From the Integrity of Potency Assays to Safe Clinical Intervention: Legal Perspectives.

Potency assays associated with the efficacy of investigational pharmaceutical products are one of the critical quality attributes that need to be carefully monitored during advanced therapy medicinal product (ATMP) development projects. Ensuring integrity of relevant potency assays for stem cell-based ATMPs is of paramount importance for safety and efficacy of clinical interventions. Yet, due to the complex and heterogeneous nature of stem cell-based ATMPs, creation of an appropriate set of potency assays is associated with a number of specific challenges ranging from intrinsic and operational to legal and regulatory ones. This chapter provides an overview of the EU regulatory landscape for advanced therapies, highlighting important aspects that need to be taken into consideration when preparing a strategic plan to meet the EU regulatory requirements.

Homecare Encounters: An Organizational Response to Innovative Care for Patients Undergoing Hematopoietic Stem Cell Transplantation During COVID-19.

BACKGROUND: Healthcare delivery has been significantly changed because of the COVID-19 pandemic. Patients undergoing hematopoietic stem cell transplantation (HSCT) are vulnerable to infections because of their immunocompromised status. The risk of nosocomial infection may be reduced by providing care to patients at home. OBJECTIVES: This article describes one cancer center's approach for delivering safe patient care through homecare encounters, the benefits of home care for HSCT, and future directions. METHODS: Patients received detailed information on home encounters. Advanced practice providers visited patients daily and then returned to the clinic to formulate a plan of care with the interprofessional care team. Transplantation RNs visited patients on the same day to provide the prescribed care. FINDINGS: Based on evaluations from 32 patients and 12 providers, the results indicated that home care was safe, feasible, and beneficial for patient care post-HSCT during the COVID-19 pandemic.

Medical management of adrenocortical carcinoma: Current recommendations, new therapeutic options and future perspectives.

Adrenocortical carcinoma is a rare malignant tumor of poor prognosis, frequently requiring additional treatments after initial surgery. Due to its adrenolytic action, mitotane has become the first-line medical treatment in patients with aggressive adrenocortical carcinoma. Over the last 2years, apart from the classical chemotherapy based on etoposide and platinum salts, several studies reported the use of drugs such as temozolomide, tyrosine kinase inhibitors or immunotherapy, with more or less convincing results. The aim of this review is to give further insights in the use of these drugs, and to describe potential therapeutic perspectives based on recent pangenomic studies, for the future management of these still difficult to treat tumors.

Development of a clinical scale for assessment of patients with diffuse intrinsic pontine glioma (DIPG) receiving experimental therapy: the PONScore.

PURPOSE: Monitoring neurological side-effects in experimental therapy for diffuse intrinsic pontine glioma (DIPG) can be challenging. We aimed to develop a neurological scale that could be used by non-specialists to quantify neurological changes during experimental treatment of DIPG. METHODS: We developed the Pontine Observational Neurological Score (PONScore) to measure signs and symptoms of DIPG by adapting validated assessment scales of neurological signs and symptoms in children. We developed a prototype score, taught it to paediatric intensive care nursing staff, who used the Score to assess children receiving awake pontine infusion of chemotherapy for treatment of DIPG. We used their feedback to develop the PONScore. Points are allocated for headache, ophthalmoplegia, facial and tongue weakness, dysarthria, paraesthesia, limb weakness and dysmetria with increasing scores reflecting increasing disability. The PONScore was administered every hour during awake pontine infusion. Correlation and agreement calculations between nursing staff, as non-specialists, and a specialist rater were performed in 30 infusions in 6 children (aged 8-11). Changes in PONScore versus volume of infusion are described in a further 55 infusions in 8 children (aged 3-11). RESULTS: The PONScore demonstrated excellent intra-rater reliability with an intra-class co-efficient of 0.98 (95% CI 0.97-0.99; p-value < 0.001) between a specialist and non-specialist raters with strong correlation between scores and a Spearman correlation coefficient of 0.985 (p < 0.001). PONScores increased from 3.3 to 5.7 (p-value < 0.001) during infusion reflecting accumulation of neurological signs and symptoms during infusion. CONCLUSIONS: We describe a novel neurological scale that can be used by non-specialists to describe acute neurological changes in children receiving experimental therapy for DIPG. Prospective validation as part of a clinical trial is required.

