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.

Decadal climate variability in the tropical Pacific: Characteristics, causes, predictability, and prospects.

Climate variability in the tropical Pacific affects global climate on a wide range of time scales. On interannual time scales, the tropical Pacific is home to the El Niño­Southern Oscillation (ENSO). Decadal variations and changes in the tropical Pacific, referred to here collectively as tropical Pacific decadal variability (TPDV), also profoundly affect the climate system. Here, we use TPDV to refer to any form of decadal climate variability or change that occurs in the atmosphere, the ocean, and over land within the tropical Pacific. "Decadal," which we use in a broad sense to encompass multiyear through multidecadal time scales, includes variability about the mean state on decadal time scales, externally forced mean-state changes that unfold on decadal time scales, and decadal variations in the behavior of higher-frequency modes like ENSO.

The Impact of Upcoming Treatments in Huntington's Disease: Resource Capacity Limitations and Access to Care Implications.

BACKGROUND: The most advanced disease-modifying therapies (DMTs) in development for Huntington's disease (HD) require intrathecal (IT) administration, which may create or exacerbate bottlenecks in resource capacity. OBJECTIVE: To understand the readiness of healthcare systems for intrathecally administered HD DMTs in terms of resource capacity dynamics and implications for patients' access to treatment. METHODS: Forty HD centres across 12 countries were included. Qualitative and quantitative data on current capacity in HD centres and anticipated capacity needs following availability of a DMT were gathered via interviews with healthcare professionals (HCPs). Data modelling was used to estimate the current capacity gap in HD centres. RESULTS: From interviews with 218 HCPs, 25% of HD centres are estimated to have the three components required for IT administration (proceduralists, nurses and facilities). On average, 114 patients per centre per year are anticipated to receive intrathecally administered DMTs in the future. At current capacity, six of the sampled centres are estimated to be able to deliver DMTs to all the anticipated patients based on current resources. The estimated waiting time for IT administration at current capacity will average 60 months (5 years) by the second year after DMT availability. CONCLUSION: Additional resources are needed in HD centres for future DMTs to be accessible to all anticipated patients. Timely collaboration by the HD community will be needed to address capacity gaps. Healthcare policymakers and payers will need to address costs and navigate challenges arising from country- or region-specific healthcare delivery schemes.

Recurrent heart failure hospitalizations increase the risk of cardiovascular and all-cause mortality in patients with heart failure in Sweden: a real-world study.

AIMS: Heart failure (HF) is a leading cause of hospitalization and is associated with high morbidity and mortality. We examined the impact of recurrent HF hospitalizations (HFHs) on cardiovascular (CV) mortality among patients with HF in Sweden. METHODS AND RESULTS: Adults with incident HF were identified from linked national health registers and electronic medical records from 01 January 2005 to 31 December 2013 for Uppsala and until 31 December 2014 for Västerbotten. CV mortality and all-cause mortality were evaluated. A time-dependent Cox regression model was used to estimate relative CV mortality rates for recurrent HFHs. Assessment was also done for ejection fraction-based HF phenotypes and for comorbid atrial fibrillation, diabetes, or chronic renal impairment. Overall, 3878 patients with HF having an index hospitalization were included, providing 9691.9 patient-years of follow-up. Patients were relatively old (median age: 80 years) and were more frequently male (55.5%). Compared with patients without recurrent HFHs, the adjusted hazard ratio (HR [95% confidence interval; CI]) for CV mortality and all-cause mortality were statistically significant for patients with one, two, three, and four or more recurrent HFHs. The risk of CV mortality and all-cause mortality increased approximately six-fold in patients with four or more recurrent HFHs vs. those without any HFHs (HR [95% CI]: 6.26 [5.24-7.48] and 5.59 [4.70-6.64], respectively). Similar patterns were observed across the HF phenotypes and patients with comorbidities. CONCLUSIONS: There is a strong association between recurrent HFHs and CV and all-cause mortality, with the risk increasing progressively with each recurrent HFH.

Burden of Treatment-Induced Peripheral Neuropathy in Patients with Multiple Myeloma in Sweden.

