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.

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.

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.

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.

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.

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.

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.

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.

FDA and NIST collaboration on standards development activities supporting innovation and translation of regenerative medicine products.

The development of standards for the field of regenerative medicine has been noted as a high priority by several road-mapping activities. Additionally, the U.S. Congress recognizes the importance of standards in the 21st Century Cure Act. Standards will help to accelerate and streamline cell and gene therapy product development, ensure the quality and consistency of processes and products, and facilitate their regulatory approval. Although there is general agreement for the need of additional standards for regenerative medicine products, a shared understanding of standards is required for real progress toward the development of standards to advance regenerative medicine. Here, we describe the roles of standards in regenerative medicine as well as the process for standards development and the interactions of different entities in the standards development process. Highlighted are recent coordinated efforts between the U.S. Food and Drug Administration and the National Institute of Standards and Technology to facilitate standards development and foster science that underpins standards development.

Evaluation of a pilot innovative cognitive-behavioral therapy-based psychoeducation group treatment for functional non-epileptic attacks.

A high proportion of patients presenting at epilepsy clinics experience functional non-epileptic attacks (FNEA), and while psychological treatment is generally thought to be the required intervention, evidence regarding psychological treatment of FNEA is limited. A small number of psychoeducation treatments have been evaluated, with promising results. As part of routine care within a neuropsychiatry service, a 3-session cognitive-behavior therapy- (CBT-) informed psychoeducation group was developed. Patients with comorbid epilepsy were included. The group's effectiveness was evaluated in terms of attack frequency, mood, illness perception, dissociative experiences, and patient feedback. Pre- and post-treatment data were obtained for 19 patients. The proportion of patients experiencing attacks significantly decreased, with almost 40% of treatment completers reporting being attack-free at the end of treatment. Significant improvements were also found on level of psychological distress, illness beliefs, and understanding of the condition. No significant changes in mood or general functioning were observed. High satisfaction was reported by almost all patients. Treatment outcome was not significantly affected by the level of dissociative experiences. The results suggest that CBT-based psychoeducation group treatment can be a beneficial part of treatment for those with FNEA, even for those experiencing high levels of dissociation. Further controlled studies with larger sample sizes are required.

Development of advanced therapies in Italy: Management models and sustainability in six Italian cell factories.

On November 10, 2014, the representatives of all six certified Good Manufacturing Practices (GMP) cell factories operating in the Lombardy Region of Italy convened a 1-day workshop in Milan titled "Management Models for the Development And Sustainability of Cell Factories: Public-Private Partnership?" The speakers and panelists addressed not only the many scientific, technological and cultural challenges faced by Lombardy Cell Factories, but also the potential impact of advanced therapy medicinal products (ATMPs) on public health and the role played by translational research in this process. Future perspectives for research and development (R&D) and manufacturing processes in the field of regenerative medicine were discussed as well. This report summarizes the most important issues raised by the workshop participants with particular emphasis on strengths and limitations of the R&D and manufacturing processes for innovative therapeutics in Lombardy and what can be improved in this context while maintaining GMP standards. The participants highlighted several strategies to translate patient-specific advanced therapeutics into scaled manufacturing products for clinical application. These included (i) the development of a synergistic interaction between public and private institutions, (ii) better integration with Italian regulatory agencies and (iii) the creation of a network among Lombardy cell factories and other Italian and European institutions.

Getting Clearer About Surgical Innovation: A New Definition and a New Tool to Support Responsible Practice.

OBJECTIVES: This article presents an original definition of surgical innovation and a practical tool for identifying planned innovations. These will support the responsible introduction of surgical innovations. BACKGROUND: Frameworks developed for the safer introduction of surgical innovations rely upon identifying cases of innovation; oversight cannot occur unless innovations are identified. However, there is no consensus among surgeons about which interventions they consider innovative; existing definitions are vague and impractical. METHODS: Using conceptual analysis, this article synthesizes findings from relevant literature, and from qualitative research with surgeons, to develop an original definition of surgical innovation and a tool for prospectively identifying planned surgical innovations. The tool has been developed in light of feedback from health care professionals, surgeons, and policy makers. RESULTS: This definition of innovation distinguishes between variations, introduction of established interventions, and innovations in surgical techniques or use of devices. It can be applied easily and consistently, is sensitive to the key features of innovation (newness and degree of change), is prospective, and focuses on features relevant to safety and evaluation. The accompanying tool is deliberately broad so that appropriate supports may, if necessary, be provided each time that a surgeon does something "new." CONCLUSIONS: The definition presented in this article overcomes a number of practical challenges. The definition and tool will be of value in supporting responsible surgical innovation, in particular, through the prospective identification of planned innovations.

Assessing Awareness and Implementation of a Recommendation for Surgical Innovation Committees: A Survey of Academic Institutions.

