How to define the indication for your product in China?
To successfully obtain the NMPA approval, one must provide an indication for your product that the NMPA reviewer can accept. As a foreign product, the NMPA reviewer usually asks you to provide the same indication as your home country’s approval. For example, a device using US FDA as home country clearance/approval shall not submit indications using for European approval unless the US and EU indications are the same, or the EU indication is more accurate than the US indication. NMPA reviewer does not accept indication that is out of the scope of your home country approval.
Takeaway: Green Innovation Registration Pathway does not require home country approval for the products
How to determine the performance indicators in the PTR?
In the registration dossier CH3.5.01, it is required to provide the basis for determining the performance indicators in the Product Technical Requirements (PTR). The manufacturer shall provide the Verification and Validation Report instead of the factory inspection report. NMPA reviewers often ask the applicant to explain how the performance indicators were defined in the PTR during the supplementary phase. To avoid such issues, BradyKnows will refer to both Chinese standards and the client’s V&V reports while drafting the PTR to ensure that the performance indicator is compliant and retrievable.
Takeaway: The performance indicators listed in the PTR could be considered during type testing, hospital bidding, random national inspection, and even be referenced by the stability study reports in the research materials.
Self-testing vs. Type-testing in China
When using self-testing report to replace a type testing report, the following requirements need to be considered:
- Make sure that the self-testing report refers to the current Chinese standards that are acceptable by the NMPA
- The lab where the self-testing will be conducted should possess the corresponding qualifications, tools, and personnel per NMPA requirements and guidelines.
- On July 23, 2021, the China NMPA issued the further modified draft guidance on the Self-testing of Medical Devices for China Registration based on previous comments collected from the public. NMPA is now releasing the second draft guidance for public opinions. The final version of the guidance has not been released yet.
Takeaway: It is recommended to perform self-testing at your local laboratories with the help of consultants who are experts in running type-testing in China. There are a lot of details to consider making sure your self-testing reports are compliant with NMPA requirements.
Make sure you get the real registration strategy but not a quotation
Registration strategy is a roadmap to the success of NMPA approval. It relies heavily on the input information provided by the manufacturer and the experience of the consulting company from the perspective of the registration process, cases of similar products approved in China, the mastery of past and current regulations, and the judgment of new policies. A qualified consulting company should help clients find a balance between the client’s needs and NMPA requirements at the strategy phase, such as the registration unit, indication, clinical requirements/pathways, standards, testing requirements, and any potential risks along with the registration. The consulting company shall also be able to communicate with the NMPA reviewer on behalf of the manufacturer.
Takeaway: Some consulting companies only provide a simple quotation disguised as a registration strategy, which will be revised or even overturned in the later registration process.
Active Medical Device Lifetime vs. Passive Medical Device Shelf-life
China NMPA requires medical device manufacturers to provide the product lifetime or shelf-life and related research material to support such claims.
For active medical devices, the lifetime can be determined by key component test, whole machine test, post-marketing experience data, or choose the most suitable one for your product.
For passive medical devices, the shelf life can be determined by real-time or accelerated aging tests. In the test, we should use three batches of products and pick three checkpoints. At each checkpoint, tests from the Product Technical Requirements (PTR) should be performed to examine the product’s performance.
Takeaway: Currently, it is unlikely to obtain NMPA approval without providing the lifetime or shelf-life research materials.
How to register medical device consumables?
Active medical device consumables can be registered independently. In most of cases, commonly used consumables should not be included in the registration unit and are not included in the registration unit. For consumables of particular use, we need to refer to relevant NMPA guidance.
Takeaway: Medical device consumables in the same sterile packaging might be registered as one single registration unit.
Smallest sales unit vs. registration unit
Smallest sales unit and registration unit are two different concepts. As part of the registration dossier, NMPA requires manufacturers to provide the label sample of the smallest sales unit. We usually need to modify the label as per NMPA requirements.
Takeaway:NMPA has a guideline for the determination of a registration unit for medical device registration. Do not confuse the concepts of the smallest sales unit with the registration unit.
Device-based combination product vs. Drug-based combination product
In China, combination products are defined as a single entity that consists of both drug and medical devices. If the medical device plays the leading role, it will be classified as a device-based combination product. Otherwise, it will be classified as a drug-based combination product. NMPA has issued a draft guideline for the registration review of Device-based combination products. It is also recommended to submit a request to NMPA to get the official classification for your combination product.
Takeaway: The drug part of the device-based combination product should be already approved in China.
Pre-submission supplementary notice vs. post-submission supplemental notice
When you submit the registration dossier to NMPA, the reviewer will perform a preliminary review. You will likely receive a pre-submission supplementary notice at this stage. It is also expected that you will receive several pre-submission requests until the reviewer thinks you are eligible for official submission acceptance. There is no due date for addressing the pre-submission requests. After official acceptance, you need to pay the application fee, and the first-round technical review will be performed. After several months, you will receive post-submission supplemental notice from the reviewer, for which you will have one-year time limit to address all the issues.
Takeaway: The reviewer who performs the pre-submission review is the same reviewer for the official technical review. As per NMPA statistics, an applicant receives 2.73 pre-submission supplemental notices on average.
