Technical Guidelines for Clinical Evaluation on Medical Devices

Transcription

1 Appendix Technical Guidelines for Clinical Evaluation on Medical Devices I. Preparation Objective The clinical evaluation of medical devices refers to the process for conforming whether the products meet the operating requirements or range of application carried out by the registration applicants with the clinical literature, clinical experience data and clinical trials. The Guidelines are designed to provide technical guidance for the registration applicants to conduct the clinical evaluation, and for food and drug administration to review the clinical evaluation materials. II. Legal Basis (I) Regulation on the Supervision and Administration of Medical Devices (Decree of the State Council, No. 650); (II) Measures for the Administration of Registration of Medical Devices (Decree of China Food and Drug Administration, No. 4); (III) Relevant provisions on clinical trials quality management of medical devices. III. Range of Application The Guidelines applies to the clinical evaluation on medical devices of class II and class III in the process of registration application, but not applies to the clinical evaluation on IVD reagents managed as medical devices. If there are technical guidelines for clinical evaluation aiming at specific products, the clinical evaluation on corresponding products shall follow the relevant requirements. IV. Basic Principles The clinical evaluation shall be comprehensive and objective, and shall collect the relevant data with various means such as clinical trials; the clinical performance and safety data, as well as both positive and negative data collected in the clinical evaluation process shall be included in the analysis. The depth and breadth of clinical evaluation, the required data type and amount shall match the design features, key technologies, range of application and degree of risk of the products, and shall also match the level and extent of non-clinical studies. The clinical evaluation shall confirm the products range of application (such as the target people, body parts, mode of contact with human body, indication, degree and stage of the disease, operating requirements, and operating environment), methods of application, contraindication, preventive measures, warning information and other clinical use 1

2 information. The registration applicants shall make the following conclusion through the clinical evaluation: Under normal conditions of use, the products can achieve the desired performance; compared with the prospective benefits, the risk of products is acceptable; both the clinical performance and safety of the products are supported by appropriate evidence. V. Requirements of Clinical Evaluation on Products in the Catalogue of Medical Devices Free from Clinical Trials As for the products being listed in the Catalogue of Medical Devices Free from Clinical Trials (hereinafter referred to as the Catalogue), the registration applicants shall submit the information of comparison between the relevant information of products and the contents of the Catalogue, and the explanation of comparison between the application products and the medical devices in the Catalogue getting the domestic registration. The requirements on the detailed clinical evaluation data that shall be submitted are shown as follows: (I) Submit the information of comparison between the relevant information of products and the contents of the Catalogue; (II) Submit the explanation of comparison between the application products and the medical devices in the Catalogue getting the domestic registration; the explanation of comparison shall include Table of Comparison between Application Products and Medical Devices in the Catalogue Getting the Domestic Registration (see Appendix 1) and the corresponding supporting data. The submitted materials mentioned above shall be able to prove that the application products are equivalent to those listed in the Catalogue. If such equivalence cannot be proved, the corresponding work shall be carried out in accordance with other requirements of the Guidelines. VI. Requirements for Analysis and Evaluation with Data Getting from Clinical Trials of Medical Devices of the Same Variety or Clinical Application (I) Medical devices of the same variety 1. Definition of medical devices of the same variety Medical devices of the same variety refer to the products after domestic registration being basically equivalent to the application products in aspects of the basic principles, structural composition, making materials (Active products use the making materials contacting with the human body), manufacturing technique, performance requirements, safety evaluation, the applicable national/industrial standard, and intended applications. The difference between the application products and medical devices of the same variety will not have negative effects on safety and effectiveness of the products, and they can be regarded as being basically equivalent to each other. 2

