To analyze the regulatory status of clinical evaluation for implantable closed-loop neurostimulators during registration submissions to the U.S. Food and Drug Administration (FDA), aiming to provide insights for the pre-market clinical evaluation of such products in China. Methods: We retrieved data on the clinical applications and mechanisms of implantable closed-loop neurostimulators, reviewed their market approval status in the U.S., and summarized and analyzed the clinical evaluation pathways and clinical trial designs for medical devices such as closed-loop spinal cord stimulation (CL-SCS) and closed-loop deep brain stimulation (CL-DBS). Results: The U.S. FDA requires closed-loop stimulators to undergo clinical evaluation via the clinical trial pathway. Clinical trial designs should be based on the intended use, closed-loop mechanism, and target population, while appropriately selecting clinical evaluation endpoints, follow-up durations, and sample sizes. Conclusion: By summarizing the design rationales and protocols for pre-market clinical trials of implantable closed-loop neurostimulators under FDA regulation, this study offers valuable insights that can serve as a reference for the regulatory approval of similar products in China.