used, the applicant should submit a power of attorney for the production process and clinical data of medical devices of the same variety. "Fifth Interpretation of Medical Device Registration Management Regulations" further interprets the authorization requirements for clinical evaluation data of medical devices, and proposes authorization requirements for non-public data of the same type of medical devices to be used to ensure the legality of data sources; use public publication The data, such as publicly published documents, data, information, etc., do not need to obtain authorization. Therefore, when conducting clinical evaluation through comparison of medical devices of the same variety, if the products of other registrants are selected as medical devices of the same variety, if the data comes from public data, test and measurement, industry consensus, etc., it is not required to provide a data use authorization.

2. What should I do if the clinical literature of the same kind of medical device cannot be retrieved when conducting clinical evaluation based on the clinical data of the same kind of medical device?

Answer: The collection, analysis, and evaluation of clinical data of medical devices of the same variety have different roles according to the design features, key technologies, scope of application, and degree of risk of the declared products, including confirming whether the safety and effectiveness of medical devices of the same type have been clinically obtained. It is generally accepted whether the risk benefit is within the acceptable range; fully identify the clinical use risks of the same variety of medical devices, and provide information for the risk benefit analysis of the declared products; confirm the residual risk of non-clinical studies through clinical data; for some non-clinical studies (such as Bench test) Evaluation of test results provides clinical data, etc.

In addition to clinical literature data, clinical data of products of the same variety also include clinical experience data and clinical trial data. Clinical experience data includes completed clinical research data sets, adverse event data sets and clinical risk-related corrective action data sets, of which adverse events The data set can be publicly obtained through complaints and adverse events after the listing of the regulatory agency.

In addition, the applicant also needs to confirm whether the selected product of the same variety is a product with high clinical attention and safety and effectiveness among similar products, and whether the literature search strategy is appropriate and can ensure the comprehensiveness of the search.

3. A product has been upgraded from Class II to Class III. Can the adjusted product use its own clinical data as clinical data of the same variety for clinical evaluation?

Answer: Yes, but it should fully collect the pre-market and post-market data when it is a Class II product for a reasonable summary and analysis. The main concern is whether the declared product can achieve the expected performance under normal use conditions; compared with the expected benefit, whether the risk of the product is acceptable; whether the clinical performance and safety of the product are supported by appropriate evidence.

4. When conducting parallel controlled clinical trials, if for similar reasons cannot use similar products on the market as control products, can similar products be selected as control products?

A: When conducting parallel controlled clinical trials, if the similar products on the market cannot be used as control products for reasonable reasons, the product design characteristics, pre-clinical research results, risk and benefit analysis, clinical trial objectives, clinical trial evaluation indicators and follow-up can be comprehensively considered Factors such as time, consider the selection of similar products that have been recognized as effective and safe, have the same scope of application as the test device, and have similar evaluation indicators set in the clinical trial that are comparable to the test device.

5. For products with clinical trial data of overseas medical devices, if there are also clinical trial guidelines for the corresponding products published in China, must the clinical trial data of the product meet the requirements of the corresponding domestic guidelines?

Answer: Clinical trials conducted overseas may meet the technical review requirements of the country (region) where the trial is conducted, but may not fully meet the relevant review requirements of my country. For example, when designing clinical trials, some countries only require clinical trials to draw conclusions that device performance reaches a certain observation endpoint. However, when applying for registration in my country, the performance of the device may be required to reach multiple observation endpoints to confirm its effectiveness, and the safety of the medical device is supported by appropriate evidence.

If the guidelines for technical review of specific medical devices issued by the State Drug Administration contain relevant requirements for its clinical trials, the overseas clinical trials of the device should consider the relevant requirements, and if there are inconsistencies, provide sufficient and reasonable reasons and basis.

6. When accepting clinical trial data of overseas medical devices, is it necessary to include Chinese trial data in the overseas clinical trial data?

A: When accepting clinical trial data from overseas medical devices, it is not necessary to include Chinese trial data in the overseas clinical trial data.

According to the "Guiding Principles for Accepting Medical Device Overseas Clinical Trial Data", the factors that may have an impact on the clinical trial results are not limited to racial differences. It is necessary to comprehensively consider the impact of differences in the test population and clinical trial conditions based on product characteristics. Although these factors are known to exist objectively and have a certain impact on clinical trials, the determination of the degree of influence of each factor should also be made in accordance with the characteristics of the device to be declared and the purpose of clinical trials.

