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Regulatory Focus™ > News Articles > 2019 > 9 > Challenges in Clinical Evaluation for the EU Versus China

Challenges in Clinical Evaluation for the EU Versus China

Posted 17 September 2019 | By Jasmin HunterMichael Yan 

Challenges in Clinical Evaluation for the EU Versus China

This article illustrates how to write a Clinical Evaluation Report (CER) based on China’s National Medical Products Administration (NMPA) guidance and how to convert and submit existing EU CER requirements for NMPA, formerly the China Food and Drug Administration (CFDA). The authors compare and contrast the process of converting an MDR compliant CER for submission in China by demonstrating the differences in requirements, outlining specific requirements for China and providing locations to the required information in MDR compliant documentation. They conclude it is possible to convert an MDR-compliant CER for submission in China if care is taken to add the necessary additional NMPA requirements. 
 
Introduction
 
Current medical device regulations in both the European Union (EU) and China require Clinical Evaluation Reports (CERs). These reports should be based on Guidelines on Medical Devices: MEDDEV 2.7/1 Revision 4, June 2016 and CFDA Technical Guidelines for the Clinical Evaluation of Medical Device (CFDA Announcement 2015 No. 14).1,2 The EU has additional clinical evaluation requirements contained in the MDR 2017/745.3 The industry has attempted to use the EU guidance - with slight modifications for CER submissions in China. However, although requirements in the guidelines between EU and China may look similar, CERs for China written using EU guidance are always rejected by Chinese authorities.
 
While this article aims at explaining the process of converting an MDR compliant CER for submission in China by demonstrating the differences in China and EU requirements, outlining specific requirements in China and providing locations to the required information in MDR compliant documentation, a brief look at the global harmonization effort for clinical evaluation is first required.
 
Global Harmonization of Clinical Evaluation Process
 
In June 2019, the following three project consultation documents4-6 were released globally by the International Medical Device Regulators Forum (IMDRF) for comments:
 
  1. Clinical Evidence: Key Definitions and Concepts
  2. Clinical Evaluation
  3. Clinical Investigation
 
The consultation of the proposed update to clinical evaluation documents closed on 5 June 2019.
According to the IMDRF Management Committee Document Transmittal Record, the purpose of the project has been to promote regulatory convergence in clinical evaluation among multiple regulatory jurisdictions and to improve the effectiveness and efficiency of premarket reviews.7 This can be conducted by promoting increased global harmonization in approach and requirements on leveraging and evaluating available clinical evidence, such as from comparable devices, overseas clinical trials or any other reasonable approach. Consideration is also given to methods for reducing the number of potentially redundant clinical trials by integrating the principles of postmarket clinical follow-up and real-world evidence available in the literature and other sources.
 
To improve the effectiveness and efficiency of premarket review of clinical data on a global scale, the Global Harmonization Task Force (GHTF) updated the following documents essential to the process:
 
  1. GHTF SG5 N1R8: Clinical Evidence: Key Definitions and Concepts8
  2. GHTF SG5 N2R8: 2007 Clinical Evaluation9
  3. GHTF/SG5/N3: 2010 Clinical Investigations10
 
The drafts now reference guidance documents from the China CFDA, the European Union (EU) and the US Food and Drug Administration (FDA) on clinical evaluation and acceptance of (overseas) clinical trial data.
 
China, as an IMDRF member and president for the current cycle (starting in 2018), proposed the global harmonization project for clinical evaluation. After approval by all IMDRF members, NMPA appointed a Working Group Chair. For first time China, as project sponsor, put forward a new proposal, showing how the role of medical device supervision in China has changed from participation in an international effort to global leadership.
 
According to working group chair, Liu Yinghui, deputy director of clinical and biostatistics department of Center for Medical Device Evaluation, NMPA, the reason China wants to lead the project of clinical evaluation is to promote globalization, science, standardization and rationalization of Chinese laws and regulations by learning from international experience. “On the other hand, we also want to give some thoughts and research results on clinical evaluation to our international counterparts for reference," she said, adding that to better update the existing documents they collected more than 340 clinical evaluation-related documentation from IMDRF, GHTF and other member states authorities.
 
The expected release date of the updated clinical evaluation documents will be September 2019. The outcomes will be implemented into Chinese regulations and guidelines afterward. The EU is being pressed to accept these documents once officially published. This would be good news for industry, especially for global medical device companies, as they can follow the harmonized guidelines to compile their clinical evaluation reports, generate clinical data and use them for different regulatory agencies across the globe to reduce management costs and enhance product safety and effectiveness. However, it is not clear if the EU’s interpretation of the IMDRF guidance will be similar enough to China’s to allow the same documents to be used in both regulatory environments.
 
