International Society for Cell & Gene Therapy Position Paper: Key considerations to support evidence-based cell and gene therapies and oppose marketing of unproven products.

The field of regenerative medicine, including cellular immunotherapies, is on a remarkable growth trajectory. Dozens of cell-, tissue- and gene-based products have received marketing authorization worldwide while hundreds-to-thousands are either in preclinical development or under clinical investigation in phased clinical trials. However, the promise of regenerative therapies has also given rise to a global industry of direct-to-consumer offerings of prematurely commercialized cell and cell-based products with unknown safety and efficacy profiles. Since its inception, the International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy has opposed the premature commercialization of unproven cell- and gene-based interventions and supported the development of evidence-based advanced therapy products. In the present Guide, targeted at International Society for Cell & Gene Therapy members, we analyze this industry, focusing in particular on distinctive features of unproven cell and cell-based products and the use of tokens of scientific legitimacy as persuasive marketing devices. We also provide an overview of reporting mechanisms for patients who believe they have been harmed by administration of unapproved and unproven products and suggest practical strategies to address the direct-to-consumer marketing of such products. Development of this Guide epitomizes our continued support for the ethical and rigorous development of cell and cell-based products with patient safety and therapeutic benefit as guiding principles.

Ethical analysis of the first porcine cardiac xenotransplantation.

In this article, we provide an ethical analysis of the first porcine cardiac xenotransplant, performed in Maryland, USA in early 2022. David Bennett was offered the experimental procedure after he was deemed ineligible for human heart transplantation and mechanical circulatory support, based on a history of non-compliance. It was reported that Mr Bennett's previous instances of non-compliance were for medically non-life-threatening conditions years earlier, where the risks of non-compliance were not as high. We argue that, in Mr Bennett's case, a history of non-compliance in a different context, should not necessarily rule him ineligible for a potentially life-saving treatment now. Furthermore, using previous non-compliance to exclude individuals from donor organs may have the unintended effect of placing the burden of testing xenotransplantation on those who are already disadvantaged. We then argue that it is not enough to rely on patient consent to ethically justify xenotransplantation research. Taking a broad ethical perspective is crucial when mapping a clinical pathway for xenotransplantation.

Participatory Design and Evaluation of the "Stem Cells Australia" Website for Delivering Complex Health Knowledge: Mixed Methods Study.

BACKGROUND: The internet has become a commonly used information source for people seeking to understand their health care options. However, inconsistent representation about what stem cell treatments are available and from whom, coupled with the lack of transparency about what has been shown to work or is even safe, can distract and mislead users. Given these challenges, there is a need to develop effective evidence-based tools for delivering information about health care options involving stem cells. OBJECTIVE: A need to redesign an existing website in Australia was identified to provide trustworthy information about stem cell research and to counter misinformation. Using a participatory design approach to generate an understanding of what information users need for stem cell treatments, the Stem Cells Australia website serves as a case study for the development and evaluation of websites delivering complex messages about science and health. METHODS: This study comprised 3 steps. First, a focus group and several one-on-one interviews with a purposive sample of users (n=12) were conducted to identify their needs and requirements. Second, we designed a new version of the website based on findings from the focus group and interviews. Finally, for evaluating the participatory design process, we collected 180 days of Google Analytics data for both the original and redesigned versions (90 days for each) and compared their differences using 2-sample z tests. RESULTS: The feedback from participants was grouped into 3 themes-needed and unwanted information, how and where to obtain information, and their information preferences. These were translated into requirements for rebuilding the website. The redesigned version reached users in other continents, despite the daily numbers of users (-61.2%; P<.001) and sessions (-61.7%; P<.001) decreasing. The redesigned version also showed substantial decrease in daily bounce rate (-97.2%; P<.001), significant increase in the daily average of page reads per session (+110.8%; P<.001), and long daily average for session duration (+22.9%; P=.045). Navigation flow analysis showed more traffic toward web pages related to health conditions in the redesigned version. CONCLUSIONS: Websites about stem cell research need to provide content for vulnerable global audiences. Participatory design that addresses knowledge gaps and information needs can produce better performance and engagement, which can be evaluated using Google Analytics, a common web analytics tool used by many websites. Learnings for improving the metrics regarding website identity, research updates, and clinical trials are concluded, which can inform the future design of websites seeking to engage users and provide reliable and accessible science and health information including but not limited to stem cell research and therapies.

Developing a Reflexive, Anticipatory, and Deliberative Approach to Unanticipated Discoveries: Ethical Lessons from iBlastoids.

