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The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ABassan is an employee of Syncopation Life Sciences. EB is an employee of Novartis. CB is an employee of Cellectis. SBC is an employee of CRISPR Therapeutics and has stock ownership in CRISPR. DSH has participated in advisory boards for AstraZeneca and Bayer and has received institutional funding from Incyte, Pfizer, Bristol Myers Squibb, Merck Sharpe Dohme, Lilly. LH is an employee of Miltenyi Biomedicine. IDH is an employee of Tessa Therapeutics. BKM is an employee of Kite, a Gilead company. YM is an employee of Takeda Pharmaceuticals International. SM has participated in advisory boards for Novartis and Wugen and received clinical trial support from Novartis. LP is an employee of GlaxoSmithKline. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene and consulted for Lilly and Developmental Therapeutics Consortium Limited MP is an employee of Autolus Limited. AQ-C is an employee of TCR2 Therapeutics. RR is an employee of Celgene/Bristol Myers Squibb. CR has participated in advisory boards for Amgen, BMS, Celgene, Novartis and Pfizer. MAS is an employee and stock ownership of Gracellbiotechnologies Inc. SKT receives research funding from Incyte Corporation and Beam Therapeutics and as participated in advisory boards of Aleta Biotherapeutics and Kura Oncology. MCZ has been a constant for Incyte, Sanofi, BMS, Novartis, Pfizer, Jazz, Abbvie, Roche and Takeda; has received institutional funding from Jazz, Pfizer, Takeda, Abbvie and funding for travel from Jazz. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Extracellular vesicles (EV) are emergent therapeutic effectors that have reached clinical trial investigation. To translate EV-based therapeutic to clinic, the challenge is to demonstrate quality, safety, and efficacy, as required for any medicinal product. EV research translation into medicinal products is an exciting and challenging perspective. Recent papers, provide important guidance on regulatory aspects of pharmaceutical development, defining EVs for therapeutic applications and critical considerations for the development of potency tests. In addition, the ISEV Task Force on Regulatory Affairs and Clinical Use of EV-based Therapeutics as well as the Exosomes Committee from the ISCT are expected to contribute in an active way to the development of EV-based medicinal products by providing update on the scientific progress in EVs field, information to patients and expert resource network for regulatory bodies. The contribution of our work group "Extracellular Vesicle translatiOn to clinicaL perspectiVEs - EVOLVE France", created in 2020, can be positioned in complement to all these important initiatives. Based on complementary scientific, technical, and medical expertise, we provide EV-specific recommendations for manufacturing, quality control, analytics, non-clinical development, and clinical trials, according to current European legislation. We especially focus on early phase clinical trials concerning immediate needs in the field. The main contents of the investigational medicinal product dossier, marketing authorization applications, and critical guideline information are outlined for the transition from research to clinical development and ultimate market authorization., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Florence Gazeau, Amanda Karine Andriola Silva, Claire Wilhelm and Gabriel Rahmi are co-founders of the spin-off Evora Biosciences. Amanda Karine Andriola Silva and Claire Wilhelm are co-founders of the spin-off EverZom. Max Piffoux is consultant and owns stocks in the spin-off Evora Biosciences and in the spin-off EverZom., (Copyright © 2021 Elsevier B.V. All rights reserved.)

One of the biggest challenges in pediatric drug development is defining a safe and effective dose in pediatric populations, which span across a wide age and development range from neonates to adolescents. Model-informed drug development approaches are particularly suited to address knowledge gaps including data leveraging to increase the success of pediatric studies. Considering the often limited number of patients available for study and logistic difficulties to collect the necessary data in pediatric populations, the application of pharmacometrics and modeling and simulation techniques can improve clinical trial efficiency, increase the probability of regulatory success, and optimize therapeutic individualization in support of dedicated trials. This review describes the state of pediatric model-informed drug development to define the right dose for children and provides suggestions for future development., (© 2021, The American College of Clinical Pharmacology.)

Getting the right dose regimen for children and adolescents is important but poses great scientific, practical, and ethical challenges. At the same time, the availability of data in adults is a huge advantage and needs to be used optimally when designing studies in children and analyzing pediatric data. Furthermore, the processes of maturation and growth are always key when selecting doses for children. All the above make study adaptations and model-informed approaches imperative for dose exposure-response characterization and dose selection in children. This article summarizes the experience gained in the European Medicines Agency on this topic and proposes some general guiding principles for defining objectives, study designs, and methodology tools for pediatric dose selection., (© 2021, The American College of Clinical Pharmacology.)