Comparison of CER Requirements for the EU and China
 
While both regulatory frameworks allow equivalent devices to be used as a basis for clinical data for a new device, the subsequent steps to compliance and documentation differ between the EU and China. Key differences include:
 
The EU requires updating clinical evaluation documentation throughout a device’s lifetime. Doing this requires Postmarket Clinical Follow-up (PMCF). While PMCF is not required in China, an update to the CER is required for a design change submission, however.
China also requires Chinese language literature sources and clinical data from the Chinese population.
 
Table 1 provides a detailed comparison between Chinese CER requirements and EU CER requirements and the different concepts concerning clinical data and analysis.
 
Table 1. Comparison Between Chinese CER Requirements and EU CER Requirements
Required Information China CER (Technical Guidance on Clinical Evaluation of Medical Devices) MEDDEV 2.7/1 Rev. 4/MDR 2017/745
Equivalent Device The equivalent device has to be approved in China, the comparison items with the equivalent device shall include, but not be limited to the items listed in Annex 2 of the guidance (Table 2), including the qualitative and quantitative data, the verification and validation results. The similarities and differences between the two products should be described in detail.
 
Clinical, technical and biological characteristics shall be taken into consideration for the demonstration of equivalence. The only clinical data considered as relevant are the data obtained when the equivalent device is a CE-marked medical device used in accordance with its intended purpose as documented in the IFU. Exceptions can be considered. (Appendix: A1 of the MEDDEV).
 
The MDR, has added requirements for clinical for consideration of the user and biological equivalence in relation to duration of contact with the human body and degradation products and leachables in the materials used (MDR Annex XIV Part A).
Evaluation Approach The clinical evaluation approach in China is primarily related to device equivalence.  If an equivalent device cannot be found, a clinical trial is required. Equivalence must be supported by nonclinical studies, and/or clinical literature data, and/or clinical experience data, and/or clinical trial data conducted in China (now overseas clinical trial data is also acceptable). See Workflow 1. The Clinical evaluation process requires a Clinical Evaluation Plan (CEP) with a literature search protocol that includes search terms and databases to be used with a justification provided. Under the MDR, a clinical development plan is also required (Annex XIV Part A point 1). This can be part of the CEP or a separate document. The clinical evaluation should then be documented in a Clinical Evaluation Report (CER).
 
Clinical evaluation based on equivalence to another manufacturer’s device can be used in the EU. The MDR requires manufacturers of Class III devices to have a contract in place with another manufacturer, the original clinical evaluation has been performed in compliance with requirements of the MDR and the manufacturer of the device under evaluation provides clear evidence thereof (Article 61 point 5) in order to claim equivalence.
 
Under the MDR, a clinical evaluation requires consideration of currently available alternative treatment options for the same clinical purpose. The clinical evaluation should be updated throughout the lifecycle of the device (Article 61 points 1, 3 and 11). Class III devices require clinical investigations, except for devices that meet the requirements of points 4 and/or 6 in Article 61.
 
Article 61 point 10 of the MDR, provides exemption and direction for devices that do not require clinical data.
Identification/Appraisal of Pertinent Data Pertinent data including:
  • Data sets of clinical study
  • Data sets of complaints and adverse events
  • Data sets of corrective measures associated with clinical risks
  • Data sets of Chinese population
  • Comprehensive evaluation and conclusion of multiple data sets
  • Data of clinical trials conducted in China
  • Other supporting documents
 
Appraisal of the literature: See Workflow 2.
 
Requirements of Literature Search and Screening see Annex 5 of the guidance, in which the requirements of search database, search means, search terms and logical relationship of search terms, procedure and criteria of literature screening, and the output of literature search and screening results are described.
Pertinent data including:
  • All premarket clinical investigations
  • All clinical data generated from risk management activities and the Post Market Surveillance (PMS) programs
  • Relevant pre-clinical studies
  • Clinical data relevant to the device under evaluation, which are data that relate either to the device under evaluation or to the equivalent device (if equivalence is claimed)
  • Current knowledge/the state of the art
  • Literature search strategy
 
Appraisal of the pertinent data:
  • Criteria for determining the methodological quality and the scientific validity of each data set.
  • Criteria for determining the relevance to the clinical evaluation
  • Criteria for weighting the contribution of each data set to the overall clinical evaluation
 
