How Can Overseas Clinical Trial Data Be Used to Evaluate the Safety and Effectiveness of Medical Devices

In January 2018, China’s State Drug Administration issued the Technical Guiding Principles for Accepting Overseas Clinical Trial Data of Medical Devices (hereinafter referred to as the guiding principles), which clearly explained the definition, acceptance principles and requirements of overseas clinical trial data, however, in practice, how to submit overseas clinical trial data meeting the requirements of the guiding principles is still the focus of many applicants. Based on the relevant contents of the guiding principles, this paper expounds the precautions in the process of submitting overseas clinical trial data.

1.What is the overseas clinical trial data of medical devices

Before submitting overseas clinical trial data of medical devices, it is necessary to clarify the definition of overseas clinical trial data. According to the guiding principles, the overseas clinical trial data of medical devices refers to the research data generated in the process of confirming the safety and effectiveness of the medical devices to be applied for registration in China under normal use conditions in all or the same period in the overseas clinical trial institutions that meet the requirements of the country (region) where the clinical trials are carried out. Therefore, the overseas clinical trial data of medical devices accepted by China must meet at least the following two conditions:

(1)The country (region) carrying out clinical trials shall have relevant laws and regulations on clinical trial quality management, and the institution carrying out clinical trials shall meet the relevant requirements of the country (region) on clinical trial quality management;

(2)The purpose of this clinical trial shall be to confirm the safety and effectiveness of medical devices under normal use conditions, and shall be confirmatory research rather than exploratory research.

Therefore, to judge whether the overseas clinical trial data initially meet the requirements of the guiding principles, we can judge from the following aspects:

（1）Whether the applicant can provide the complete clinical trial scheme, clinical trial report, clinical trial approval (or ethical opinion) and clinical trial agreement of the clinical trial to confirm that the trial is carried out in accordance with the relevant clinical trial quality management system.

（2） Under the condition of meeting 1, judge whether the clinical trial is a “confirmatory study”, such as whether there are clear statistical assumptions in the scheme, whether there is sufficient basis for the confirmation of sample size, etc.

At present, few of the “overseas clinical trial data” meet the above two requirements at the same time. The “overseas clinical trial data” mentioned by most applicants are “clinical literature data” or “exploratory research data” of scientific research nature. Applicants are often unable to provide clinical trial plans or reports, or these studies do not have strict statistical assumptions and sample size calculation. These “overseas clinical trial data” do not meet the requirements of the guiding principles. In general, the data applicable to overseas clinical trials submitted in accordance with the guiding principles often come from clinical trials conducted by applicants to obtain approval for overseas listing.

2.How to submit overseas clinical trial data

According to the requirements of the guiding principles, overseas clinical trials can be used as clinical supporting data for clinical evaluation of the same variety, and can also be directly registered and submitted as clinical evaluation data of declared products. When overseas clinical trial data are directly used as clinical evaluation data, the applicant shall submit clinical trial scheme, clinical trial report and ethical opinions (ethical approval).If necessary, the clinical trial agreement and the clinical trial approval certificate issued by the regulatory authority of the country (region) where the trial is carried out (such as the clinical trial approval letter issued by the Ministry of health and welfare of Taiwan when the clinical trial is carried out in Taiwan) shall be submitted. At the same time, according to the requirements of Filing Review Form for Clinical Evaluation of Medical Devices (Trial), the applicant shall also submit the norms and standards or international norms and standards formulated by the relevant clinical trial ethics, laws and regulations of the country (region) where the trial is carried out. The regulations are generally the GCP regulations of the country (region), such as a trial carried out in Taiwan, when submitting clinical trial data, it is necessary to submit the Excellent Clinical Trial Benchmark for Medical Equipment at the same time.

In addition to the above data, according to the requirements of the guiding principles and the Filing Review Form for Clinical Evaluation of Medical Devices (Trial), when submitting overseas clinical trial data, it is necessary to submit the discussion and explanation of the differences between the requirements of overseas GCP and the requirements of China’s code for quality management of clinical trials of medical devices. For example, when using clinical trials carried out in Taiwan as clinical evaluation data for registration and submission, the requirements of Excellent Clinical Trial Benchmark for Medical Equipment and Quality Management Standards for Clinical Trials of Medical Devices can be summarized and compared one by one in the form of a comparison table. Generally speaking, the differences of GCP regulations in different countries (regions) mainly focus on the requirements of informed consent, the preservation of original records of clinical trials, the monitoring process of clinical trials, etc. these differences generally will not affect the results of clinical trials. However, during the comparison, attention should be paid to whether the definitions of adverse events, serious adverse events, device defects and other events involving safety evaluation are consistent with the relevant definitions in China’s Code for Quality Management of Clinical Trials of Medical Devices. If there is no clear definition of the above safety evaluation events in overseas GCP or the definition is inconsistent with China’s Code for Quality Management of Clinical Trials of Medical Devices, check whether the definition of relevant events in the test plan meets the requirements of China’s Code for Quality Management of Clinical Trials of Medical Devices. If there are still differences in relevant definition standards, it is suggested to re count and analyze the definition standards of adverse events, serious adverse events, device defects and other events involving safety evaluation in accordance with China’s Code for Quality Management of Clinical Trials of Medical Devices,.

Considering that in general, clinical trials conducted overseas are usually used for overseas registration and declaration at first, and the design, observation / evaluation end points of clinical trials may meet the regulatory requirements of the countries (regions) to be listed, but may not meet the review requirements of China, in principle, for some medical device products with specific technical guidelines in China, If overseas clinical trial data is used for registration and declaration, its clinical trial shall comply with the requirements of relevant technical guiding principles. When overseas clinical trial data are inconsistent with the requirements of relevant guiding principles in China, sufficient and reasonable demonstration basis shall be provided.

In addition to the differences in technical review requirements, according to the requirements of the guiding principles, when submitting overseas clinical trial data, it is also necessary to analyze and evaluate the applicability of clinical trial data, including ethnic differences and differences in clinical trial conditions. For example, the clinical data of Taiwan area are used to register the rigid gas permeable contact lens products for corneal shaping. Although the subjects are all Chinese, the matching process in Taiwan may be different from that in Chinese mainland. Therefore, when submitting the data of overseas clinical trials, the applicant should submit the product matching process at the same time ，and compare with the relevant standards of Chinese mainland to evaluate the impact of clinical trial conditions on clinical trial results.

Generally speaking, the basic idea of submitting overseas clinical trial data is to judge whether the clinical trial meets the basic conditions of the guiding principles. Then, in the form of a comparison table, the differences between the clinical trial management regulations, overseas clinical trial design and Chinese review standards, trial population and trial conditions are compared item by item.

The differences were demonstrated and analyzed from the aspects of disease mechanism, clinical trial data, clinical literature data and so on. On the other hand, for overseas clinical trials of diagnostic products (such as in vitro diagnostic reagents), because the test results are often affected by race, diagnostic criteria, disease prevalence, medical and health conditions and other factors, the test data are often difficult to be directly used for registration, so it is generally recommended to carry out additional clinical trials in China in order to confirm the safety and effectiveness of these products in the Chinese population.

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