3 2. Determination of medical devices of the same variety The registration applicants shall conduct the analysis and evaluation with the data getting from the clinical trials or clinical application for medical devices of the same variety; if the safety and effectiveness of the medical devices are to be proved, the application products shall first be compared with one or more medical devices of the same variety to prove that they are basically the same. The items for comparing with each medical device of the same variety shall include but not limited to the items listed in Appendix 2; the comparing contents include the qualitative and quantitative data, and the verification and affirmation result, whose uniformity and difference shall be described in details. As for the matter whether the difference has an adverse influence on safety and effectiveness of the products shall be verified and/or determined with the data of the application products, such as the non-clinical research data, clinical literature data, clinical experience data, and the data of clinical trials carried out in China aiming at the difference. The collection, analysis and evaluation of the corresponding data shall conform to (III) and (IV) of this part and requirements of the relevant appendixes. The clinical trials shall conform to the related requirements of GCP. The registration applicants shall provide the information of comparison in the form of table (see the format in Appendix 3). If there are inapplicable items, the reasons shall be explained. (II) Evaluation Path See the specific evaluation path in Appendix 4. (III) Collection of data getting from clinical trials or application for medical devices of the same variety The data getting from clinical trials or application (hereinafter referred to as clinical data) can be from scientific literature published in China and foreign countries and legally acquired data, including clinical literature data, and clinical experience data. The registration applicants can choose the appropriate data source and collection method according to the practical conditions of the products. 1. Collection of clinical literature data As for the collection of the clinical literature data, the literature shall be accurate and complete. See the factors of literature search and screen in Appendix 5. Before literature search, the literature search and screen scheme (see the contents and format in Appendix 6) shall be prepared. After completing literature search and screen, the literature search and screen report (see the contents and format in Appendix 7) shall be prepared. The clinical literature search and screen shall be repeatable. The literature search and screen personnel shall have the related professional knowledge and practical experience. 2. Collection of clinical experience data 3

4 The collection of clinical experience data shall include the collection of the data of completed clinical researches, adverse events, and corrective actions being related to clinical risks. (1) Collection of data of completed clinical researches According to the design types, clinical researches can be divided into prospective research, retrospective research, randomized controlled research, non-randomized controlled research, single group research, and case report, etc. The registration applicants shall collect and provide the comment of Ethics Committee (if applicable), the clinical research scheme and clinical research report. (2) Collection of data of adverse events The registration applicants shall collect the data of adverse events in the complaint and adverse event database established by the registration applicants, and those issued by regulatory institutions in various countries, such as the Bulletin of Medical Device Adverse Event Information and Medical Device Alert issued by China Food and Drug Administration, as well as MAUDE issued by FDA and MDA issued in the United Kingdom. The registration applicants shall provide the information of the quantity of complaints and adverse events of medical devices of the same variety, the classification of reasons, the quantity of complaints and adverse events due to various reasons, and whether the complaints and adverse events are related to the products. As for the severe complaints and adverse events, the event description, reason analysis, processing mode and other specific information shall be provided in the form of tables. As for the application products, the time-to-market in different countries, accumulated sales volume, severe adverse event processing results and other specific information shall be provided. (3) Collection of data of corrective actions being related to clinical risks The registration applicants shall collect and provide the specific information of corrective actions being related to the clinical risks (such as recall, announcement, and warning), and the adopted risk control measures. (IV) Analysis and evaluation on clinical data of medical devices of the same variety 1. Evaluation on data quality The registration applicants shall classify the data included into the analysis according to the recognized clinical evidence level evaluation standards (such as the clinical evidence level evaluation standard formulated by Oxford Centre for Evidence-based Medicine). As for the clinical data being unfit for the effectiveness evaluation, they, if applicable, can be used for the product safety evaluation. 4

5 2. Establishment of data set According to the difference in data type and data quality, the collected clinical data can be summarized into several data sets. The registration applicants can also establish the data sets according to different evaluation objectives, for example, there are racial differences in clinical performance and/or safety of some products, so in order to evaluate the performance and/or safety when the products are used by Chinese people, the data sets for Chinese people can be established. 3. Statistic analysis of data The appropriate data analysis method shall be selected to carry out the statistic analysis for different data sets. The analysis method for data sets formed by several research results includes the qualitative analysis and quantitative analysis. 4. Data evaluation Synthesize the analysis results of different data sets to evaluate whether the products can reach the predicted performance under regular service conditions; and whether the risks of products are acceptable comparing with the expected benefits. (V) Clinical evaluation report After the completion of the clinical evaluation, the clinical evaluation report (see the format in Appendix 8) shall be prepared, and shall be submitted ad the clinical evaluation data during the process of application for registration. VII. Relevant requirements of clinical trials As for the medical devices whose clinical trials are carried out in China, the clinical trials shall be conducted in the qualified clinical trial institutes in accordance with the requirements of the good clinical practice of clinical trials for medical devices. In the process of making the application for registration, the registration applicants shall submit the clinical trial scheme and clinical trial report. As for the imported medical devices whose clinical trials are carried out in overseas countries, if their clinical trials conform to China's relevant laws and regulations and the corresponding technical requirements in the registration guidelines, such as the sample capacity, control group selection, evaluation index and principles, therapeutic evaluation index, and other requirements. When making the application for registration, the registration applicants can submit the clinical trial data that is submitted to the overseas departments in charge of medical devices when the products are sold in market. The data shall at least include the comments of the Ethics Committee, clinical trial scheme and clinical trial report, and the applicants shall also submit the relevant supporting data for demonstrating whether there are racial differences in the clinical performance and/or safety of the products. The clinical trials shall be conducted in China for medical devices listed in the Catalogue 5