According to the development status of medical devices, clinical use experience, and knowledge of related diseases and diagnosis and treatment methods, it is not required to prove one by one when it can be determined that the clinical trial data of most medical devices has no actual clinical significance.

When it is possible to determine whether certain factors have a clinically meaningful impact on clinical trial data, or if it is difficult to determine whether certain factors have a clinically meaningful impact on clinical trial data, the applicant should clarify the methods used to reduce or eliminate the impact of various differences Methods, such as subgroup design for the test population, or subgroup analysis of existing clinical trial data, can be considered as needed.

7. Do medical devices listed in the "Category 3 of Medical Devices Subject to Clinical Trial Approval" have to carry out clinical trials in China?

A: According to the "Guiding Principles for Accepting Medical Device Overseas Clinical Trial Data Technical Guidelines", medical devices listed in the "Category III Medical Device Catalogue that Needs Clinical Trial Approval" can submit overseas clinical trial data in accordance with these guidelines. On the basis of ethical principles, legal principles and scientific principles, if overseas clinical trial data meets the technical requirements for registration in my country, the data is scientific, complete and sufficient, and clinical trials may not be carried out in China.

8. Can the products in the "Category 3 of Medical Devices Subject to Clinical Trial Approval" be declared with overseas clinical trial data? Do clinical trials still need to be approved in China?

Answer: According to the "Guiding Principles for Accepting Medical Device Overseas Clinical Trial Data Technology" published in January 2018, the medical devices included in the "Category 3 of Medical Devices Subject to Clinical Trial Approval" (hereinafter referred to as the "Catalog") are also Foreign clinical trial data can be used for declaration in accordance with the above guidelines. For the products of clinical trials of products that do not meet the corresponding requirements, the products in the "Catalogue" that still need to be clinically tested in China, the clinical trials still need to be approved before they can be launched.

9. If the registered product includes two models A and B, can the sponsor choose a typical model A model for clinical trials?

Answer: A typical model A can be selected for clinical trials. For a model B that has not undergone clinical trials, the similarity and difference between the B model and the A model should be detailed to evaluate whether the difference has an adverse effect on the safety and effectiveness of the product.

10. Interpretation of issues related to the quality management of clinical trials of medical devices:

Answer: For the clinical trials of medical devices carried out in two clinical trial institutions, if the clinical trial design meets the relevant requirements of multi-center clinical trials in the "Quality Management Standards for Medical Device Clinical Trials", one clinical trial institution should be identified as the lead unit. At the same time, clinical trials are carried out in accordance with the same test plan to ensure consistency in the implementation of clinical test plans and the use of medical devices for testing. The statistical analysis principles and methods of the above clinical trials can be conducted with reference to the requirements of multi-center clinical trials. The lead unit organizes and summarizes the test summary of the two clinical trial institutions to form a clinical trial report and affixes the seals of the two clinical trial institutions.

11. If a parallel control design is used for clinical trials of medical devices, what are the principles for selecting control products?

A: For therapeutic products, when choosing a positive control, priority is given to similar products on the market that have been clinically recognized for their efficacy and safety. If it is not possible to use similar products on the market for reasonable reasons, the products that are as similar as possible can be used as a positive control, followed by standard treatment.

Standard treatments include a variety of situations, including medication. When the test device does not have the same or similar marketed product or corresponding standard treatment method, if the test device has a consolation effect, the trial design needs to consider the placebo control. At this time, ethical factors need to be considered comprehensively. If the efficacy of the products already on the market has not yet been clinically recognized, the trial design may consider standard treatment methods or comfort controls according to the specific circumstances. Applicants need to fully demonstrate the reasons for the selection of controls.

12. What is the definition and construction principle of the target value in the design of single-group target value medical device clinical trials?

Answer: The single-group design compared with the target value needs to specify the clinically meaningful target value of the main evaluation index in advance. By examining whether the result of the main evaluation index of the single-group clinical trial is within the specified target value range, the effectiveness of the test device is evaluated/ safety. Because there is no control group, single-target clinical trials cannot confirm the superiority, equivalence, or non-inferiority of the test device. They can only confirm that the effectiveness/safety of the test device reaches the lowest standard recognized in the professional field.

