Systemic Failures in Human Neuroscience Trials and How to Fix Them

Clinical trials in neuroscience have resulted in significant improvements, but they have also revealed persistent flaws in safety assessment, participant consent, ethics, and post-trial device/technology governance. This review combines high-impact incidents, regulatory analyses, and empirical studies to identify recurring failure modes: incomplete preclinical translation resulting in catastrophic adverse events, inadequately informed consent (particularly for cognitively vulnerable participants), ethically fraught placebo/sham surgical designs, insufficient long-term follow-up and device maintenance, data governance and cybersecurity gaps, and underreporting of harms. We examine representative case studies (such as the TGN1412 cytokine storm, the BIA 10-2474 FAAH inhibitor neurotoxicity, arguments about sham surgery in deep brain stimulation, and device post-trial care failures) to demonstrate systemic causes and consequences. For each shortcoming, we propose specific solutions, including updated preclinical-to-human dose strategies, improved consent processes (layered consent and ongoing consent assessment), independent safety oversight for high-risk first-in-human studies, device stewardship policies for implanted neurotechnologies, and increased transparency and adverse-event reporting. To our knowledge, no thorough analysis has rigorously examined the linked ethical, technological, regulatory, and methodological flaws found in all types of human neuroscience clinical trials globally. The existing literature is compartmentalized, focusing on individual case studies, ethical issues, or device-specific failures. This is the first integrated framework that combines translational failures, consent vulnerabilities, sham surgery controversies, neurodevice stewardship gaps, data governance deficiencies, and post-trial obligations into a unified failure-mode taxonomy, backed up by cross-regional analysis and high-impact case data. The analysis closes with a recommended checklist and research agenda for making neuroscience studies safer, more ethical, and socially responsible.

Neuroscience clinical trials; First-in-human studies; Neuroethics; Translational failure; Informed consent; Adverse event reporting; Neurotechnology; Safety monitoring

1. Suntharalingam, G., Perry, M. R., Ward, S., Brett, S. J., Castello-Cortes, A., Brunner, M. D., & Panoskaltsis, N. (2006). Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. The New England journal of medicine, 355(10), 1018-1028. https://doi.org/10.1056/NEJMoa063842 [Google Scholar] [Crossref]

2. Rocha, J. F., Santos, A., Gama, H., Moser, P., Falcão, A., Pressman, P., Wallace Hayes, A., & Soares-da- [Google Scholar] [Crossref]

3. Silva, P. (2022). Safety, Tolerability, and Pharmacokinetics of FAAH Inhibitor BIA 10-2474: A DoubleBlind, Randomized, Placebo-Controlled Study in Healthy Volunteers. Clinical pharmacology and therapeutics, 111(2), 391-403. https://doi.org/10.1002/cpt.2290 [Google Scholar] [Crossref]

4. Horng, S. H., & Miller, F. G. (2007). Placebo-controlled procedural trials for neurological conditions. Neurotherapeutics, 4(3), 531-536. https://doi.org/10.1016/j.nurt.2007.03.001 [Google Scholar] [Crossref]

5. Lázaro-Muñoz, G., Pham, M. T., Muñoz, K. A., Kostick-Quenet, K., Sanchez, C. E., Torgerson, L., Robinson, J., Pereira, S., Outram, S., Koenig, B. A., Starr, P. A., Gunduz, A., Foote, K. D., Okun, M. S., Goodman, W., McGuire, A. L., & Zuk, P. (2022). Post-trial access in implanted neural device research: Device maintenance, abandonment, and cost. Brain stimulation, 15(5), 1029-1036. https://doi.org/10.1016/j.brs.2022.07.051 [Google Scholar] [Crossref]

6. Ghooi R. B. (2011). The Nuremberg Code-A critique. Perspectives in clinical research, 2(2), 72-76. https://doi.org/10.4103/2229-3485.80371 [Google Scholar] [Crossref]

7. Broussard, G., Rubenstein, L.S., Robinson, C. et al. Challenges to ethical obligations and humanitarian principles in conflict settings: a systematic review. Int J Humanitarian Action 4, 15 (2019). https://doi.org/10.1186/s41018-019-0063-x [Google Scholar] [Crossref]

8. World Medical Association (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA, 310(20), 2191-2194. https://doi.org/10.1001/jama.2013.281053 [Google Scholar] [Crossref]

9. Tariq, M. U. (2025). The Belmont Report: Guiding Ethical Principles in Human Research. In R. Throne [Google Scholar] [Crossref]

10. (Ed.), IRB, Human Research Protections, and Data Ethics for Researchers (pp. 245-268). IGI Global Scientific Publishing. https://doi.org/10.4018/979-8-3693-3848-3.ch010 [Google Scholar] [Crossref]