6 of Medical Devices of Class III Needing Clinical Trial Approval. Appendix: 1. Table of Comparison between Application Products and Medical Devices in the Catalogue Getting the Domestic Registration 2. Comparing Items between Application Products and Medical Devices of the Same Variety 3. Format of Table of Comparison between Application Products and Medical Devices of the Same Variety 4. Analysis and Evaluation Path of Data Getting from Clinical Trials of Medical Devices of the Same Variety or Clinical Application 5. Literature Searching and Screening Requirements 6. Literature Search and Screen Scheme 7. Literature Search and Screen Report 8. Report on of Analysis and Evaluation with Data Getting from Clinical Trials of Medical Devices of the Same Variety or Clinical Application 6

7 Appendix 1 Table of Comparison between Application Products and Medical Devices in the Catalogue Getting the Domestic Registration Items Medical Devices in the Catalogue Application products Difference Overview Supporting Data of Basic principles (Working principles/action mechanism) Structural composition Making materials of the products or materials contacting with human body Performance requirements Sterilization/disinfecti on method Range of application Application method Note: The items can be added according to the actual situations. 7

8 Appendix 2 Comparing Items between Application Products and Medical Devices of the Same Variety (Passive Medical Devices) Items 1. Basic principles 2. Structural composition 3. Manufacturing technique 4. Making materials (such as material designation, material of animal origin, allogeneic material, ingredients, pharmaceutical ingredients, bioactive substances, applicable standards and other information) 5. Performance requirements 6. Safety evaluation (such as biocompatibility, and biosecurity, etc.) 7. National/industrial standards being applicable for the products Passive Medical Devices 8.Range of application: (1) Target people (2) Target parts (3) Mode of contact with human body (4) Indications (5) Applicable stage and extent of diseases (6) Usage environment 9. Application method 10. Contraindication 11. Precautions and warnings 12. Delivery status 13. Sterilization/disinfection method 14. Packaging 15. Label 16. Product Specification 8

9 Comparing Items between Application Products and Medical Devices of the Same Variety (Active medical devices) Items 1.Basic principles (1)Working principles (2) Action mechanism 2.Structural composition (1) Product composition (2) Core parts 3. Manufacturing technique 4. Materials contacting with human body (such as material designation, material of animal origin, allogeneic material, ingredients, pharmaceutical ingredients, bioactive substances, and the met standards and other information) Active medical devices 5. Performance requirements (1) Performance parameters (2) Function parameters 6. Safety evaluation (such as biocompatibility, biosecurity, electric safety, and radiation safety, etc.) 7. Software core function 8. National/industrial standards that the products meet 9. Range of application: (1) Target people (2) Target parts (3) Mode of contact with human body (4) Indications (5) Applicable stage and extent of diseases (6) Usage environment 10. Application method 11. Contraindication 12. Precautions and warnings 13. Sterilization/disinfection method 9

10 14. Packaging 15. Label 16. Product Specification 10

11 Appendix 3 Format of Table of Comparison between Application Products and Medical Devices of the Same Variety Items Medical devices of the same variety Application products Difference Overview Supporting Data of Basic principles Structural composition Note: Items shall at least include all items listed in Appendix 2. 11

12 Appendix 4 Analysis and Evaluation Path of Data Getting from Clinical Trials of Medical Devices of the Same Variety or Clinical Application Medical Device N Is it different from medical devices of the same variety? Y Collect and analyze the clinical literature and/or clinical experience data of medical devices of the same variety. Y Whether can it be proved that the difference does not have an adverse impact on the safety and effectiveness of products with the non-clinical research data, and/or clinical literature data, and/or clinical experience data, and/or data of clinical trials conducted in China aiming at the difference? N Form a clinical evaluation report and complete the clinical evaluation. The analysis and evaluation cannot be conducted with the data getting from the clinical trials or usage of medical devices of the same variety. The applicant shall submit the corresponding clinical trial data in accordance with the provisions. 12

