Under China’s regulatory framework for medical devices, innovative neurosurgical devices, due to their technical complexity and high application risks, must undergo stringent approval processes. This article, using three specific examples—neurosurgical planning software, implantable deep brain nerve stimulation electrodes, and implantable cardiac pacing electrode leads—discusses the key considerations manufacturers should address during preclinical and clinical trials. It aims to provide guidance and reference for companies engaged in the registration process for innovative neurosurgical medical devices.
This article is based on the NMPA review reports for the three devices released in October 2024. These reports serve as important references for you to understand what the regulatory authorities are thinking and evaluating during their review process. We have been following the list for the past several years and review the relevant ones for our clients’ specific products to gain more clarity and be more efficient in their submission and approval process. As NMPA standardizes and streamlines the review process for fast-track approval, domestic and overseas players can benefit from our expertise and experience.
Requirements and Considerations for Preclinical Trials
Preclinical trials form the foundation of the medical device registration and approval process. They aim to verify the design rationality and performance stability of the device through a series of standardized tests. For innovative neurosurgical devices, preclinical trials encompass multiple aspects, including product performance evaluation, biocompatibility, sterilization methods, product shelf life and packaging validation, as well as necessary animal testing. These results not only provide data to support clinical trials but are also critical in ensuring product safety and effectiveness.
1. Key Aspects and Challenges in Product Performance Evaluation
In performance evaluation, manufacturers must comprehensively assess whether the technical specifications of the device meet the design requirements and verify the stability and reliability of actual performance through experiments. For example, in the registration process of neurosurgical planning software, performance studies include key functionalities such as multimodal image fusion, 3D reconstruction, and stereotactic parameter calculation. These technical details are directly related to the precision of surgical planning by clinicians. As such, related tests must cover accuracy testing, operational efficiency assessments, and cybersecurity validation. Applicants must submit detailed technical materials and test reports following the Guideline for Medical Device Software Registration to ensure the controllability and safety of software design and development.
For implantable devices like deep brain nerve stimulation electrodes and cardiac pacing electrode leads, performance studies focus on the physical properties, mechanical strength, and electrical characteristics of the materials. For instance, deep brain electrodes require testing for corrosion resistance, tensile load, and bending fatigue performance to ensure stability in complex physiological environments. Additionally, electrical safety and electromagnetic compatibility tests are essential to ensure long-term safety and reliability during use. For cardiac pacing electrode leads, parameters such as connector insertion force, electrode leakage current, and drug release rates must undergo rigorous testing to meet clinical application requirements.
In summary, the key to performance evaluation lies in designing scientifically sound testing protocols tailored to the technical characteristics of the device, ensuring data completeness and consistency. For complex systems, further multi-control experiments are needed to validate the stability of performance.
2. Comprehensive Biocompatibility Studies
Biocompatibility studies are central to assessing the saf.ty of implantable medical devices. For devices in prolonged contact with human tissues or blood, such as deep brain nerve stimulation electrodes and cardiac pacing electrode leads, applicants must prioritize evaluations of cytotoxicity, sensitization, implant response, and chronic toxicity. According to the GB/T 16886 series of standards, the scope of biocompatibility studies must be comprehensive and incorporate risk analysis based on specific use scenarios to ensure that materials used in the device do not cause adverse effects under clinical conditions. For instance, the metal materials and insulating coatings of deep brain electrodes undergo rigorous toxicity assessments and long-term contact safety tests to ensure they do not damage surrounding neural tissues.
It is critical to recognize that the success of biocompatibility studies directly impacts the approval process. Therefore, manufacturers must ensure the integrity and traceability of test data and proactively address potential risks by providing experimental evidence to mitigate or control them.
3. Validation of Sterilization Processes and Packaging Design
Sterilization studies are an indispensable part of the approval process for all implantable medical devices. For neurosurgical innovative devices, sterilization processes must accommodate the complexity of the materials and structures involved. For example, deep brain nerve stimulation electrodes, including components such as electrode locking covers and tool kits, must undergo separate sterilization validations to ensure each part achieves the required sterility assurance level (SAL). Additionally, manufacturers must specify measures to control residual sterilant levels, ensuring ethylene oxide residues do not exceed the regulatory limit of 10 μg/g.
Packaging design related to sterilization is equally important. Whether it is the sealed packaging of neurosurgical planning software or the sterile packaging of implantable devices, manufacturers must conduct pressure resistance, puncture resistance, and sealing performance tests to ensure the product remains uncontaminated or undamaged during transportation and storage. Shelf-life validation involves accelerated aging and real-time aging tests to confirm the stability of packaging over the product’s intended shelf life.