INTRODUCTION: Treatment-induced peripheral neuropathy (TIPN) is a complication of multiple myeloma (MM) treatment. OBJECTIVE: This real-world, retrospective study used electronic medical record (EMR) data from 3 Swedish clinics to assess the occurrence and economic burden of TIPN in patients with MM. METHODS: Eligible patients had an MM diagnosis in the Swedish Cancer Registry between 2006 and 2015 and initiated treatment during that period. Follow-up was until last EMR visit, death, or study end (April 2017). The current analyses included patients receiving bortezomib, lenalidomide, carfilzomib, or thalidomide at any treatment line. To discern healthcare resource utilization (HCRU) and costs associated with TIPN from other causes, patients with TIPN were matched with those without on baseline characteristics, treatment, and line of therapy. All analyses were descriptive. RESULTS: Overall, 457 patients were included; 102 (22%) experienced TIPN. Patients experiencing TIPN during first-line treatment mostly received bortezomib-based regimens (n = 48/57 [84%]); those with TIPN during second- and third/fourth-line treatment mostly received lenalidomide/thalidomide-based regimens (19/31 [61%], 8/14 [57%], respectively). Patients with TIPN had higher HCRU/costs than those without TIPN (mean differences in hospital outpatient visits: 5.2, p = 0.0031; total costs per patient-year: EUR 17,183, p = 0.0007). CONCLUSIONS: Effective MM treatments associated with a reduced incidence of TIPN could result in decreased healthcare expenditure.

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.

Patient journey and treatment patterns in adults with IPF based on health care data in Sweden from 2001 to 2015.

BACKGROUND: For patients with idiopathic pulmonary fibrosis (IPF), there is limited real-world data on patient journey and treatment patterns. AIM: To explore predictors of early diagnosis and treatment initiation, and treatment patterns in IPF patients using linked data from Swedish registers and electronic medical records (EMRs). POPULATION: A national cohort (C1) of 17,247 pulmonary fibrosis patients (ICD-10 code J84.1; no competing diagnosis) diagnosed between 2001 and 2015, and an EMR-based regional subset (C2) comprising 1755 IPF patients diagnosed between 2004 and 2017. The time from early disease symptoms to diagnosis, use of anti-fibrotic medications, time from diagnosis to initiation of anti-fibrotic treatment, and adherence, persistence and treatment length with pirfenidone were explored in these patients. RESULTS: In C1, the median time to diagnosis from the first symptoms dyspnoea, cough and fatigue were 307, 563 and 639 days, respectively. Glucocorticoids were the most frequently prescribed medication. Less than 10% of patients undergoing or initiating treatment, used pirfenidone or nintedanib. Males had a higher probability of initiating anti-fibrotic treatment than females within a year of diagnosis. One-year persistence in pirfenidone patients was 42% in C1 and 25% in C2. CONCLUSION: Diagnosis of pulmonary fibrosis was delayed in patients with cough and fatigue, which are early symptoms of IPF. This, and lower than expected utilisation of anti-fibrotic medications, suggests missed opportunities for early disease diagnosis and treatment. The high rate of treatment discontinuation underscores the importance of supporting and guiding patients to persist with their medications to ensure an accrual benefit of treatment.

Epidemiology of heart failure and trends in diagnostic work-up: a retrospective, population-based cohort study in Sweden.

PURPOSE: The purpose of this study was to examine the trends in heart failure (HF) epidemiology and diagnostic work-up in Sweden. METHODS: Adults with incident HF (≥2 ICD-10 diagnostic codes) were identified from linked national health registers (cohort 1, 2005-2013) and electronic medical records (cohort 2, 2010-2015; primary/secondary care patients from Uppsala and Västerbotten). Trends in annual HF incidence rate and prevalence, risk of all-cause and cardiovascular disease (CVD)-related 1-year mortality and use of diagnostic tests 6 months before and after first HF diagnosis (cohort 2) were assessed. RESULTS: Baseline demographic and clinical characteristics were similar for cohort 1 (N=174,537) and 2 (N=8,702), with mean ages of 77.4 and 76.6 years, respectively; almost 30% of patients were aged ≥85 years. From 2010 to 2014, age-adjusted annual incidence rate of HF/1,000 inhabitants decreased (from 3.20 to 2.91, cohort 1; from 4.34 to 3.33, cohort 2), while age-adjusted prevalence increased (from 1.61% to 1.72% and from 2.15% to 2.18%, respectively). Age-adjusted 1-year all-cause and CVD-related mortality was higher in men than in women among patients in cohort 1 (all-cause mortality hazard ratio [HR] men vs women 1.07 [95% CI 1.06-1.09] and CVD-related mortality subdistribution HR for men vs women 1.04 [95% CI 1.02-1.07], respectively). While 83.5% of patients underwent N-terminal pro-B-type natriuretic peptide testing, only 36.4% of patients had an echocardiogram at the time of diagnosis, although this increased overtime. In the national prevalent HF population (patients with a diagnosis in 1997-2004 who survived into the analysis period; N=273,999), death from ischemic heart disease and myocardial infarction declined between 2005 and 2013, while death from HF and atrial fibrillation/flutter increased (P<0.0001 for trends over time). CONCLUSION: The annual incidence rate of HF declined over time, while prevalence of HF has increased, suggesting that patients with HF were surviving longer over time. Our study confirms that previously reported epidemiological trends persist and remain to ensure proper diagnostic evaluation and management of patients with HF.

