ARTICLE SUMMARY:
State Order 739 was handed down in China last summer, delivering significant reforms in medical device regulation that the National Medical Products Administration (NMPA) is now putting into place at rapid speed. Here’s a look at the underlying principles of the reforms, including clinical evaluation updates, from Grace Palma, CEO of consulting firm China Med Device.
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Grace Palma is CEO and founder of China Med Device. With offices in Boston and Beijing, China Med Device offers overseas manufacturers a local point of contact and China-based technical, clinical, and commercial expertise, including regulatory, CRO, and commercialization turnkey solutions for medical device, IVD, CDx, and combination products. Palma, who grew up in Beijing, is a regular speaker at medtech conferences and writer for multiple journals on NMPA regulatory and clinical topics. She is also the founder of the Chinese American Heart Association. |
China NMPA is implementing rapid reforms to its oversight of medical devices, driven by State Order 739, the newly revised Regulations on the Supervision and Administration of Medical Devices that was released on June 1, 2021. The updated framework is intended to strengthen supervision with a higher scientific standard and more emphasis on globalization. China NMPA has consistently been active in releasing new regulatory guiding documents to support the reforms.
Here, we introduce some key updates from State Order 739 and the principles behind the changes. Beyond improving the efficiency of reviews and approval processes, and reducing unnecessary burdens, NMPA has been rebuilding clinical evaluation pathways. This article will provide insights on clinical evaluation pathway strategy.
Four Key Principles
State Order 739 incorporates a large array of changes to China’s regulation of devices, but most of them fit under one of four key principles that underlie the reforms:
1. Marketing Authorization Holder formalized with strict accountabilities
The Marketing Authorization Holder (MAH) system is an internationally accepted medical device supervision system, which positively impacts developers (companies and research institutions) that have limited manufacturing capabilities. Under MAH, now formally accepted in China with strict accountabilities, developers can focus on product R&D with ownership and control of marketing and outsourced production to one or multiple qualified contract manufacturing organizations. The implementation of the MAH system enables R&D departments to concentrate on development and innovation, while the contract manufacturers serve a major role within manufacturing and quality management system (QMS) compliance.
2. Streamlined approval in clinical and technical requirements to encourage innovation and reduce MAH burden
NMPA encourages and supports innovation with new regulations, including those introducing priority review and fast-track access. There are also several other reforms embedded in Order 739, relating to type testing and clinical evaluation and clinical trial management, which will reduce burdens on medical technology innovators.
Under the old system (Order 680), NMPA required that device samples be physically tested by NMPA-certified Type Testing Centers. Under 739, NMPA does not mandate any specific type of testing at authorized centers, providing the overseas manufacturer the option to perform self-testing as an alternative. This adjustment of the testing system in response to industrial development and requests from industry adds time-saving flexibility for companies.
The newly updated order also strengthens the scientific and reasonable methods applied to the clinical evaluation process to ensure the safety and effectiveness of the products. China NMPA reclassified medical devices based on a comprehensive consideration of product description and intended use. It also added certain devices to the clinical evaluation exemption list or in some cases recommended the predicate comparison pathway, allowing manufacturers to avoid the lengthy and costly clinical trials.
NMPA is also streamlining procedures for companies to launch clinical trials. For certain high-risk, Class III medical devices that used to require preapproval before clinical trial initiation, Order 739 allows implied permission to start the clinical trial. After NMPA receives the clinical trial application, the sponsor may initiate the trial after waiting 60 days, as long as it doesn’t receive a rejection or deficiency notice.
3. Complete product life-cycle supervision
Order 739 expands inspection activities, including on-site inspections, which are no longer limited to the manufacturer site. NMPA may inspect corresponding personnel as well as third parties. Additionally, the overseas inspections can apply to not only manufacturing sites, but also to overseas R&D sites.
In addition, as the regulatory system develops to be more comprehensive, NMPA is taking devices into consideration that address rare disease or are otherwise challenged with lower participation in clinical trials. For these cases, certain conditional approval systems are in place, allowing reduction in the required number of trials subjects or even outright clinical evaluation exemption.
4. Harsher violation penalties for enterprises, as well as individuals
NMPA increases the violation penalties for enterprises as well as individuals by expanding the range of fines, extending the premarket preparation time before market entry, and extending violation penalties to particular individuals within device companies, such as legal representatives.
Further, as part of the reforms, NMPA introduces Unique Device Identification (UDI) in four pilot zones. The implementation of the UDI strengthens the data connection of medical devices and therefore improves the supervision of production, operation, adverse event tracking, and sampling.
How to Determine the Best-Fit Clinical Evaluation Pathway?
NMPA encourages manufacturers to use the most effective way to demonstrate the safety and performance of medical devices. In this context, clinical trials might be exempted or replaced with a predicate comparison for Class II and Class III devices. To determine the appropriate clinical evaluation pathway, manufacturers should consider the following resources:
- Classify the product based on NMPA’s up-to-date “Medical Device Classification Catalog.”
- Determine the pathway based on “Guideline on Decision Making of Conducting Clinical Trial for Medical Devices” (released by NMPA on September 28, 2021).
- Notably, NMPA is issuing recommended clinical evaluation pathways for more and more medical device categories.
Exceptions for Clinical Trial
A major change between Order 739 and Order 680 for medical devices is the replacement of the “Clinical Trial Exempt Catalog” with the “Clinical Evaluation Exempt Catalog of Medical Device” (hereinafter referred as the “Clinical Evaluation Exempt Catalog”). Previously, for Class II and Class III medical devices in the “Clinical Trial Exempt Catalog,” a clinical trial was not required and the applicant only needed to submit a basic clinical evaluation report (CER). Now, the first thing to do when deciding the clinical pathway for China registration is to check the “Clinical Evaluation Exempt Catalog.” If the device is included in the “Clinical Evaluation Exempt Catalog,” a clinical trial is not required. But instead of a basic CER, the applicant needs to submit the comparison document between the product to be registered and both the corresponding content in the catalog andthe predicate already approved in China.
More Guidelines for Clinical Evaluation
Another important part of NMPA’s efforts to implement its new clinical evaluation framework is through guidance documents. The agency has issued seven key guidances on the topic, outlined in the following table:
| Issue Addressed |
Guidance Document |
| To initiate a clinical evaluation |
Technical Guideline for Clinical Evaluation |
| To write a Clinical Evaluation Report |
Technical Guideline for Clinical Evaluation Report |
| Is there a need to initiate a clinical trial? |
Guideline on Whether to Initiate Clinical Trial for Medical Device |
| How to start a clinical trial? |
Guideline for the Design of Clinical Trial of Medical Device |
| Submission of clinical trial data |
Guideline for Submission of Clinical Trial Data of Medical Device |
| To demonstrate equivalence |
Technical Guideline for Equivalence of Medical Device |
| To use real-world data to support clinical evaluation |
Guideline of Application of Real-World Data in Clinical Evaluation of Medical Device |
Future Outlook on China NMPA
China has undergone rapid reforms of its regulatory system for medical device supervision and those will continue to develop in 2022 and beyond. By incorporating the four mentioned principles, and encouraging more and more manufacturers to demonstrate the safety, efficacy, and performance of their products in the most effective way, NMPA is enhancing China’s review and approval system, and building toward a more scientific and rational approach to regulation.