4. Design and Execution of Animal Studies
Animal studies play a crucial role in preclinical trials, simulating physiological conditions to evaluate the safety and effectiveness of devices. Deep brain nerve stimulation electrodes use chronic pig models for 90-day implantation studies, where clinical observations, laboratory analyses, and histopathological assessments confirm that the product does not cause significant histological changes in target neural tissues. Similarly, cardiac pacing electrode leads are validated using canine models to assess their electrical performance under various pacing system conditions and MRI compatibility. These studies lay the groundwork for transitioning to clinical trials.
When conducting animal studies, manufacturers must strictly adhere to ethical guidelines, design scientifically robust research protocols for control and test groups, and ensure the validity and reliability of study results.
Requirements and Considerations for Clinical Trials
Clinical trials represent the core component of medical device registration and approval, aiming to verify the safety and effectiveness of products in real-world clinical settings. For innovative neurosurgical devices, clinical trial designs must align with the device’s intended use and target population while adhering to scientific and ethical standards.
1. Scientific Trial Design
The design of clinical trials underpins the entire study process, and its scientific rigor directly influences the credibility of trial results. For example, neurosurgical planning software adopts the equivalent device pathway for clinical evaluation, comparing the new product with previous navigation systems to assess improvements in image fusion accuracy and parameter calculation precision. Meanwhile, trials for deep brain nerve stimulation electrodes employ a prospective, multicenter, double-blind randomized controlled design, with primary evaluation metrics focusing on symptom control duration and improvements in Unified Parkinson’s Disease Rating Scale (UPDRS) scores, ensuring quantitative assessments of the product’s clinical value.
Additionally, the clinical trials for cardiac pacing electrode leads emphasize safety and effectiveness under MRI conditions. Divided into pacing system implantation and MRI compatibility studies, the trial comprehensively evaluates the device’s real-world performance. Scientific trial designs not only enhance the reliability of experimental data but also provide a standardized framework for subsequent data analysis.
2. Inclusion Criteria and Ethical Compliance
Inclusion criteria for clinical trials must align closely with the product’s intended use to ensure the generalizability of results. For example, the target population for deep brain nerve stimulation electrodes includes mid-to-late-stage Parkinson’s disease patients with levodopa-responsive symptoms. The inclusion criteria strictly limit disease duration, drug response, and severity of motor symptoms, reducing confounding factors during the trial and effectively controlling ethical risks.
Moreover, trial protocols must adhere to ethical principles, safeguarding the informed consent and safety of participants. For MRI-related clinical trials, detailed contingency plans must be in place to address potential adverse reactions.
3. Data Collection and Analysis
Comprehensive data collection covering all evaluation metrics is essential, and scientific statistical analysis is critical to validating the superiority or non-inferiority of the product. For instance, in the clinical trials of deep brain nerve stimulation electrodes, the analysis of ITT and PPS datasets demonstrated significant improvements in symptom control duration compared to the control group. Similarly, the analysis of changes in pacing thresholds after MRI scans confirmed the safety of cardiac pacing electrode leads under MRI conditions.
Long-term follow-up data are an important component of clinical trials for innovative medical devices. In the deep brain nerve stimulation electrode trial, the longest follow-up lasted five years, dynamically observing UPDRS scores and adverse event rates to provide critical evidence of the product’s long-term safety.
4. Safety and Adverse Event Analysis
Safety evaluation is a central component of clinical trials. In trials for deep brain nerve stimulation electrodes, the serious adverse event rate related to stimulation was 0.7%, demonstrating safety comparable to similar products. Similarly, adverse event analyses for cardiac pacing electrode leads during MRI scans highlighted their MRI compatibility.
Conclusion and Recommendations
The registration and approval of innovative medical devices require a comprehensive approach to preclinical and clinical trials. Manufacturers must focus on the following aspects:
- Regulatory Compliance: Strictly adhere to relevant guidelines and technical standards.
- Scientific Rigor: Ensure that experimental designs and data analyses meet statistical requirements.
- Comprehensive Data: Provide complementary preclinical and clinical evidence to substantiate the safety and effectiveness of the device.
By addressing these key areas, manufacturers can streamline the approval process, bringing innovative neurological products to market more efficiently to deliver safer and more effective medical solutions for Chinese patients.