OBJECTIVE: In 2008, a Position Statement of the Society of University Surgeons (SUS) recommended the creation of institutional surgical innovation committees (SICs) to ensure appropriate oversight of surgical innovations. The purpose of this study was to determine the level of awareness of the position statement, and how innovations are handled in academic departments of surgery. METHODS: An electronic survey was designed to determine the level of awareness of the SUS recommendations among members of the Society of Surgical Chairs; the existence and characteristics of SICs; and alternative means of oversight of surgical innovations. RESULTS: The survey was distributed to 150 persons, and 65 (43%) surveys were returned; 84% reported their institution promoted innovative surgery as a strength, but 55% were unaware of the SUS recommendations; 23% reported that their institution has an SIC, and 20% said their institution has discussed or plans an SIC. Existing SICs have a median of 7 members; 57% reviewed 3 or fewer procedures in the prior year; and only 7% reviewed 10 or more. The majority of respondents reported alternative mechanisms of oversight, including morbidity/mortality conferences (88%), peer review (77%), and outcomes registries (51%). CONCLUSIONS: A minority of Surgery Department Chairs is aware of the SUS Position Statement. Although most reported surgical innovation was an institutional strength, only 23% had an SIC and most rely on other mechanisms of oversight. It is unclear whether academic surgical departments are committed to providing education and awareness of the appropriate development and implementation of surgical innovations.

Systematic review of surgical innovation reporting in laparoendoscopic colonic polyp resection.

BACKGROUND: The IDEAL framework (Idea, Development, Exploration, Assessment, Long-term study) proposes a staged assessment of surgical innovation, but whether it can be used in practice is uncertain. This study aimed to review the reporting of a surgical innovation according to the IDEAL framework. METHODS: Systematic literature searches identified articles reporting laparoendoscopic excision for benign colonic polyps. Using the IDEAL stage recommendations, data were collected on: patient selection, surgeon and unit expertise, description of the intervention and modifications, outcome reporting, and research governance. Studies were categorized by IDEAL stages: 0/1, simple technical preclinical/clinical reports; 2a, technique modifications with rationale and safety data; 2b, expanded patient selection and reporting of both innovation and standard care outcomes; 3, formal randomized controlled trials; and 4, long-term audit and registry studies. Each stage has specific requirements for reporting of surgeon expertise, governance details and outcome reporting. RESULTS: Of 615 abstracts screened, 16 papers reporting outcomes of 550 patients were included. Only two studies could be put into IDEAL categories. One animal study was classified as stage 0 and one clinical study as stage 2a through prospective ethical approval, protocol registration and data collection. Studies could not be classified according to IDEAL for insufficient reporting details of patient selection, relevant surgeon expertise, and how and why the technique was modified or adapted. CONCLUSION: The reporting of innovation in the context of laparoendoscopic colonic polyp excision would benefit from standardized methods.

Beyond the dichotomy: a tool for distinguishing between experimental, innovative and established treatment.

STUDY QUESTION: The precise delineation of the research phase is a recurrent subject of debate: When is the evidence base firm enough to decide that a new technology or treatment no longer needs to be regarded as 'experimental'? SUMMARY ANSWER: We propose a framework that distinguishes between three instead of two types of treatment and describes a continuum from experimental over innovative to established treatment, offering a tool meant to facilitate decision-making about the introduction of new technologies in the clinic. WHAT IS KNOWN ALREADY: Traditionally, guidelines from medical societies on the notion of 'experimental treatment' depart from a dichotomy between experimental and established treatment. However, in the field of reproductive medicine, there are several problems with a dichotomous framework. First, it does not offer an adequate account of the reality in the clinic. Secondly, this view may bring about several negative effects for the patient, such as techniques being considered established too early, holding risks unknown to patients. A further drawback of the dichotomy is that if a technique is no longer considered experimental, centres offering the technique may no longer consider it useful gathering and critically examining (follow-up) data. STUDY DESIGN, SIZE, DURATION: The framework and scoring tool were developed over several phases during which the authors operated as a consensus group of experts. PARTICIPANTS/MATERIALS, SETTING, METHODS: The scoring tool reflects the continuous progression of a new procedure from experimental through innovative to established. For this evolution, four criteria were considered relevant. The first (efficacy) is a categorical criterion (pass/fail). The other three criteria (safety, procedural reliability and transparency and effectiveness) are ordinal in nature. Thresholds have been introduced for all four criteria to avoid that a technology scoring high on procedure and effectiveness but extremely low on safety could move to the next level because of a sufficiently high overall score. MAIN RESULTS AND THE ROLE OF CHANCE: Only treatments that are rated above the thresholds for all four criteria could be considered at least innovative treatments. When they score 4 or higher on the last three criteria, they are considered established treatments. LIMITATIONS, REASONS FOR CAUTION: Knowledge about the procedures or techniques under discussion is essential in order to use the tool. WIDER IMPLICATIONS OF THE FINDINGS: The tool is designed to be used on a macro-level (e.g. by professional societies) although it could also be valuable in the local setting. Both the framework and the tool can bring more clarity on the notion of 'experimental treatment', especially with regard to how to decide when a specific technology or treatment falls in this category and when it can move into one of the other categories. STUDY FUNDING/COMPETING INTEREST(S): none. TRIAL REGISTRATION NUMBER: none.