* There are detailed descriptions on how to conduct the appraisal (Ch 9.3 of MEDDEV 2.7/1 Rev 4).
Analysis and Evaluation Both a device under evaluation and an equivalent device need to be analyzed using the pertinent data. Analysis and evaluation of:
  • Quality Evaluation of Data
  • Establishment of Data Sets
  • Statistical Analysis of Data
  • Data Evaluation
 
Based on the analysis results of different data sets, the applicant should evaluate whether the registration device could reach the expected performance in normal conditions of use, and whether the risks are acceptable balanced with the expected benefits.
To demonstrate compliance, the evaluators should:
  • Use sound methods
  • Make a comprehensive analysis
  • Determine if additional clinical investigations or other measures are necessary
  • Determine PMCF needs
  • Consider both favorable and unfavorable data (MDR Annex XIV Part A Point 4)
 
The goal of the analysis is to determine if the appraised data sets available for a medical device collectively demonstrate compliance with each of the general safety and performance requirements pertaining to the clinical performance and clinical safety of the device, when the device is used according to its intended purpose.
* There are detailed descriptions on the evaluation considerations (Ch 10 of the MEDDEV).
Evaluation Report A clinical evaluation report should be prepared after completion of the clinical evaluation and should be submitted as a part of the clinical evaluation materials during registration application. The report must strictly follow the format in the guidance (Annex 1 - Annex 8). A clinical evaluation report shall be compiled to document the clinical evaluation and its output.
 
A suggested format for the clinical evaluation report is located at Appendix A9 of the MEDDEV (clinical evaluation report - proposed table of contents, examples of contents).
 
The clinical evaluation plan, clinical development plan, and clinical evaluation report should be submitted as part of the technical documentation as described in the MDR in Annex XIV Part A Point 4.
The highest weighted literature needs to be provided as attachments of the evaluation report.
PMS/AE/recall data needs to be provided as attachments of the evaluation report.
Clinical study report/clinical use data need to be provided as attachments of the evaluation report.
The report should include references to literature-based data and full text articles of sources included in the evaluation, as well as the titles and investigational codes (if relevant and available) of any clinical investigation reports, with cross-references to the location in the manufacturer’s technical documentation.
* The clinical evaluation needs to be submitted as part of the new registration or change registration, there is no channel to update the CER standalone. The practice approach is to write or update the CER with the submission strategy. The amount of information may differ according to the history of the device or technology. Where a new device or technology has been developed, the report would need to include an overview of the developmental process and the points in the development cycle at which all clinical data have been generated. All of the clinical evaluation documentation (CEP, CDP and CER) should be updated throughout the lifecycle of the device.







 

 

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Clinical Evaluation Process in China

Similar to EU requirements, clinical data requirements in China are broken down by device classes, with Class II and III devices requiring clinical data. In China, Class I devices require only a basic clinical description. The process begins with a review of the New Device Clinical Trial Exemption Catalogues. These catalogues have been available since 2014 and new ones are routinely published. The catalogues contain a list of product types that do not require clinical trial data or clinical evaluation report. Instead, documentation of two comparisons is required, the first being a basic comparison of the product under evaluation with a similar product type listed in the catalog. The second is a comparison of the device under evaluation with an equivalent device approved in China. Figure 1 provides an overview of the clinical evaluation process in China.

Figure 1. Clinical Evaluation Process in China

Hunter-fig-1-(2).png

 
Table 2 summarizes the requirements for establishing equivalence to a device already approved in China. If the differences between the two devices impact safety, then a clinical trial is required. It should be noted that there is a “push” for multi-use devices, making sterilization an important element in the approval process.
 
Table 2. The Comparison Items of Device Under Application and the Equivalent Device
ITEM # Active Medical Device Non-Active Medical Device
1 Basic principle (operation and mechanism) Basic principle
2 Components (composition and core parts) Components
3 Manufacturing process
4 Material that contact with human body (e.g., material grade number, animal origin material, allogeneic material, pharmaceutical ingredients, biologically active substances and standards the materials comply with.
5 Technical requirements (performance and features) Technical requirements
6 Safety evaluation (e.g., biocompatibility, biosafety, electrical safety, radiation safety, etc.) Safety evaluation (e.g., biocompatibility, biosafety, etc.)
7 Software core features Applicable national/industry standards
8 Applicable national/industry standards Intended use (intended population, intended treatment part, way of contact with human body, indication, applicable disease stage and extent and intended environment)
9 Intended use (intended population, intended treatment part, way of contact with human body, indication, applicable disease stage and extent, and intended environment) Operation method
10 Operation method Contraindication
11 Contraindication Precautions and warnings
12 Precautions and warnings Delivery status
13 Sterilization/disinfection method
14 Packaging
15 Label
16 Instruction for use
 
Devices meeting the equivalency requirements in Table 2 should have a clinically exempt CER, which has similar literature search and reporting requirements as listed in MEDDEV 2.7/1 Rev 4. Workflow 1 and 2 demonstrate the process for CERs written for China. The manufacturer will have to create a Product Technical Requirement (PTR) document to set up required testing for performance and safety (verification and validation) at approved facilities in China.
 