13 Appendix 5 I. Search Databases Literature Searching and Screening Requirements The registration applicants shall choose the database according to the specific conditions of the application products/medical devices of the same variety (such as the design features and range of application), and shall also explain the reason in the scheme. The choosing of databases shall be comprehensive, and see the examples of databases that can be considered below. 1. Scientific Databases: Such as CNKI, Medline, and EM. 2. Clinical Trial Databases: Such as Cochrane Center, and ClinicalTrials.gov. 3. Systematic Review Databases: Such as Cochrane Library. 4. Specialized Databases: Such as MEDION and Bone and Joint Registration Database. II. Search Approaches, Search Words, and Logical Relations between Search Words In order to comprehensively and accurately search the clinical literature of application products/medical devices of the same variety, the choosing of search approaches, search words and the logical relations between search words shall be comprehensively considered, and the scientific searching strategy shall be made. The common search approaches include subject term search, keyword search, abstract search, and full text search, etc. The search words shall adapt to the selected search approaches; the factors to consider shall include the generic name, product name, manufacturer, basic principles, structural composition, making materials, design features, key technology, and range of application, etc. While making the logic matching of search words, the correct logical operators shall be selected to express the logical relation between search words, such as OR for expanding the search range, and AND for shrinking the search range. The search approaches, search words, and the reason for determining the logical relation between search words shall be explained in the search scheme. III. Literature Screening Process and Standards The choosing of screened literature shall be conducted according to the procedure set in Fig. 1. The registration applicants can screen the literature that may conform to the requirements according to the literature titles and abstracts; screen the literature that may be involved into the analysis according to the full text of the literature; if the literature cannot be determined to be involved into the analysis according to the full text, the writer can be connected for judging or excluding. The standards for screening literature, namely the inclusion and exclusion standards, shall be clear and operational. IV. Literature Search and Output of Search Results Literature search and output of search results shall adopt the reference form, and the format shall be consistent; the literature reference form includes the author, title, journal name, date of publishing, volume (phase), and page. Those being involved into the clinical evaluation shall offer the full text. 13

14 Figure 1 Literature Screen Process Searched Literature Read the title and abstract N Conform to the screen standards? Y Literature may be qualified Read the full text Exclusion N Conform to the screen standards? Y Involve in the analysis Uncertain Contact the author N Conform to the screen standards? Y 14

15 Appendix 6 Literature Search and Screen Scheme Product Name: Type and Specification: Range of Time: Database: Database Selection Reason: Search Approaches: Search Words: Logical Matching of Search Words: Reason for Determining the Search Approaches, Search Words, and Logical Matching of Search Words: Output Form of Search Results: Literature Screen Process: Literature Screen Standard: Reason for Making the Literature Screen Standard: Output Form of Literature Search Results: Name of Literature Search and Screen Personnel: 15

16 Appendix 7 Product Name: Type and Specification: Range of Time: Database: Search Approaches: Search Words: Logical Matching of Search Words: Output of Search Results: Literature Search and Screen Report Description of Deviation, Reason and Influence on Results: Literature Screen Process: Literature Screen Standard: Excluded Literature: Exclusion Reason: Output of Literature Search Results: Description of Deviation, Reason and Influence on Results: Note: The searched and screened literatures shall be listed in the same format, and it is suggested including the information of the author, title, journal name, date of publishing, volume (phase), and page. Signature of Literature Search and Screen Personnel: Time: 16

17 Appendix 8 Report on of Analysis and Evaluation with Data Getting from Clinical Trials of Medical Devices of the Same Variety or Clinical Application Product Name: Type and Specification: Signature of Personnel: Completion Time: 17

