Post-Trial Considerations for an Early Phase Optogenetic Trial in the Human Brain

Abstract

For many clinical trials, the issue of post-trial access to research treatments is straightforward. Sponsors offer a range of follow-on studies, compassionate use programs or expanded access programs to allow participants to continue accessing beneficial experimental treatments. But there are times when this is not always the case and participants are required to stop beneficial treatments and return to standard care. Guidance states that post-trial access should be made available for "those participants who still need an intervention identified as beneficial". This broad statement has allowed sponsors to make their own interpretation of when an intervention is still "needed" and when it is "beneficial". As a result, there have been a number of situations where participants of clinical trials have been left afterwards with feelings of abandonment. Participants involved in studies with long-term, invasive treatments can be seen as being particularly vulnerable. Optogenetic technology has the potential to offer hope to people with neurological conditions, especially people who may not respond to current approved treatments. Optogenetics typically involves two components: a gene therapy medicinal product (GTMP) that induces long-term expression of light-reactive proteins within cells, and an active implantable device to stimulate the light-sensitised cells. Neither works without the other, hence for long-term patient benefit, both must remain active and may therefore require maintenance or replacement. With the potential life-long consequences of both components and the difficulty of accessing the brain, there is a need to reconsider post-trial guidelines and whether they are suitable to support early phase optogenetic trial participants. This paper considers the ethical and regulatory requirements in place for post-trial access and care in relation to optogenetic treatments of neurological conditions. We propose that a new perspective with wider responsibilities for sponsors is required when it comes to these types of novel therapies.

Brain Pioneers and Moral Entanglement: An Argument for Post‐trial Responsibilities in Neural‐Device Trials

“…First, there are the risks of neurosurgery for implantation and, if necessary, explantation. In addition, there are risks related to the unknown long‐term effects of implanting hardware in neural tissue and of maintaining the hardware; 38 risks that mental health issues will arise from explantation, 39 the abrupt end to the study, 40 or feelings of abandonment if the device is taken away; 41 and risks connected to privacy and security 42 . Some of the risks related to implantable devices are not unique to the neural context, 43 but when they arise in relation to the brain, at least some of them may feel more momentous, given the brain's central role in maintaining human well‐being.…”

“…The lack of significant compensation, coupled with the risks and the investment of time and energy, suggest that neural-device trial participants shoulder a substantial burden. To be clear, participants often embrace the opportunity to experience a novel technology that provides a new way of interacting with the world, 44 and they gain a sense of contributing to a valuable shared endeavor. Those nonfinancial benefits deserve acknowledgment and should not be discounted.…”

Bioluminescence as a functional tool for visualizing and controlling neuronal activity in vivo

“…Still, one of the difficulties, and probably the limiting factors for translating this technology from the bench to the bedside, is the challenge associated with bringing the stimulating light in vicinity of the opsin. 87 In this context, bioluminescence has a great potential for cell or even synapse specific modulation 3 and could possibly overcome the light delivery challenge to deep regions in the brain. 2 …”

“…These results demonstrate that luciferase-channelrhodopsin functional coupling can successfully be employed to overcome the challenges related to light delivery before clinical trials can commence in the human brain. 87 It is worth noting, though, that the application of luminopsins per se cannot overcome spatial discontinuities and signaling between cells, as the luciferase and the channelrhodopsin are fused and thus being expressed together on the same cell.…”

Ethics and regulation of neuronal optogenetics in the European Union

“…In both fields, as in the context of ethical analysis, independent but nevertheless interrelated legal questions arise, for example concerning the (legal) status of cerebral organoids or the handling of laboratory animals. Given the results already achieved, especially in studies on neuronal optogenetics in animals, the medical application of neuronal optogenetics in humans is already being discussed [ 1 , 72 , 73 ]. The partial recovery of visual function using optogenetic methods in a blind patient is a first clinical success of optogenetics [ 52 ].…”