The target value is the minimum standard that should be achieved for the effectiveness/safety evaluation index of a certain type of medical device in the professional field, including two types of objective performance criteria (OPC) and performance goals (PG). The target value is usually a binary (such as valid/invalid) indicator or a quantitative indicator, including the target value and the one-sided confidence interval limit (usually 97.5% one-sided confidence interval limit). When performing statistical analysis on clinical trial results, it is necessary to calculate the point estimates of the main evaluation indicators and the limit values of the unilateral confidence intervals, and compare them with the target values.

The construction of the target value usually requires comprehensive collection of clinical research data with a certain quality level and a considerable number of cases, and scientific analysis (such as meta analysis). As device technology and clinical skills improve, OPC may change, and clinical data needs to be re-analyzed to confirm.

13. How to determine the sample size in clinical trials of medical devices?

Answer: The test sample size is determined by the main evaluation index of the test. The relevant elements for determining the sample size and the specific calculation method for the sample size need to be explained in the clinical trial plan.

The relevant elements for determining the sample size include the design and comparison types of clinical trials, the types and definitions of the main evaluation indicators, the main evaluation indicators have clinically meaningful thresholds δ (if applicable), and the relevant parameters of the main evaluation indicators (if expected Efficiency, mean, standard deviation, etc.), type Ⅰ error rate α and type Ⅱ error rate β, and the expected proportion of subjects dropping out.

The relevant parameters of the main evaluation indicators are estimated based on published data or the results of exploratory trials. It is necessary to clarify the source of these estimates in the clinical trial protocol. For the non-inferiority test design of the aortic stent graft, it is generally recommended that α take 0.05 on both sides and β is not greater than 0.20.

For details, please refer to "Guidelines for the Design of Clinical Trials of Medical Devices". For medical devices with clearly defined sample sizes in the relevant guidelines, the corresponding requirements in the guidelines should also be considered.

14. For a medical device product, the text description of the scope of application is different from that in the "Exemption from Clinical Trials for Medical Device Catalog", is it allowed? When the product has multiple scopes of application that are included in the "Exempt from Clinical Trials Medical Device Catalog", how should clinical evaluation information be provided during product registration?

Answer: 1. The wording of the scope of application of the declared product can be adjusted slightly, on the premise that it is substantially equal to the scope of application stated in the Catalog.

2. For products with multiple scopes of application, the applicant shall compare the scope of application of the declared product with the content of the Catalogue and the products registered in the Catalogue with the corresponding scope of application and provide supporting information. Prove that the difference does not adversely affect the safety and effectiveness of the product.

15. Does the polyurethane foam dressing with viscose backing comply with the "polyurethane foam dressing" in the third category of medical device exempt from clinical trials?

A: Included in the catalog, but please note that the exemptions do not include the following 4 cases:

(1) Indications for products that can promote epithelialization, guide tissue regeneration, promote wound healing, reduce pain, hemostasis, reduce scars, and prevent adhesion;

(2) Products that can be used for wounds in the body, third-degree burns, wounds infected with wounds, wounds with more necrotic tissues, patients with wound sepsis, etc.;

(3) Products containing active ingredients: such as medicines/medicinal active ingredients, biological products/bioactive ingredients, silver, disinfectants, etc.;

(4) Other new products.

16. For the clinical trial of peripheral vascular stent products, what are the main end points?

A: For peripheral endovascular stent products, the main research endpoint currently used in clinical trials is generally recommended to be a 12-month target vascular patency rate.

17. After the application for approval of the third-class high-risk medical device clinical trial is approved, can the applicant consider that the clinical trial plan has also been approved and confirmed, and it can carry out clinical trials according to the submitted clinical trial plan?

Answer: The positioning of the third type of high-risk medical device clinical trial approval is based on the application to decide whether to agree to conduct clinical trials. The purpose is to protect the rights and interests of the subjects. The focus of the review is the pre-clinical research, clinical benefits and risk analysis of the product.

The design of the clinical plan may affect the risks and benefits that the clinical trial brings to the subjects, so the clinical trial plan is one of the contents of the review of the clinical trial approval application. However, the clinical trial approval process does not finalize the clinical trial plan submitted by the applicant.

Applicants can refer to the medical device clinical trial approval and communication with the review and approval personnel during the registration and declaration process, and revise and improve the clinical trial plan in accordance with the requirements of the "Medical Device Clinical Trial Quality Management Standards", and the technical review agency will also Comprehensive evaluation of the safety and effectiveness of products in the subsequent review and approval process