Regulatory oversight of cell therapy in China: Government's efforts in patient access and therapeutic innovation.

In recent years, remarkable progress has been made in the fundamental research and on clinical development of cell therapy. Although China has launched a series of regulations to establish a proper regulatory framework that facilitates the development of cell therapy products, the regulatory framework has not been able to meet the country's regulatory requirements. This article introduced the development of regulation and current regulatory pathways for cell therapy in China and identified the main challenges in clinical studies. China has recently tightened its policy on cell therapy clinical studies after medical chaos occurred in the area of cell therapy over the past few years. Currently the regulatory jurisdiction between NMPA and NHC are not very clear, especially for clinical somatic cell research, further efforts are necessary to establish a legislative system with a clear and functional regulatory framework for cell therapy.

[Ethics of clinical trials]. / L'éthique des essais thérapeutiques.

TITLE: L'éthique des essais thérapeutiques. ABSTRACT: La pandémie de COVID-19 a conduit certains acteurs reconnus de la médecine à renoncer aux méthodes codifiées de la recherche médicale au profit d'affirmations établies dans l'urgence et sans réelle évaluation scientifique. Autant l'on peut comprendre que certains praticiens recourent à ce qui leur est ainsi proposé, autant cette confusion entre action dans l'urgence et recherche scientifique serait lourde de conséquences si elle venait à se généraliser, et cela à de multiples points de vue : image et rôle de la science, qualité et éthique de la recherche médicale et en fin de compte sort des malades soumis à des traitements mal évalués. Ce sont ces questions qui motivent la mise au point qui suit sur les questions d'éthique associées de longue date aux « essais thérapeutiques ¼, cette procédure rationnelle d'acquisition dans les meilleurs délais d'informations fiables sur les avantages et les risques des traitements dont on envisage l'éventuelle utilisation.

How Do Drug Regulatory Bodies Deal With Potential Innovative Therapies?

Given the extensive development of new molecules over the last 10 years, regulatory authorities (RAs) have been intensively working on evaluating how to identify and manage "innovative" drugs. The purpose of this article is to analyze whether RAs have procedures capable of ensuring access to innovative drug therapies and to understand what criteria RAs around the world (Europe, USA, Canada, Australia, and Japan) use to identify innovative drugs, comparing the different strategies and tools used to prioritize the assessment of the most promising drugs. All the RAs under review consistently use two elements to speed up drug access: (1) the handling (shortening) of approval times and the (2) management of the (limited) evidence available. No international RA utilizes any state-of-the-art method to evaluate the innovativeness of medicinal products. Harmonizing a definition and the criteria used to define pharmaceutical innovation would allow faster access to patients.

Ethical, Legal and Regulatory Issues of Paediatric Translational Research. Call for an Adequate Model of Governance.

The lack of paediatric medicines, including innovative and advanced ones, is a long-lasting and well-known problem at European and international levels. Despite the existing legal frameworks and incentives, children remain deprived of many kinds of therapy because of challenges faced in appropriately study and tailoring medicinal and other products for them. In this context, the necessity to foster paediatric research addressing unsolved and uncovered issues within a 'translational approach' has appeared. This article, after having clarified the concept of translational research in the perspective of the establishment of a European paediatric research infrastructure (RI), will identify and point out ethical, legal and regulatory issues particularly relevant in a children's rights perspective. It concludes asking for the setting up of an adequate model of governance within a future RI, including adequate and independent ethical oversight and a pluridisciplinary common service dealing with ethical, legal and societal issues relevant for children.

Artificial womb technology and clinical translation: Innovative treatment or medical research?