11. Bhatt A. (2023). The revamped Good Clinical Practice E6(R3) guideline: Profound changes in principles and practice! Perspectives in clinical research, 14(4), 167-171. https://doi.org/10.4103/picr.picr_184_23 [Google Scholar] [Crossref]

12. Emami, S., & Aperce, C. (2025). The amended international health regulations: Implications and challenges for domestic legal frameworks. The International journal of health planning and management, 40(1), 234-240. https://doi.org/10.1002/hpm.3853 [Google Scholar] [Crossref]

13. International Organization for Standardization. (2020). Clinical investigation of medical devices for human subjects - Good clinical practice (ISO Standard No. 14155:2020). ISO. ISO - International Organization for Standardization [Google Scholar] [Crossref]

14. International Organization for Standardization. (2019). Medical devices - Application of risk management to medical devices (ISO Standard No. 14971:2019). ISO. ISO - International Organization for Standardization [Google Scholar] [Crossref]

15. Yuste, R. Advocating for neurodata privacy and neurotechnology regulation. Nat Protoc 18, 2869-2875 (2023). https://doi.org/10.1038/s41596-023-00873-0 [Google Scholar] [Crossref]

16. Attarwala, H. (2010). TGN1412: From Discovery to Disaster. Journal of Young Pharmacists, 2(3), 332- [Google Scholar] [Crossref]

17. https://doi.org/10.4103/0975-1483.66810 [Google Scholar] [Crossref]

18. Moore, N. (2016). Lessons from the fatal French study BIA-10-2474. BMJ, 353, Article i2727. [Google Scholar] [Crossref]

19. https://doi.org/10.1136/bmj.i2727 [Google Scholar] [Crossref]

20. Hendriks, S., Grady, C., Ramos, K. M., et al. (2019). Ethical challenges of risk, informed consent, and posttrial responsibilities in human research with neural devices: A review. JAMA Neurology, 76(12), 1506-1514. https://doi.org/10.1001/jamaneurol.2019.3523 [Google Scholar] [Crossref]

21. Shaheen, N., & Flouty, O. (2024). Unlocking the future of deep brain stimulation: innovations, challenges, and promising horizons. International journal of surgery (London, England), 110(6), 31463148. https://doi.org/10.1097/JS9.0000000000001279 [Google Scholar] [Crossref]

22. Tremblay-McGaw, A. G., Hamlat, E. J., Becker, N. C., Astudillo Maya, D. A., Krystal, A. D., & Sellers, K. K. (2025). Best practices for clinical trials of deep brain stimulation for neuropsychiatric indications.Frontiers in Human Neuroscience, 19, Article 1572972. https://doi.org/10.3389/fnhum.2025.1572972 [Google Scholar] [Crossref]

23. Johnson, S., & Goebel, A. (2023). Sham controls in device trials for chronic pain – tricky in practice: A review article. Contemporary Clinical Trials Communications, 35, Article 101203. https://doi.org/10.1016/j.conctc.2023.101203 [Google Scholar] [Crossref]

24. Cho, H. L., Danis, M., & Grady, C. (2018). Post-trial responsibilities beyond post-trial access. The Lancet, 391(10129), 1478-1479. https://doi.org/10.1016/S0140-6736(18)30761-X [Google Scholar] [Crossref]

25. Mehrotra, N., & Manchikanti, P. (2024). Post-trial access to investigational drugs in India: addressing challenges in the regulatory framework. Medical law review, 32(1), 20-41. [Google Scholar] [Crossref]

26. https://doi.org/10.1093/medlaw/fwad028 [Google Scholar] [Crossref]

27. Minen, M. T., & Stieglitz, E. J. (2021). Wearables for Neurologic Conditions: Considerations for Our Patients and Research Limitations. Neurology. Clinical practice, 11(4), e537-e543. https://doi.org/10.1212/CPJ.0000000000000971 [Google Scholar] [Crossref]

28. Muñoz, K. A., Kostick, K., Sanchez, C., Kalwani, L., Torgerson, L., Hsu, R., Sierra-Mercado, D., Robinson, J. O., Outram, S., Koenig, B. A., Pereira, S., McGuire, A., Zuk, P., & Lázaro-Muñoz, G. [Google Scholar] [Crossref]

29. (2020). Researcher Perspectives on Ethical Considerations in Adaptive Deep Brain Stimulation [Google Scholar] [Crossref]

30. Trials. Frontiers in human neuroscience, 14, 578695. https://doi.org/10.3389/fnhum.2020.578695 [Google Scholar] [Crossref]