Epidemiology of Pulmonary Fibrosis: A Cohort Study Using Healthcare Data in Sweden.

INTRODUCTION: Data on the epidemiology of idiopathic pulmonary fibrosis (IPF) in Sweden are lacking. This study estimates the incidence and prevalence of IPF in Sweden, and describes the demographic and clinical characteristics and the overall survival of patients with IPF. METHODS: Two cohorts were studied: a national cohort of 17,247 patients with pulmonary fibrosis (ICD-10 code J84.1 with no competing diagnosis) from the Swedish National Patient Register (cohort 1 [C1]); and an electronic medical record-based regional subset of C1 comprising 1755 patients having pulmonary fibrosis and a radiology procedure (C2). RESULTS: The incidence of pulmonary fibrosis in C1 ranged from 10.4 to 15.4 cases per 100,000 population per year between 2001 and 2015. The prevalence increased from 15.4 to 68.0 cases per 100,000 population per year. Patients ≥ 70 years and men had a higher incidence and prevalence of pulmonary fibrosis. Common comorbidities included respiratory infections and cardiovascular disorders. Approximately one-third of patients in each cohort were hospitalised with pulmonary fibrosis within a year of diagnosis. The median survival time from disease diagnosis was 2.6 years in C1 and 5.2 years in C2. Older patients had a higher risk of hospitalisation and mortality. Women had a better prognosis than men. CONCLUSION: This study underscores the importance of pulmonary fibrosis as a cause of respiratory-related morbidity and mortality in Sweden. The stable incidence and increasing prevalence over time suggests longer survival. The higher morbidity and mortality in older patients highlights the importance of early case detection, diagnosis and management for better prognosis. FUNDING: F. Hoffmann-La Roche, Ltd./Genentech, Inc.

Healthcare Resource Use, Cost, and Sick Leave Following Kidney Transplantation in Sweden: A Population-Based, 5-Year, Retrospective Study of Outcomes: COIN.

BACKGROUND Improved understanding of the impact of kidney transplantation on healthcare resource use/costs and loss of productivity could aid decision making about funding allocation and resources needed for the treatment of chronic kidney disease in stage 5. MATERIAL AND METHODS This was a retrospective study utilizing data from Swedish national health registers of patients undergoing kidney transplantation. Primary outcomes were renal disease-related healthcare resource utilization and costs during the 5 years after transplantation. Secondary outcomes included total costs and loss of productivity. Regression analysis identified factors that influenced resource use, costs, and loss of productivity. RESULTS During the first year after transplantation, patients (N=3120) spent a mean of 25.7 days in hospital and made 21.6 outpatient visits; mean renal disease-related total cost was €66,014. During the next 4 years, resource use was approximately 70% (outpatient) to 80% (inpatient) lower, and costs were 75% lower. Before transplantation, 62.8% were on long-term sick leave, compared with 47.4% 2 years later. Higher resource use and costs were associated with age <10 years, female sex, graft from a deceased donor, prior hemodialysis, receipt of a previous transplant, and presence of comorbidities. Higher levels of sick leave were associated with female sex, history of hemodialysis, and type 1 diabetes. Overall 5-year graft survival was 86.7% (95% CI 85.3-88.2%). CONCLUSIONS After the first year following transplantation, resource use and related costs decreased, remaining stable for the next 4 years. Demographic and clinical factors, including age <10 years, female sex, and type 1 diabetes were associated with higher costs and resource use.

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.

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.

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.