The evolution and ongoing challenge of unproven cell-based interventions.

Unproven cell-based interventions (CBIs) emerged early in the 2000s as a particularly problematic form of unproven therapy and remain a vexing policy problem to this day. These unproven interventions can harm patients both physically and financially and can complicate the process of developing a rigorous evidence base to support the translation of novel stem cell or other cell therapies. In this concise review, we examine the emergence of unproven CBIs and the various policy approaches that have been pursued or proposed to address this problem. We review the evolution of this field over the last 2 decades and explore why these policy efforts have proven challenging. We conclude by highlighting potential directions that the field could evolve and urging continued attention to both current and future forms of unproven CBIs to minimize future risks to patients and the field and to promote the development of evidence-based cell therapies.

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.

An International Society for Cell & Gene Therapy working group short report on the future of expanded access to unapproved cell and gene therapies.

Patient interest in non-trial access pathways to investigational cell-and gene-based interventions, such as expanded access in the USA, is increasing, while the regulatory and business environments for non-trial access in the cell and gene therapy field are shifting. Against this background, in 2022 the International Society for Cell & Gene Therapy (ISCT) established a Working Group on Expanded Access to identify practical, ethical, and regulatory issues emerging from the use (and possible misuse) of the expanded access pathway in the cell and gene therapy field. In this Short Report, the Working Group sets the stage for its future activities by analyzing the history of expanded access and identifying three examples of questions that we anticipate arising as uses of expanded access for investigational cell and gene-based interventions increase and evolve.

Navigating ethical challenges in the development and translation of biomaterials research.

Biomaterials--from implanted iron teeth in the second century to intraocular lenses, artificial joints, and stents today--have long been used clinically. Today, biomaterials researchers and biomedical engineers are pushing beyond these inert synthetic alternatives and incorporating complex multifunctional materials to control biological interactions and direct physiological processes. These advances are leading to novel strategies for targeted drug delivery, drug screening, diagnostics and imaging, gene therapy, tissue regeneration, and cell transplantation. While the field has survived ethical transgressions in the past, the rapidly expanding scope of biomaterials science, combined with the accelerating clinical translation of this diverse field calls for urgent attention to the complex and challenging ethical dilemmas these advances pose. This perspective responds to this call, examining the intersection of research ethics -- the sets of rules, principles and norms guiding responsible scientific inquiry -- and ongoing advances in biomaterials. While acknowledging the inherent tensions between certain ethical norms and the pressures of the modern scientific and engineering enterprise, we argue that the biomaterials community needs to proactively address ethical issues in the field by, for example, updating or adding specificity to codes of ethics, modifying training programs to highlight the importance of ethical research practices, and partnering with funding agencies and journals to adopt policies prioritizing the ethical conduct of biomaterials research. Together these actions can strengthen and support biomaterials as its advances are increasingly commercialized and impacting the health care system.

Ethical issues and public communication in the development of cell-based treatments for COVID-19: Lessons from the pandemic.

The significant morbidity and mortality of coronavirus disease 19 (COVID-19) prompted a global race to develop new therapies. These include interventions using cell- or cell-derived products, several of which are being tested in well-designed, properly controlled clinical trials. Yet, the search for cell-based COVID-19 treatments has also been fraught with hyperbolic claims; flouting of crucial regulatory, scientific, and ethical norms; and distorted communication of research findings. In this paper, we critically examine ethical issues and public communication challenges related to the development of cell-based therapeutics for COVID-19. Drawing on the lessons learned from this ongoing process, we argue against the rushed development of cell-based interventions. We conclude by outlining ways to improve the ethical conduct of cell-based clinical investigations and public communication of therapeutic claims.

A Bibliometric Measure of Translational Science.

Science funders are increasingly requiring evidence of the broader impacts of even basic research. Initiatives such as NIH's CTSA program are designed to shift the research focus toward more translational research. However, tracking the effectiveness of such programs depends on developing indicators that can track the degree to which basic research is influencing clinical research. We propose a new bibliometric indicator, the TS score, that is relatively simple to calculate, can be implemented at scale, is easy to replicate, and has good reliability and validity properties. This indicator is broadly applicable in settings where the goal is to estimate the degree to which basic research is used in more applied downstream research, relative to use in basic research. The TS score should be of use for a variety of policy analysis and research evaluation purposes.