18 I. Determination of Medical Devices of the Same Variety See the items and format of tables of comparison between application products and medical devices of the same variety in Appendix 2 and Appendix 3. II. Evaluation Path Describe the path for evaluation. III. Analysis Evaluation The registration applicants shall select the applicable articles according to the specific conditions of the application products. (I) The application product is the same as the medical device of the same variety Explain the uniformity. (II) The supporting data proving that the difference between the application products and medical devices of the same variety does not have an adverse impact on the safety and effectiveness of products (non-clinical research, clinical literature data, and clinical experience data, etc.) 1. Non-clinical research data: (1) Overview of research; (2) Non-clinical research report, which will be provided in the form of appendix. 2. Clinical literature and data collection and analysis of the application products: Select the appropriate data source and collection method according to the specific conditions of the products. Conclude the collected data into different data sets for analysis and evaluation according to the difference in data type, data quality, and evaluation objective. Provide the complete information of various data in the form of appendix in accordance with the relevant requirements of the Guidelines. The examples of data sets are shown below: (1) Clinical research data set Data overview: Such as data source, data type, and data quality; Analysis method: Make clear the specific analysis method and reason for selection; Data analysis: including data summary, analysis process, and analysis results; Explanation and evaluation on the analysis results: Appendix: Such as the involved full text literature, comment of Ethics Committee (if applicable), clinical research scheme, and clinical research report. (2) Complaint and adverse event data set Data overview: 18

19 Analysis method: Make clear the specific analysis method and reason for selection; Data analysis: including data summary, analysis process, and analysis results; Explanation and evaluation on the analysis results: Appendix: time-to-market in different countries, quantity of complaints and adverse events, classification of reasons for complaints and adverse events, quantity of complaints and adverse events of various reasons, the information whether the complaints and adverse events are related to the products. As for the severe adverse events, the event description, reason analysis, processing mode, processing results and other specific information shall be provided in the form of lists. (3) Data set of corrective actions being related to the clinical risks Data overview: Data analysis and evaluation: Appendix: The specific information of corrective actions being related to the clinical risks (Such as recall, announcement, and warning), and the adopted risk control measures. (4) Chinese population data set Data overview: Such as data source and other information; Analysis method: Make clear the specific Analysis method and reason for selection; Data analysis: including data summary, analysis process, and analysis results; Explanation and evaluation on the analysis results: Appendix: Complete information of various data. Note: The number of data sets is not limited, and they shall be prepared by the registration applicants according to the practical situations. (5) Comprehensive evaluation on several data sets and the conclusion Research overview; Literature search and screen scheme and report; Experience data collection and analysis report. 2. Data of clinical trials conducted in China aiming at the difference: (1) Overview of trials; (2) Clinical trial scheme and clinical trial report. 3. Other supporting data: (1) Data overview; 19

20 (2) Full text. 4. Conclusion IV. Analysis of clinical trials or clinical application of medical devices of the same variety Select the appropriate clinical literature data, clinical experience data source and collection method according to the specific conditions of medical devices of the same variety. Conclude the collected data into different data sets for analysis and evaluation according to the difference in data type, data quality, and evaluation objective. Provide the complete information of various data in the form of appendix in accordance with the relevant requirements of the Guidelines. The examples of data sets are shown below (1) Clinical research data set Data overview: Such as data source, data type, and data quality; Analysis method: Make clear the specific analysis method and reason for selection; Data analysis: including data summary, analysis process, and analysis results; Explanation and evaluation on the analysis results: Appendix: Such as the involved full text literature, comment of Ethics Committee (if applicable), clinical research scheme, and clinical research report. (2) Complaint and adverse event data set Data overview: Analysis method: Make clear the specific analysis method and reason for selection; Data analysis: including data summary, analysis process, and analysis results; Explanation and evaluation on the analysis results: Appendix: quantity of complaints and adverse events, classification of reasons for complaints and adverse events, quantity of complaints and adverse events of various reasons, the information whether the complaints and adverse events are related to the products. As for the severe adverse events, the event description, reason analysis, processing mode, processing results and other specific information shall be provided in the form of lists. (3) Data set of corrective actions being related to the clinical risks Data overview: Data analysis and evaluation: Appendix: The specific information of corrective actions being related to the clinical risks (Such as recall, announcement, and warning), and the adopted risk control measures. (4) Chinese population data set 20

21 Data overview: Such as data source and other information; Analysis method: Make clear the specific Analysis method and reason for selection; Data analysis: including data summary, analysis process, and analysis results; Explanation and evaluation on the analysis results: Appendix: Complete information of various data. Note: The number of data sets is not limited, and they shall be prepared by the registration applicants according to the practical situations. (5) Comprehensive evaluation on several data sets and the conclusion Research overview; Literature search and screen scheme and report; Experience data collection and analysis report. (6). Conclusion V. Conclusion VI. Other Problems Needing to be Explained (if applicable) 21