In this paper, we explore the recent creation of "iBlastoids," which are 3-D structures that resemble early human embryos prior to implantation which formed via self-organization of reprogrammed adult skin cells. We explore some of the ethical, philosophical, social, and regulatory issues related to this research, with focus particularly on what it means to "anticipate" research outcomes when using novel methods or when serendipitous discoveries are made. We defend the need for reflexive, anticipatory, and deliberative ethical and conceptual work by researchers working in emerging and contentious research domains, in collaboration with interdisciplinary scholars, as well as regulators, funders, and publics.

Academic physician specialists' views toward the unproven stem cell intervention industry: areas of common ground and divergence.

BACKGROUND AND AIMS: Premature commercialization of unproven stem cell interventions (SCIs) has received significant attention within the regenerative medicine community. Patients considering SCIs may encounter misinformation and seek out guidance from their physicians who are trusted brokers of health information. However, little is known about the perspectives of academic physician specialists toward the SCI industry. The purpose of this study was to capture the attitudes of physician specialists with experience addressing patient questions about unproven SCIs. METHODS: The authors undertook 25 semi-structured interviews with academic physicians in cardiology, ophthalmology, orthopedics, pulmonology and neurology primarily from one academic center. RESULTS: The authors identified two major themes: concerns and mediators of appropriateness of offering SCIs as therapies to patients. Specialists were generally aware of the industry and reported scientific and commercial concerns, including the scientific uncertainty of SCIs, medical harms to patients, misleading marketing and its impact on patient informed consent and economic harms due to large out-of-pocket costs for patients. All specialists outside of orthopedics voiced that it was inappropriate to be offering SCIs to patients today. These views were informed by previously expressed concerns surrounding safety and properly informing patients, levels of evidence needed prior to offering SCIs therapeutically and desired qualifications for clinicians. Among the specialties, orthopedists reported that under certain conditions, SCIs may be appropriate for patients with limited clinical options but only when safety is adequate, expectations are managed and patients are well informed about the risks and chances of benefit. Most participants expressed a desire for phase 3 studies and Food and Drug Administration approval prior to marketing SCIs, but some also shared the challenges associated with upholding these thresholds of evidence, especially when caring for out-of-option patients. CONCLUSIONS: The authors' results suggest that medical specialists are aware of the industry and express several concerns surrounding SCIs but differ in their views on the appropriateness and clinical evidence necessary for offering SCIs currently to patients. Additional educational tools may help physicians with patient engagement and expectation management surrounding SCIs.

Ethical issues in human organoid and gastruloid research.

Research involving human organoids and gastruloids involves ethical issues associated with their derivation as well as their current and future uses. These include unique issues related to the extent of maturation that can be achieved in vitro or through chimeric research, as well as fundamental ethical considerations such as those concerning the provenance of human biomaterials and the use of gene-editing technologies. Many of these issues are not specifically addressed by existing ethics oversight mechanisms, but these mechanisms might be easily extended to help ensure that human organoid and related research moves forward in an ethically appropriate manner.

Unconventional Practice, "Innovative" Interventions and the National Law.

This column explores a recent health profession disciplinary case which throws light on the problems of unconventional interventions by medical practitioners under the Health Practitioner Regulation National Law Act 2009 (Qld). The case involved "innovative" practices which were later found to have been scientifically unsupported, dangerous to patients and grounds for cancelling the health practitioner's registration. This column looks at common features of these kinds of cases in Australia and then examines recent attempts by the Medical Board of Australia to draft policy guidance around the use of unconventional practice in medicine. This column concludes with a number of changes to improve the effectiveness of the proposed policy.

Navigating the cartographies of trust: how patients and carers establish the credibility of online treatment claims.

Digital media offer citizens novel ways of 'enacting' health and illness, and treatment and care. However, while digital media may so 'empower' citizens, those searching for credible information will be confronted with various, often-conflicting claims that may have 'disempowering' effects. This article uses Gieryn's concept of the 'cultural cartography' to explore the criteria that patients and carers employ in establishing the credibility of information on alleged treatments. Drawing on data from interviews with Australian patients and carers who have travelled or considered travelling abroad for unproven commercial stem cell treatments, the article examines how individuals assess rival sources of epistemic authority - science-based and non-science-based - as they search for credible information. As we argue, in a context where conventional treatment options are perceived to be limited or non-existent - which is likely to be the case with those suffering severe, life-limiting conditions - and the credibility of sources uncertain, matters of opinion and belief are prone to being interpreted as matters of fact, with potentially far-reaching implications for citizens' health. Revealing the mechanisms by which individuals ascribe credibility to health information, we conclude, has become crucial as digital media assume a growing role in health and healthcare and governments encourage citizens to become 'digitally literate'.

What if stem cells turn into embryos in a dish?

Recent studies show that pluripotent stem cells can undergo self-organized development in vitro into structures that mimic the body plan of the post-implantation embryo. Modeling human embryogenesis in a dish opens up new possibilities for the study of early development and developmental disorders, but it may also raise substantial ethical concerns.