A multiscale simulation framework for the manufacturing facility and supply chain of autologous cell therapies.

BACKGROUND AIMS: Autologous cell therapy (AuCT) is an emerging therapeutic treatment that is undergoing transformation from laboratory- to industry-scale manufacturing with recent regulatory approvals. Various challenges facing the complex AuCT manufacturing and supply chain process hinder the scale out and broader application of this highly potent treatment. METHODS: We present a multiscale logistics simulation framework, AuCT-Sim, that integrates novel supply chain system modeling algorithms, methods, and tools. AuCT-Sim includes a single facility model and a system-wide network model. Unique challenges of the AuCT industry are analyzed and addressed in AuCT-Sim. Decision-supporting tools can be developed based on this framework to explore "what-if" manufacturing and supply chain scenarios of importance to various cell therapy stakeholder groups. RESULTS: Two case studies demonstrate the decision-supporting capability of AuCT-Sim where one investigates the optimal reagent base stocking level, and the other one simulates a reagent supply disruption event. These case studies serve as guidelines for designing computational experiments with AuCT-Sim to solve specific problems in AuCT manufacturing and supply chain. DISCUSSION: This simulation framework will be useful in understanding the impact of possible manufacturing and supply chain strategies, policies, regulations, and standards informing strategies to increase patient access to AuCT.

State performance in pluripotent and adult stem cell research, 2009-2016.

AIM: To examine how the geographic distribution of pluripotent and adult stem cell research publications within the USA differs from other areas of biomedical research. MATERIALS & METHODS: Publication count data for pluripotent stem cell research, adult stem cell research and a comparison group representative of biomedical research more broadly were collected and analyzed for each US state from 2009 to 2016. RESULTS: The distribution of pluripotent stem cell research differed from the other fields with overperformance in pluripotent stem cell research observed in California, as well as Wisconsin, Massachusetts, Maryland and Connecticut. CONCLUSION: Our analysis suggests that permissive state stem cell policy may be one of the several factors contributing to strong state performance in pluripotent stem cell research.

Differences in the utilization of gestational surrogacy between states in the U.S.

Gestational surrogacy policy in the USA varies by state, but information on state differences is lacking. This study used data from the National Assisted Reproductive Technology Surveillance System from 2010 to 2014 to calculate state differences in gestational carrier cycle characteristics. Of the 662,165 in-vitro fertilization cycles in the USA between 2010 and 2014, 16,148 (2.4%) used gestational carriers. Non-USA residents accounted for 18.3% of gestational carrier cycles, and 29.1% of gestational carrier cycles by USA residents were performed in a state other than the state of residence of the intended parent. USA gestational surrogacy practice varies by state, potentially impacting patients' access to surrogacy services.

Medical societies, patient education initiatives, public debate and marketing of unproven stem cell interventions.

Businesses marketing unproven stem cell interventions proliferate within the U.S. and in the larger global marketplace. There have been global efforts by scientists, patient advocacy groups, bioethicists, and public policy experts to counteract the uncontrolled and premature commercialization of stem cell interventions. In this commentary, we posit that medical societies and associations of health care professionals have a particular responsibility to be an active partner in such efforts. We review the role medical societies can and should play in this area through patient advocacy and awareness initiatives.

Erratum: Revisiting the Warnock rule.

This corrects the article DOI: 10.1038/nbt.4015.

Assessing the use of assisted reproductive technology in the United States by non-United States residents.