For acceptance, devices requiring a clinical trial and with data generated outside of China will be reviewed on a case-by-case basis. The NMPA estimates that 30% of these devices will require a clinical trial. Hospital sites no longer need to be certified. The sponsor must put in a request to the local/provincial NMPA office to initiate a clinical trial. Devices containing human blood or organ- derived products require one to three months for approval of a trial. The trial requires a clinical research coordinator and the implementation of Helsinki ethical principles.
 
Workflow 1. Evaluation Approach
Hunter-Workflow-1-(1).png


 
Workflow 2. Literature Screening Procedure

Hunter-Workflow-2-(1).png

 
Conclusion
 
Adapting EU Documentation for Submission in China
 
Without success, many manufacturers have submitted EU formatted CERs for acceptance in China. There are many reasons for this rejection, including the literature source requirements and the ethnicity of the patient population presented in required clinical data. However, it is possible to convert an MDR compliant CER for a submission in China if care is taken to add the necessary additional requirements. Figure 2 demonstrates how to effectively use sections of technical documentation formatted for the EU for a submission in China.
 
Figure 2. Effective Conversion of an MDR Compliant CER for China
Hunter-fig-2-(1).png


References
 
  1. MEDDEV 2.7/1 Rev 4. Clinical Evaluation: a Guide for Manufacturers and Notified Bodies Under Directives 93/42/EEC and 90/385 EEC. https://www.qarad.com/Data/Documents/z26rve9b/41/ODM017---27_1-rev4-Clinical-Evaluations-June-2016.pdf. Accessed 3 September 2019.
  2. China CER (Technical Guidance on Clinical Evaluation of Medical Devices). http://www.michaelyan.online/2019/06/11/china-cer-technical-guidance-on-clinical-evaluation-of-medical-devices/. Accessed 3 September 2019.
  3. Europe’s Medical Devices Regulation. MDR 2017/745. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745. Accessed 23 September 2019.
  4. GHTF SG5 N1R8: Clinical Evidence – Key Definitions and Concepts. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n1r8-clinical-evaluation-key-definitions-070501.pdf, Accessed 3 September 2019.
  5. GHTF SG5 N2R8: 2007 Clinical Evaluation. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n2r8-2007-clinical-evaluation-070501.pdf. Accessed 3 September 2019.
  6. GHTF/SG5/N3: 2010 Clinical Investigations. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n3-clinical-investigations-100212.pdf. Accessed 3 September 2019.
  7. Draft Document International Medical Device Regulators Forum: Requirements for Regulatory Authority Recognition of Conformity Assessment Bodies Conducting Medical Device Regulatory Reviews. IMDRF GRRP Working Group. 27 June 2019. http://www.imdrf.org/docs/imdrf/final/consultations/imdrf-cons-rrar-cabc-mdrr.pdf. Accessed 3 September 2019.
  8. Op cit 4.
  9. Op cit 5.
  10. Op cit 6.
 
About the Authors
 
Jasmin Hunter is a clinical and regulatory affairs consultant at Qserve Group US, Inc. Qserve provides a practical approach to fulfilling EU MDR, US FDA and Chinese NMPA requirements. Hunter specializes in clinical requirements for the EU MDR and US FDA 510K applications. In addition to her medical writing expertise, Hunter has more than 20 years of experience generating and evaluating data for pharmaceuticals, IVDs and medical devices. Currently, she has more than eight years of experience designing and implementing clinical evaluation strategies for CE certifications for a variety of medical devices. She can be contacted at jasmin.hunter@Qservegroup.com.
 
Michael Yan is a consultant for Qserve Group China. He is part of the Chinese Regulatory Affairs team providing CE certification and CFDA registration. Areas of expertise include regulatory strategy, design verification and CER writing. Yan has more than 12 years of experience in the regulatory affairs sector, with a major focus on medical devices industry working primarily in industry. As RA specialist, he has strong experience with product registration for CFDA, FDA and CE certification. He can be contacted at Michael.Yan@Qservegroup.com.
 
Cite as: Hunter J and Yan M. “Challenges in Clinical Evaluation for the EU Versus China.” Regulatory Focus. September 2019. Regulatory Affairs Professionals Society.

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