In 2017 and 2019, two research teams claimed 'proof of principle' for artificial womb technology (AWT). AWT has long been a subject of speculation in bioethical literature, with broad consensus that it is a welcome development. Despite this, little attention is afforded to more immediate ethical problems in the development of AWT, particularly as an alternative to neonatal intensive care. To start this conversation, I consider whether experimental AWT is innovative treatment or medical research. The research-treatment distinction, pervasive in regulation worldwide, is intended to isolate research activities and subject them to a greater degree of oversight. I argue that there is a tendency in the literature to conceptualize AWT for partial ectogenesis as innovative treatment. However, there are sufficiently serious ethical concerns with experimental AWT that mean that it must not be first used on humans on the basis that it is a 'beneficial treatment'. First, I outline the prospects for translation of AWT animal studies into treatment for human preterms. Second, I challenge the conceptualizations of experimental AWT as innovative treatment. It must be considered medical research to reflect the investigatory nature of the process and guarantee sufficient protections for subjects. Identifying that AWT is research is crucial in formulating further ethico-legal questions regarding the experimental use of AWT. Third, I demonstrate that clinical trials will be a necessary part of the clinical translation of AWT because of requirements laid out by regulators. I consider the justification for clinical trials and highlight some of the crucial ethical questions about the conditions under which they should proceed.

New Technologies and Applications in Sacral Neuromodulation: An Update.

Recently rechargeable devices have been introduced for sacral neuromodulation (SNM) with conditional safety for full-body magnetic resonance imaging (MRI). Currently a recharge-free SNM device represents the standard implant; however, it is only approved for MRI head scans. As further new technologies with broader MRI capabilities are emerging, the advantages as well as disadvantages of both rechargeable versus recharge-free devices will be briefly discussed in this commentary from the perspective of patients, healthcare professionals, and providers.

Personalised Nutrition Technologies and Innovations: A Cross-National Survey of Registered Dietitians.

BACKGROUND: Commercial technology-enabled personalised nutrition is undergoing rapid growth, yet its uptake in dietetics practice remains low. This survey sought the opinions of dietetics practitioners on personalised nutrition and related technologies to understand the facilitators and barriers to its application in practice. METHOD: A cross-section of registered dietitians were recruited in the USA, UK, Australia, Canada, Israel, Mexico, Portugal, Spain, and South Africa. The questionnaire sought their views on the risks of genetics technology, the ethics of genetic testing, the usefulness of new personalised nutrition technologies, entrepreneurism, and the perceived importance of new technologies to dietetics. Validated scales were included to assess personality (Big Five) and self-efficacy (NGSEI). The survey was available in English, Spanish, and Portuguese. Regression analyses were performed to identify factors associated with the integration of nutrigenetic testing into practice, and to identify factors associated with the perceived importance of bio-information, and mobile technology to dietetics practice. RESULTS: A total of 323 responses (response rate 19.7%) were analysed. Dietetics practitioners who had integrated personalised nutrition technology into practice perceived technologies to be less risky (p = 0.02), biotechnology to be more important (p < 0.01), and professional skills to be less important (p = 0.04) than those who had not. They were also more likely to see themselves as entrepreneurs (p < 0.01) and to perceive lower risks to be associated with technology (p < 0.01). Practitioners of nutrigenetics were lower on neuroticism (p < 0.01) and higher on self-efficacy (p < 0.01), extraversion (p < 0.01), and agreeableness (p < 0.01). A higher perceived importance of biotechnology to dietetics practice was associated with higher perceived usefulness of omics tests (p < 0.01). Perceived importance of information technology was associated with the perceived importance of biotechnology (p < 0.01). Mobile technology was perceived as important by dietitians with the highest level of education (p = 0.02). CONCLUSIONS: For dietitians to practice technology-enabled personalised nutrition, training will be required to enhance self-efficacy, address the risks perceived to be associated with new technologies, and instil an entrepreneurial mindset.

The nexus of opioids, pain, and addiction: Challenges and solutions.