31. López Bernal, S., Huertas Celdrán, A., & Martínez Pérez, G. (2022). Neuronal Jamming cyberattack over invasive BCIs affecting the resolution of tasks requiring visual capabilities. Computers & Security, 112, Article 102534. https://doi.org/10.1016/j.cose.2021.102534 [Google Scholar] [Crossref]

32. Kaur, R., Sidhu, P., & Singh, S. (2016). What failed BIA 10-2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials. Journal of pharmacology & pharmacotherapeutics, 7(3), 120-126. https://doi.org/10.4103/0976-500X.189661 [Google Scholar] [Crossref]

33. Farah, M. J., Smith, M. E., & Moody, S. (2014). Brain stimulation ethics and sham-controlled designs. JAMA Psychiatry, 71(5), 543-544. https://doi.org/10.1001/jamapsychiatry.2013.4544 [Google Scholar] [Crossref]

34. Brim, R. L., & Miller, F. G. (2012). The potential benefit of the placebo effect in sham-controlled trials: Implications for risk-benefit assessments and informed consent. Journal of Medical Ethics, 38(12), 748751. [Google Scholar] [Crossref]

35. Krishnamoorthy, U., Lakshmipathy, P., Ramya, M. et al. Navigating the future of healthcare with innovations and challenges in implantable battery technology for biomedical devices. Discov Appl Sci 6, 584 (2024). https://doi.org/10.1007/s42452-024-06278-2 [Google Scholar] [Crossref]

36. Jiang, X., Fan, J., Zhu, Z., Wang, Z., Guo, Y., Liu, X., Jia, F., & Dai, C. (2023). Cybersecurity in neural interfaces: Survey and future trends. Computers in Biology and Medicine, 167, 107604. https://doi.org/10.1016/j.compbiomed.2023.107604 [Google Scholar] [Crossref]

37. Kaushik, A., Kaushik, A., Mor, R., Kaura, S., & Sharma, S. (2023). Synthesis and characterization of Gum Acacia encapsulated Ursolic acid nanoparticles enhancing bioavailability and acetylcholinesterase inhibition for therapeutic approach of Alzheimer’s disease. African Journal of Biological Sciences, 5(3), 156-169. https://afjbs.com/issue-content/synthesis-and-characterization-of-gum-acacia-encapsulatedursolic-acid-nanoparticles-enhancing-bioavailability-and-acetylcholinesterase-inhibition-for-therapeuticapproach-of-alzheimer-s-disease-8097 [Google Scholar] [Crossref]

38. Kaushik, A., Kaura, S., & Mor, R. (2025). Synthesis and characterization of Pullulan encapsulated [Google Scholar] [Crossref]

39. Ursolic acid nanoparticles for enhanced bioavailability and acetylcholinesterase inhibition in [Google Scholar] [Crossref]

40. Alzheimer’s disease therapy. International Journal of Pharmacy Research & Technology (IJPRT), 15(1), 124-139. https://ijprt.org/index.php/pub/article/view/334 [Google Scholar] [Crossref]

41. Kaushik, A., Mor, R., Kaushik, A., & Kaura, S. (2025). Redefining preclinical neuroscience: AI-driven in-silico models as ethical and efficient alternatives to animal testing in Alzheimer’s nanomedicine research. International Journal of Research and Scientific Innovation (IJRSI), 12(15), 2003-2016. Special Issue on Public Health. https://doi.org/10.51244/IJRSI.2025.1215000154P [Google Scholar] [Crossref]

42. Kaushik, A., Mor, R., & Kaura, S. (2025). The potential of Ursolic acid nanoformulations as drug delivery systems in Alzheimer’s disease therapy and research. International Journal of Latest Technology in Engineering Management & Applied Science, 14(4), 795-800. https://doi.org/10.51583/IJLTEMAS.2025.140400094 [Google Scholar] [Crossref]

43. Kaushik, A., & Mor, R. (2025). Predicting Human Neurotherapeutic Response through Preclinical Imaging Intelligence. International Journal of Research and Innovation in Applied Science (IJRIAS), 10(10). https://doi.org/10.51584/IJRIAS.2025.10100000171 [Google Scholar] [Crossref]

44. Kaushik, A., Mor, R., Kaushik, A., Kaura, S., & Sharma, S. (2025, December). AI approach to Education and Research Acceleration in Neuroscience and Nanobiomedicine [Conference presentation]. Two Days International Multidisciplinary Conference on "Global Shifts in Knowledge, Policy, and Practice: Multidisciplinary Approaches to Education, Innovation, and Sustainable Futures," Tantia University, Sri Ganganagar, Rajasthan, India. Retrieved from (PDF) AI approach to Education and Research Acceleration in Neuroscience and Nanobiomedicine [Google Scholar] [Crossref]