OBJECTIVE: To study cross-border reproductive care (CBRC) by assessing the frequency and nature of assisted reproductive technology (ART) care that non-U.S. residents receive in the United States. DESIGN: Retrospective study of ART cycles reported to the Centers for Disease Control and Prevention's National ART Surveillance System (NASS) from 2006 to 2013. SETTING: Private and academic ART clinics. PATIENT(S): Patients who participated in ART cycles in the United States from 2006 to 2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Frequency and trend of ART use in the U.S. by non-U.S. residents, countries of residence for non-U.S. residents, differences by residence status for specific ART treatments received, and the outcomes of these ART cycles. RESULT(S): A total of 1,271,775 ART cycles were reported to NASS from 2006 to 2013. The percentage of ART cycles performed for non-U.S. residents increased from 1.2% (n = 1,683) in 2006 to 2.8% (n = 5,381) in 2013 (P<.001), with treatment delivered to residents of 147 countries. Compared with resident cycles, non-U.S. resident cycles had higher use of oocyte donation (10.6% vs. 42.6%), gestational carriers (1.6% vs. 12.4%), and preimplantation genetic diagnosis or screening (5.3% vs. 19.1%). U.S. resident and non-U.S. resident cycles had similar embryo transfer and multiple birth rates. CONCLUSION(S): This analysis showed that non-U.S. resident cycles accounted for a growing share of all U.S. ART cycles and made higher use of specialized treatment techniques. This study provides important baseline data on CBRC in the U.S. and may also prove to be useful to organizations interested in improving access to fertility treatments.

Science, ethics and communication remain essential for the success of cell-based therapies.

Cell-based therapeutics, such as marrow or peripheral blood stem cell transplantation, are a standard of care for certain malignancies. More recently, a wider variety of cell-based therapeutics including the use of mesenchymal stromal/stem cells, T-cells, and others show great promise in a wider range of diseases. With increased efforts to expand cell-based treatments to several clinical settings, many institutions around the world have developed programs to explore cellular therapy's potential for safe and effective applications. In legitimate investigations, usually conducted through academic centers or biotechnology industry-sponsored efforts, these studies are regulated and peer-reviewed to ensure safety and clear determination of potential efficacy. However, in some cases, the use of cell-based approaches is conducted with insufficient preclinical data, scientific rationale, and/or study plan for the diseases claimed to be treated, with patients being charged for these services without clear evidence of clinical benefit. In this context, patients may not be properly informed regarding the exact treatment they are receiving within a consenting process that may not be completely valid or ethical. Here, the authors emphasize the importance of distinguishing "proven cell-based therapies" from "unproven" and unauthorized cell-based therapies. This publication also addresses the necessity for improved communication between the different stakeholders in the field, patient associations, and advocacy groups in particular, to favor medical innovation and provide legitimate benefits to patients. Considering the progressive growth of cell-based treatments, their increasing therapeutic value and the expectation that society has about these therapies, it is critically important to protect patients and ensure that the risk/benefit ratio is favorable. This paper is a review article. Literature referred to in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching PubMed. Some original points in this article come from the laboratory practice in our research centers and the authors' experiences.

Navigating Bioethical Waters: Two Pilot Projects in Problem-Based Learning for Future Bioscience and Biotechnology Professionals.

We believe that the professional responsibility of bioscience and biotechnology professionals includes a social responsibility to contribute to the resolution of ethically fraught policy problems generated by their work. It follows that educators have a professional responsibility to prepare future professionals to discharge this responsibility. This essay discusses two pilot projects in ethics pedagogy focused on particularly challenging policy problems, which we call "fractious problems". The projects aimed to advance future professionals' acquisition of "fractious problem navigational" skills, a set of skills designed to enable broad and deep understanding of fractious problems and the design of good policy resolutions for them. A secondary objective was to enhance future professionals' motivation to apply these skills to help their communities resolve these problems. The projects employed "problem based learning" courses to advance these learning objectives. A new assessment instrument, "Skills for Science/Engineering Ethics Test" (SkillSET), was designed and administered to measure the success of the courses in doing so. This essay first discusses the rationale for the pilot projects, and then describes the design of the pilot courses and presents the results of our assessment using SkillSET in the first pilot project and the revised SkillSET 2.0 in the second pilot project. The essay concludes with discussion of observations and results.