Pain and addiction are complex disorders with many commonalities. Beneficial outcomes for both disorders can be achieved through similar principles such as individualized medication selection and dosing, comprehensive multi-modal therapies, and judicious modification of treatment as indicated by the patient's status. This is implicit in the term "medication assisted treatment" (MAT) for opioid use disorders (OUD), and is equally important in pain management; however, for many OUD and pain patients, medication is central to the treatment plan and should neither be denied nor withdrawn if critical to patient well-being. Most patients prescribed opioids for pain do not develop OUD, and most people with OUD do not develop it as a result of appropriately prescribed opioids. Nonetheless, concerns about undertreatment of pain in the late 20th century likely contributed to inappropriate prescribing of opioids. This, coupled with a shortfall in OUD treatment capacity and the unfettered flood of inexpensive heroin and fentanyl, behavioral economics and other factors facilitated the 21st century opioid epidemic. Presently, injudicious reductions in opioid prescriptions for pain are contributing to increased suffering and suicides by pain patients as well as worsening disparities in pain management for ethnic minority and low-income people. Many of these people are turning to illicit opioids, and no evidence shows that the reduction in opioid prescriptions is reducing OUD or overdose deaths. Comprehensive, science-based policies that increase access to addiction treatment for all in need and better serve people with pain are vital to addressing both pain and addiction.

Innovations in efforts to expand treatment for opioid use disorder.

Fewer than 20% of Americans with opioid use disorder receive empirically-supported treatment. There is a critical need for innovative approaches to support expansion of evidence-based opioid treatment, particularly in rural geographic areas so impacted by the current opioid public health crisis. Doing so will require more diverse pathways into treatment, novel pharmacological tools, improved integration and efficiency among treatment modalities, and harm reduction when treatment is not available. In this invited commentary, we review exciting recent efforts to accomplish these aims as well as offer additional considerations for future clinical and research efforts to increase the availability of treatment for opioid use disorder.

Uncertainty and Cures: Discontinuation, Irreversibility, and Outcomes-Based Payments: What Is Different About a One-Off Treatment?

Payers are concerned that one-off "cures" bring great uncertainty with the consequential risk of incorrect adoption decisions, and significant budget impact from large one-off payments. Innovators worry about bias against "cures" in favor of repeat treatment, which is not in patients' interests. We find that even in the absence of a difference in uncertainty of outcomes, adverse pay-offs differ. The greater financial risk associated with a cure is related to the issue of treatment discontinuation, driven by irreversibility. This paper uses a stylized example to illustrate the need to separate three different elements of the issue: (i) one-off versus repeat or ongoing treatment, (ii) duration of treatment effect, and (iii) the potential role of financial arrangements or risk sharing to mitigate the financial risk to the payer. It concludes that: (i) prevalence and discontinuation issues mean that the impact on the payer of an incorrect decision is greater with a one-off treatment than a repeat therapy; (ii) with evidence collection this risk diminishes over time (a form of CED or OWR); and (iii) financial arrangements or risk sharing can eliminate differences for the payer as between one-off and repeat therapy. The impact of (iii) also addresses payer concerns about budget impact.

Innovative Practice, Clinical Research, and the Ethical Advancement of Medicine.

Innovative practice occurs when a clinician provides something new, untested, or nonstandard to a patient in the course of clinical care, rather than as part of a research study. Commentators have noted that patients engaged in innovative practice are at significant risk of suffering harm, exploitation, or autonomy violations. By creating a pathway for harmful or nonbeneficial interventions to spread within medical practice without being subjected to rigorous scientific evaluation, innovative practice poses similar risks to the wider community of patients and society as a whole. Given these concerns, how should we control and oversee innovative practice, and in particular, how should we coordinate innovative practice and clinical research? In this article, I argue that an ethical approach overseeing innovative practice must encourage the early transition to rigorous clinical research without delaying or deferring the development of beneficial innovations or violating the autonomy rights of clinicians and their patients.