By Alex Harris & Frederic Gilbert.

There are increasing numbers of clinical trials assessing high risk, irreversible treatments.  While a clinical trial aims to assess the safety and efficacy of a clinical intervention, participants enrolled in trials of high risk, irreversible treatments may be left with significant ongoing or emerging burdens after exiting the trial. This raises concerns around the types and levels of post-trial support which are available to these participants. Post-trial support is a complex issue requiring input from a range of disciplines, which is the focus of our JME article. This post describes how the authors began working on this topic, our approach to investigating bioethical issues, and summarises the main outcomes of the JME article.

The authors began collaborating on ethical topics in 2012 while they were both members of the multi-university ARC Centre of Excellence for Electromaterials Science. This multi-disciplinary centre aimed to develop new materials for applications ranging from bionics to energy formation and storage, and assess related ethical issues. Dr Harris was a lab based researcher developing new materials and assessing them in bionics applications, while A/Prof Gilbert investigated bioethical issues related to neuroscience in pre-clinical and clinical research.

Over the duration of an internal group conference, we discussed the possibility of collaborating on an article. At the time, the recently developed optogenetics methodology was receiving some speculative interest in its ability to cure blindness. An open call for commentary in American Journal of Bioethics Neuroscience provided us an opportunity to publish an initial short piece calling for efficacy, as well as safety, to be assessed in first-in-human clinical trials of an optogenetics treatment, due its irreversible nature (https://www.tandfonline.com/doi/full/10.1080/21507740.2012.666323). This potential treatment was of further interest by the need to combine gene therapy with a medical device to deliver the high intensity optical image to the patients’ retina (https://link.springer.com/article/10.1007/s00417-021-05477-6). This type of combined therapy is poorly accounted for in current regulatory approaches, which divide treatments into drugs or devices. Follow-up publications have since expanded our investigation into clinical trials of irreversible treatments, including development of a risk based framework to guide clinical trial design, including the necessary preclinical data for commencing a trial and the post-trial obligations (https://link.springer.com/chapter/10.1007/978-3-030-80443-5_16).

More recently, we have begun investigating the potential clinical applications of stem cell-derived tissue constructs (eg. organoids and bioprinted tissues) and their related ethical issues (https://molecularpsychology.org/articles/2-8). This has included their potential role as drug and phenotypic disease screening platforms or for regenerative medicine applications. Subsequently, we have extended our initial work on clinical trial design for optogenetics and bionics into other irreversible, high risk treatments including stem cell therapies.

A key factor in our interdisciplinary collaboration has been focussing on immediate ethical issues and avoiding speculation around the scientific and technological capabilities of the biomedical research we have been investigating. For instance, cortical organoids have received significant interest within the bioethics community for their potential to develop consciousness and subsequent concerns over their moral status, which may result in a moratorium on their use (https://www.wired.com/story/brain-organoids-consciousness/). Similarly, bionics and optogenetics have been receiving interest in their ability to read and alter patients’ minds, leading to concerns ranging from privacy, rights to disconnect from work, and intrusive marketing (https://humanrights.gov.au/about/news/opinions/lets-not-elevate-brain-tech-over-our-humanity). While these topics may be of fundamental interest and can act as thought experiments in developing bioethical theory, they are far removed from current experimental evidence. This type of speculative ethics has a risk of generating unfounded concerns of these technologies with the public and media, and alienating lab based researchers and clinicians, which can unnecessarily impact biomedical research and lead to patient harms from lost opportunity. Our approach has rather focussed on how these technologies should be developed, assessed in clinical trials and utilised clinically to minimise patient harm and maximise the technologies potential.

Our current JME article builds on our previous work by investigating the post-trial support needs of trial participants. We became interested in the post-trial period due to a number of recently reported issues which resulted in significant patient burdens, including Second Sight Medical Products ceasing support of their Argus II retinal prosthesis; and the forced explantation of a deep brain stimulator at the end of a clinical trial, against the participants wishes (https://link.springer.com/article/10.1007/s12152-014-9224-1). Our initial aim was to call for an extension in insurance coverage for participants involved with trials of high risk irreversible treatments. However, discussions with insurance agencies quickly demonstrated how limited this approach would be, and that there were a far wider range of stakeholders associated with post-trial support. As a result, the article expanded into three crucial areas:

1. It provides a more formal definition of an irreversible treatment which distinguish themselves by one or more of the following attributes: 1) they may pose long-term risks of serious harm to trial participants (potentially occurring after trial conclusion), 2) it may not be possible to assess safety through administration of sub-therapeutic doses, 3) treatments may require ongoing interventions (beyond trial conclusion) to maintain safety or efficacy, 4) the trial is of a long duration where participants may experience significant health, mental or lifestyle changes, 5) participants may be excluded from future therapeutic options, and 6) participation in the trial may require changes to a person’s treatment regimen, leading to permanent deterioration of their health status.
2. It articulates some current limitations of the informed consent processes and post-trial support available to trial participants. This can be associated with medical, psychological and social; technical; or financial needs. There are currently no regulations or guidance documents covering post-trial support for participants. And there is a common misconception that trial participants are covered by trial insurance. Rather, participants must rely on their own public or private health insurance and the goodwill of the sponsors (where they remain in operation). However, even these health insurance options may exclude first-in-human or high risk treatments, or be invalidated by participants modifying the treatment. This can result in participants being potentially out-of-pocket for any post trial needs, while the sponsors and general public gain benefit of new knowledge and potential therapeutic options. This fundamentally impacts on the trials risk/benefit ratio and may invalidate any informed consent. Furthermore, participants may be highly vulnerable with short life predictions, so the concept of post-trial support may not be appropriately rated beforehand, further impacting on the validity of any informed consent.
3. It demonstrates the wide range of stakeholders involved in the provision of post-trial support and provides some initial suggestions for how trial participants could be better supported. This includes creating a register of participants so they can network and advocate on common issues; designing trials to take into account post-trial needs; standardising medical and financial regulations across jurisdictions; and performing exit interviews or new rounds of informed consent at trial conclusion so participants are provided sufficient information or resources for their desired on-going health status.

Our aim for this article is to highlight the concept and current lack of post-trial support for trial participants. We acknowledge this is a difficult issue to address, and hope it spurs others to shift their efforts from speculative bioethics towards developing approaches with more immediate impact on patients and researchers. And key to this is the development (over a sustained period) of strong connections between lab based researchers with bioethicists and other clinical research stakeholders.

Paper title: The need for greater post-trial support for clinical trial participants assessing high-risk, irreversible treatments

Authors: Alex Harris & Frederic Gilbert

Affiliations: University of Melbourne; University of Tasmania

Competing interests: None to declare

Social media accounts of post author(s): https://twitter.com/alexrharris1