Starting from historic reflections, the current SARS-CoV-2 induced COVID-19 pandemic is examined from various perspectives, in terms of what it implies for the implementation of non-pharmaceutical interventions, the modeling and monitoring of the epidemic, the development of early-warning systems, the study of mortality, prevalence estimation, diagnostic and serological testing, vaccine development, and ultimately clinical trials. Emphasis is placed on how the pandemic had led to unprecedented speed in methodological and clinical development, the pitfalls thereof, but also the opportunities that it engenders for national and international collaboration, and how it has simplified and sped up procedures. We also study the impact of the pandemic on clinical trials in other indications. We note that it has placed biostatistics, epidemiology, virology, infectiology, and vaccinology, and related fields in the spotlight in an unprecedented way, implying great opportunities, but also the need to communicate effectively, often amidst controversy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy., Competing Interests: Conflict of interest statement LM has participated in advisory boards for Novartis, AstraZeneca, Roche/Genentech, Mundipharma, Bayer and Amgen, has received honoraria from Celgene and Novartis for educational events and travel grants from Mundipharma, Celgene and Amgen, and is a member of the Executive Committee of SIOPEN, a non-profit organisation that receives royalties for the sales of dinutuximab beta. SGD has received travel expenses from Loxo Oncology, Roche, and Salarius and consulting fee from Loxo Oncology. BG has participated in advisory boards for Roche/Genentech, Bayer, BMS, Celgene, Merck KG, Tesaro and Boehringer Ingelheim. MI provides advice to Bayer Canada. SB is an employee of, and owns shares in, Pfizer Ltd. HC is an employee of, and owns shares in, Hoffman La Roche. SD is an employee of Cyclacel Limited. MM and PM are employees of Astrazeneca. JS is 6-THIO-DG Scientific Founder and MAIA Scientific Advisor. GV provides advice to Roche, BMS, Celgene, Takeda, Aceta Pharma, Merck, Bayer, Servier and Novartis. ADJP provides advice to Novartis, Takeda, Merck, Lilly and Celgene., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: In 2017 the WHO published a global priority list of 12 antibiotic-resistant bacteria (ARB) in urgent need of new antibiotics. We aimed to identify and assess publicly accessible mandatory surveillance systems and outbreaks reporting for these pathogens in the 28 European Union and four European Free Trade Association member states., Methods: Compulsory reporting was mapped by reviewing national documents without applying language restrictions and through expert consultation. Information on surveillance targets, indicators, metrics and dissemination modalities was extracted and a qualitative assessment was performed for open access systems only., Results: Twenty-one countries (66%) had a mandate to survey at least one among the 12 WHO priority pathogens; 15 provided access to surveillance frameworks. These systems covered most frequently carbapenem-resistant Enterobacteriales (12; 38%), methicillin-resistant Staphylococcus aureus (12; 38%), and vancomycin-resistant enterococci (8; 25%). None of the European countries required reporting of resistance in Salmonella, Campylobacter, Helicobacter pylori and Neisseria gonorrhoeae. High heterogeneity was observed in data collection, reporting and dissemination among countries with clinical outcomes and risk factors being reported in less than half (22% and 25%). Only six countries (19%) implemented mandatory surveillance of outbreaks due to at least one WHO priority pathogen., Conclusions: Our review shows that despite the increasing burden of ARB on the European population, very few countries implemented mandatory surveillance and outbreak reporting of the WHO priority pathogens. International efforts are needed to define the effectiveness of implementing mandatory reporting of these pathogens and to assess their role in reducing the spread of ARB in health-care and community settings., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pediatric drug development (PDD) became an industry goal when the Food and Drug Administration (FDA) granted patent extensions. This was later expanded to obligations for pediatric studies and to the European Medicines Agency's (EMA's) strict pediatric investigation plans (PIPs). Industry now sponsors many often international studies in young patients that are difficult or impossible to recruit. PDD's intellectual foundations characterize children as "therapeutic orphans," allegedly discriminated in drug treatment and development. While toxicities occured in newborns, demanding separate efficacy and safety (E&S) studies in all age groups is wasteful and reflects hidden conflicts of interest. The American Academy of Pediatrics (AAP) successfully procured pediatric research funds; the FDA dislikes pediatric off-label use and envisions labels as instructions for physicians. Pediatricians have continuously improved child health care by careful use of available drugs. Instead of physiologically defining children vis-à-vis drug treatment, the FDA defines children as ≤16 years old, offering convincing pretense for the need for mostly senseless "pediatric" studies in young adults, adolescents, and children. Although these studies may help advance pediatric academic careers, they do not improve pediatric health care. The EMA defines children as <18 years old and demands even more senseless and potentially harmful "pediatric" studies. Young patients need pharmacokinetic/pharmacodynamic and dose finding, but not separate E&S, studies. Institutional review boards and ethics committees should suspend or reject questionable FDA/EMA-demanded "pediatric" studies. Industry and science need repositioning towards "PDD"; US/EU pediatric laws need revision. We hope this will not take decades.

Radically expanding use of real-world data (RWD) and real-world evidence (RWE) holds the potential to substantially impact drug development, pharmaceutical regulation, and payment within health care systems. Central to this is the reconfiguration of data gathering and transformation of data to information, which can be used as evidence for decision making. We discuss applications of this paradigm in the light of recent developments in both the United States and Europe on RWD and RWE., (© 2019 The British Pharmacological Society.)

Until recently, periodic Group A meningococcal meningitis outbreaks were a major public health problem in the sub-Saharan Africa. In 2001, the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and PATH, a Seattle-based NGO, and the Serum Institute of India Pvt Ltd (SIIPL) initiated discussions aimed at establishing a collaboration to develop a Group A meningococcal conjugate vaccine for this unmet medical need. Over the next 8 years the partnership made countless strategic decisions about product characteristics, raw materials, potential target populations, geographic prioritization and affordability of the vaccine to name a few. These decisions evolved into detailed plans for preclinical development, extensive field trials in Africa and India and a focused regulatory strategy specific for the Men A conjugate vaccine. Important characteristics of the process included, flexibility, transparency andeffective partnerships that included public agencies as well as private companies in Africa, Europe, the United States and India.