Alexander Harris

The clinical development of implantable neural devices raises complex ethical questions about post-trial responsibilities to participants. Continued support for participants who continue to use investigational implantable neural devices requires ongoing specialist care, technical expertise, access to tertiary clinical infrastructure, and substantial financial resources to pay for the device and related procedures. However, continued access may not be possible if the trial shows no benefit, if financial barriers limit commercial viability, or if safety concerns lead to suspension or early termination. Specific ethical guidance on post-trial responsibility is urgently needed. To address this challenge within the Australian innovation context, we conducted a modified Delphi study with a multidisciplinary panel of 24 experts, including representatives from industry, bioethics, law, neurosurgery, clinical psychology/neuropsychology, clinical research, neural engineering, regulation and governance, and lived experience advocacy. The process involved two workshops and a survey, guided by established RAND/UCLA methods with context-specific modifications. Drawing on prior empirical research and regulatory review, the panel developed 11 consensus recommendations for responsible post-trial practices. All recommendations achieved high levels of agreement and were rated as highly important for addressing ethical risks in the Australian environment. These are the first jurisdiction-specific recommendations of their kind, and we anticipate they will substantially enhance ethical and practical standards for post-trial responsibility in implantable neural device research in Australia and internationally.

There are increasing numbers of clinical trials assessing high-risk, irreversible treatments. Trial participants should only expect knowledge gain to society, no personal therapeutic benefit. However, participation may lead to long-term harms and prevent future therapeutic options. While some discussion has occurred around post-trial access to treatments for participants who received therapeutic benefit, there are no post-trial support requirements for those suffering long-term consequences from trial participation. Participants may be left with significant medical, psychological, social, technical or financial needs. All trials will end at some point, regardless of their success. Subsequently, they should be designed to take into account the post-trial period including the impact on the ongoing health of a participant and their post-trial needs.

This paper examines potential ethical and legal issues arising during the research, develop- ment and clinical use of a proposed strategy in personalized medicine (PM): using human induced pluripotent stem cell (iPSC)-derived tissue cultures as predictive models of individ- ual patients to inform treatment decisions. We focus on epilepsy treatment as a likely early application of this strategy, for which early-stage stage research is underway. In relation to the research process, we examine issues associated with biological samples; data; health; vulnerable populations; neural organoids; and what level of accuracy justifies using the iPSC-derived neural tissue system. In relation to clinical use, we examine potential uses in pre-natal screening, and effects on clinical decision-making. Although our focus is providing recommendations for researchers developing work in this area, we identify the novel issue of deciding on an acceptable accuracy level for the system. We also emphasize an issue thus far neglected in the ethics of PM: PM tends to represent treatment decisions as though they should be directed solely by biomedical information, but this in itself could be detri- mental to best personalizing treatment decisions in the clinic.

Clinical trials aim to minimise participant risk and generate new clinical knowledge for the wider population. Many military agencies are now investing efforts in pushing towards developing new treatments involving Brain-Computer Interfaces, Gene Therapy and Stem Cells interventions. These trials are targeting smaller disease groups, as such they give rise to novel participant risks of harms that are largely not accommodated by existing practice. This is of most concern with irreversible harms at early trial stages, where participants may forfeit any future therapy, and in personalised medicine, where the individual participant assumes all of the trial risk. Given these new experimental interventions involve high risk of irreversible harms, how much risk should patients be exposed to when participating in experimental testing of innovative technologies? Designing clinical trials which better balance risk/benefit ratios for participants is crucial. The aim of this book chapter is to suggest a new stratified risk framework aimed at minimising the risk-benefit ratio to participants in clinical trials associated with high risk of irrevocable harms. We will argue it demands a higher-level of clinical data capture at earlier trial stages than predicated by current trial doctrine; it also requires publication of all trial data to minimise risk to participants of any future trial.

In her article, Pascale Hess raises the issue of whether her proposed model may be extrapolated and applied to clinical research fields other than stem cell-based interventions in the brain (SCBI-B) (Hess 2012). Broadly summarized, Hess’s model suggests prioritizing efficacy over safety in phase 1 trials involving irreversible interventions in the brain, when clinical criteria meet the appropriate population suffering from “degenerative brain diseases” (Hess 2012). Although there is a need to reconsider the traditional phase 1 model, especially with respect to first-in-human clinical trials involving novel technologies, the question arises as to whether it is appropriate to advocate for a new model that prioritizes efficacy over safety across all phase 1 clinical research trials involving irreversible interventions in the brain.

Optogenetics is being optimistically presented in contemporary media for its unprecedented capacity to control cell behavior through the application of light to genetically modified target cells. As such, optogenetics holds obvious potential for application in a new generation of invasive medical devices by which to potentially provide treatment for neurological and psychiatric conditions such as Parkinson's disease, addiction, schizophrenia, autism and depression. Design of a first-in-human optogenetics experimental trial has already begun for the treatment of blindness. Optogenetics trials involve a combination of highly invasive genetic and electronic interventions that results in irreversible and permanent modifications of an individual's nervous system. Given its novelty, its uncertain benefit to patients, and its unique risk profile of irreversible physiological alteration, optogenetics requires a reassessment of the ethical challenges for protecting human participants in clinical trials, particularly at formative stages of clinical evaluation. This study explores the evolving ethical issues surrounding optogenetics’ potential harm to participants within trial design, especially focusing on whether Phase 1 trials should incorporate efficacy as well as safety endpoints in ways that are fair and respectful to research trial participants.