What are the requirements for product labels in a clinical trial?
The product label for clinical trials should indicate “Only Use for Clinical Trial.” Product label verification is an important audit step for hospital QC in clinical trials.
Takeaway: Inappropriate descriptions on product labels for clinical trials, such as “NOT FOR HUMAN USE” or “NOT FOR CLINICAL USE”, should be avoided.
How many sites should be considered for a medical device clinical trial?
Single site is not recommended for medical device clinical trials. As per China GCP requirements, at least two sites should be considered for clinical trials in China. Please note that the China Fast Track pathway offers great opportunities to discuss with NMPA on protocol design, site selection, sample size, etc.
Takeaway: Consider multi-center study design when planning a clinical trial in China
How to determine the sample size for medical device clinical trials?
The determination of sample size in a medical device clinical trial requires comprehensive understanding in the related medical field, study design, statistical methodology, information collected on the subject device, threshold established for alternative treatment modalities, country-specific regulation, overall global regulation, etc. BradyKnows will assess all available information on the investigational product and work closely with PIs and statisticians to develop a reasonable and justifiable sample size for your planned study in China.
Takeaway: Sample size determination is a complex process that requires input from multiple professional areas.
What is the HGRAC (Human Genetic Resource Administration of China) application process in China?
As per Regulation on the Administration of Human Genetic Resources (State Council, Order No. 717, effective since July 1, 2019), the Ministry of Science and Technology of China (MOST) is responsible for administering HGR materials and information. The sponsors involving foreign stakeholders should apply to HGRAC filing and obtain approval from MOST.
Takeaway: HGRAC filling, or approval is legally binding in China.
What is the AE/SAE definition and reporting requirements in China?
Adverse events: unfavourable medical events that occur during clinical trials, regardless of whether they are related to experimental medical devices.
Serious adverse events： deaths or serious deterioration of health that occur during clinical trials, including fatal diseases or injuries, permanent defects of body structure or body function, need for hospitalization or prolonged hospitalization, and need for medical treatment or surgery Intervention to avoid permanent defects in body structure or body function; events such as fatal distress, fatal death, or congenital abnormalities or congenital disabilities.
In China, CTCAE (Common Terminology Criteria for Adverse Events) is usually used for judging AE severity as Grade 1, Grade 2, Grade 3, Grade 4, and Grade 5. All AEs should be recorded in the Original Medical Record and CRF in a timely and accurate manner. SAE should be reported to the GCP office of the clinical study site, IRB, local NMPA, and local Health Commission within 24 hours.
Takeaway: SAE report is of a stringent timeframe, which should be done in 24 hours.
Do I need to report to the China NMPA for adverse events that occur overseas?
For NMPA approved products in China, an adverse event shall be reported to NMPA if it causes or is likely to cause serious injury or death.
Refer to Article 27 of the “Administrative Measures for the Monitoring and Re-evaluation of Medical Device Adverse Events” (Order No. 1 of the State Administration for Market Regulation): the agent designated by the foreign certificate holder and the certificate holder of a domestic medical device shall report within 30 days from the date of discovery or awareness.
Takeaway: Adverse events for approved in China occur overseas should be reported to NMPA within 30 days since awareness.
Do I need to report to the China NMPA for recall/field action that occurs overseas?
When a medical device is registered and marketed in China, even if the Chinese market is not affected, it still needs to be reported to the NMPA.
Refer to Article 6 of the Measures for the Administration of Medical Device Recall: The agent designated by overseas manufacturers of imported medical devices in China shall promptly report the relevant information about implementing medical device recalls abroad to the State Food and Drug Administration.
Takeaway: Recall/field action for approved in China that occurs overseas shall report to NMPA.
The validity period of the medical device registration certificate has expired. Is this medical device still available for sale?
If the production date of the medical device is within the validity period of the expired registration certificate, it can be sold. Approved medical devices for registration refer to medical devices consistent with the contents of the medical device registration certificate and accessories and manufactured within the validity period of the medical device registration certificate.
Refer to Article 112 of the “Administrative Measures for the Registration and Filing of Medical Devices.”
Takeaway: The medical device manufactured within the validity period can be sold.
Do parts and accessories need to have Chinese labels if they are imported separately?
If the parts or accessories are medical devices, they must have Chinese labels when they are imported separately.
Refer to Article 2 of the Regulations on the Administration of Medical Device Instructions and Labels: All medical devices sold and used within the territory of the People’s Republic of China shall be accompanied by instructions and labels by the requirements of these regulations.
Takeaway: Parts and accessories need to have Chinese labels.
What is a certified product？
The production date of the product is within the validity period of the registration certificate, and it is regarded as a certified product. Imported products produced outside the valid period of the registration certificate shall be regarded as unlicensed products and cannot be imported.
Approved medical devices for registration refer to medical devices consistent with the contents of the medical device registration certificate and accessories and manufactured within the validity period of the medical device registration certificate.
Refer to Article 112 of the “Administrative Measures for the Registration and Filing of Medical Devices.”
Takeaway:On Sep 2, 2021, NMPA officially mentioned that imported products produced outside the valid period of the registration certificate shall be regarded as unlicensed products and cannot be imported.