A roundtable on responsible innovation with autologous stem cells in Australia, Japan and Singapore.

We report on a roundtable event hosted in Singapore that sought to identify some of the ethical and regulatory challenges in translating autologous cell-based interventions, particularly those claiming to involve stem cells, into safe and effective therapies and to propose some solutions to encourage responsible innovation with these products. Challenges are identified in the three areas of cell manufacturing and processing, innovative uses of autologous cells in clinical practice and standards of evidence. Proposed solutions are discussed within a co-operative model of statutory laws and regulations that can enable product development with autologous cells and professional codes and standards that can encourage ethical conduct in clinical practice. Future research should be directed toward establishing regional networks for the development of internationally consistent standards in manufacturing and ethical codes of conduct for innovating with stem cells, and other autologous cells, and fostering ongoing exchange between jurisdictions.

The current state of stem cell therapy for ocular disease.

Herein, we review the safety, efficacy, regulatory standards and ethical implications of the use of stem cells in ocular disease. A literature review was conducted, registered clinical trials reviewed, and expert opinions sought. Guidelines and codes of conduct from international societies and professional bodies were also reviewed. Collated data is presented on current progress in the field of ocular regenerative medicine, future challenges, the clinical trial process and ethical considerations in stem cell therapy. A greater understanding of the function and location of ocular stem cells has led to rapid advances in possible therapeutic applications. However, in the context of significant technical challenges and potential long-term complications, it is imperative that stem cell practices operate within formal clinical trial frameworks. While there remains broad scope for innovation, ongoing evidence-based review of potential interventions and the development of standardized protocols are necessary to ensure patient safety and best practice in ophthalmic care.

The deadly business of an unregulated global stem cell industry.

In 2016, the Office of the State Coroner of New South Wales released its report into the death of an Australian woman, Sheila Drysdale, who had died from complications of an autologous stem cell procedure at a Sydney clinic. In this report, we argue that Mrs Drysdale's death was avoidable, and it was the result of a pernicious global problem of an industry exploiting regulatory systems to sell unproven and unjustified interventions with stem cells.

Participant understanding and recall of informed consent for induced pluripotent stem cell biobanking.

The ability to generate human induced pluripotent stem cells (iPSCs) has opened new avenues for human disease modelling and therapy. The aim of our study was to determine research participants' understanding of the information given when donating skin biopsies for the generation of patient-specific iPSCs. A customised 35-item questionnaire based on previous iPSC consent guidelines was sent to participants who had previously donated samples for iPSC research. The questionnaire asked pertinent demographic details, participants' motivation to take part in iPSC research and their attitudes towards related ethical issues. 234 participants were contacted with 141 (60.3 %) complete responses received. The median duration between recruitment and follow-up questioning was 313 days (range 10-573 days). The majority of participants (n = 129, 91.5 %) believed they understood what a stem cell was; however, only 22 (16.1 %) correctly answered questions related to basic stem cell properties. We found no statistically significant difference in responses from participants with different levels of education, or those with a health sciences background. The poor understanding amongst participants of iPSC research is unlikely to be unique to our study and may impact future research if not improved. As such, there is a need to develop an easily understood yet comprehensive consent process to ensure ongoing ethical progress of iPSC biobanking.

Therapeutic journeys: the hopeful travails of stem cell tourists.

The recent growth of so-called stem cell tourism reflects the high optimism that currently surrounds stem cell science. Stem cell treatments for various conditions are increasingly advertised over the Internet as being available at hospitals and clinics around the world. However, most are clinically unproven. Despite numerous warnings from scientists about the dangers posed by such treatments, many individuals are evidently prepared to take the risk, sometimes on more than one occasion. This article explores the dynamics of hope that underpin stem cell tourism. Drawing on ideas from the sociology of hope, as applied to biomedicine, the article explores how hope is constructed and shapes actions in relation to stem cell treatments. Making reference to the findings from an Australian study of patients and carers who travelled overseas to receive stem cell treatments, it is argued that hope has an ambiguous significance in the context of deregulated health care. As we explain, this has implications for patients' and carers' treatment decisions and experiences. The findings are discussed in light of current responses to stem cell tourism.

Using Google Analytics with Health Information-Seeking Model to Evaluate the Design of Health Information Websites.

Health information websites can be useful for information seekers, and their design is crucial for the success of accessing the needed information. While web analytical tools (e.g. Google Analytics) used by such websites can provide descriptive measures of users, there is a disconnection between this data and the current understanding of health information-seeking behaviour. In this work, we leverage a theoretical model to interpret the Google Analytics data. Drawn on the visualisation of user behaviours based on this model, our research shows that better website design can be informed, and the evaluation of health websites can be performed on the basis of different user profiles.