This study assesses the use of population pharmacokinetics (PopPK) in supporting pediatric dosing of novel biological drug products. The labeling for biologic drug products approved by the US Food and Drug Administration (FDA) from 2002 until 2021 was reviewed to identify those with a pediatric indication. For the drugs with a pediatric indication, the dosing regimen(s) based on age groups, dosing strategy, the use of PopPK to support the dose, and the types of pediatric clinical trials were reviewed. Data were collected from FDA\'s review documents and product labels on the Drugs@FDA website, and as needed, more clinical trial details were collected from PubMed and clinicaltrials.gov. The role of PopPK analyses in dosing was captured when mentioned in the label or review as playing a role in selecting the approved pediatric dose and/or in verifying the adequacy of the studied dose to support labeling. Between 2002 and 2021, FDA approved 169 biological products, and 78 of 169 (46%) products have an approved indication for which the label contains dosing recommendations for pediatric use. For the 78 products approved in pediatrics, there was a total of 180 clinical trials that included pediatric patients. Phase 3 pediatric trials commonly supported pediatric approval and dosing for the reviewed products (64%, 50/78 products; 56.1%, 101/180 trials). PopPK analyses were reported to play a critical role in dose selection, prediction, and verification for 40 of the 78 products (51%), including informing pediatric dosing in the absence of pediatric data (e.g., drugs approved under animal rule), comparing exposures to the exposure range observed in adults, and informing alternative dosing strategies in certain age or body weight groups. PopPK analyses have been applied in a variety of ways to inform pediatric dosing and support extrapolation from adult data or other pediatric age groups for biologics. Understanding and learning from these past cases on the use of pharmacometrics tools to support pediatric dosing of biological products can inform future pediatric development programs.

Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system (CNS) embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the direct cytopathic effect is followed, under certain circumstances, by an antitumor immune response responsible for the partial or complete debulking of the tumor mass. OVs alone or combined with other therapeutic modalities have been primarily used in adult neuro-oncology. A surge in encouraging preclinical studies in pediatric brain tumor models recently led to the clinical translation of OVs with encouraging results in these tumors. In this review, we summarize the different virotherapy tested in preclinical and clinical studies in pediatric brain tumors, and we discuss the limitations and future avenues necessary to improve the response of these tumors to this type of therapy.

Clinical trials often demonstrate treatment efficacy through change in forced expiratory volume in one second (FEV1), comparing single FEV1 measurements from post- versus pre-treatment timepoints. Day-to-day variation in measured FEV1 is common for reasons such as diurnal variation and intermittent health changes, relative to a stable, monthly average. This variation can alter estimation of associations between change in FEV1 and baseline in predictable ways, through a phenomenon called regression to the mean. We quantify and explain day-to-day variation in percent-predicted FEV1 (ppFEV1) from 4 previous trials, and we present a statistical, data-driven explanation for potential bias in ceiling and floor effects due to commonly observed amounts of variation. We recommend accounting for variation when assessing associations between baseline value and change in CF outcomes in single-arm trials, and we consider possible impact of variation on conventional standards for study eligibility.

Currently, CAR-T cell therapy relies on an individualized manufacturing process in which patient\'s own T cells are infused back into patients after being engineered and expanded ex vivo. Despite the astonishing outcomes of autologous CAR-T cell therapy, this approach is endowed with several limitations and drawbacks, such as high cost and time-consuming manufacturing process. Switching the armature of CAR-T cell therapy from autologous settings to allogeneic can overcome several bottlenecks of the current approach. Nevertheless, the use of allogeneic CAR-T cells is limited by the risk of life-threatening GvHD. Thus, in recent years, developing a method to move CAR-T cell therapy to allogeneic settings without the risk of GvHD has become a hot research topic in this field. Since the alloreactivity of αβ T-cell receptor (TCR) accounts for developing GvHD, several efforts have been made to disrupt endogenous TCR of allogeneic CAR-T cells using gene editing tools to prevent GvHD. Nonetheless, the off-target activity of gene editing tools and their associated genotoxicities, as well as the negative consequences of endogenous TCR disruption, are the main concerns of using this approach. As an alternative, CAR αβ-T cells can be replaced with other types of CAR-engineered cells that are capable of recognizing and killing malignant cells through CAR while avoiding the induction of GvHD. These alternatives include T cell subsets with restricted TCR repertoire (γδ-T, iNKT, virus-specific T, double negative T cells, and MAIT cells), killer cells (NK and CIK cells), non-lymphocytic cells (neutrophils and macrophages), stem/progenitor cells, and cell-free extracellular vesicles. In this review, we discuss how these alternatives can move CAR-based immunotherapy to allogeneic settings to overcome the bottlenecks of autologous manner without the risk of GvHD. We comprehensively discuss the pros and cons of these alternatives over the traditional CAR αβ-T cells in light of their preclinical studies and clinical trials.

While receptor tyrosine kinase-like orphan receptor 1 (ROR1) is typically expressed at low levels or absent in normal tissues, its expression is notably elevated in various malignant tumors and conditions, including chronic lymphocytic leukemia (CLL), breast cancer, ovarian cancer, melanoma, and lung adenocarcinoma. This distinctive feature positions ROR1 as an attractive target for tumor-specific treatments. Currently, several targeted drugs directed at ROR1 are undergoing clinical development, including monoclonal antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell therapy (CAR-T). Additionally, there are four small molecule inhibitors designed to bind to ROR1, presenting promising avenues for the development of PROTAC degraders targeting ROR1. This review offers updated insights into ROR1\'s structural and functional characteristics, embryonic development implications, cell survival signaling pathways, and evolutionary targeting strategies, all of which have the potential to advance the treatment of malignant tumors.

Coronary sinus reducer (CSR) implantation is an emerging treatment option for patients with refractory angina. This condition represents a major global cardiovascular healthcare challenge, with patients experiencing chronic anginal symptoms that significantly impair their quality of life and for whom few effective treatments exist. The clinical burden of refractory angina is only set to grow because of improved survival from coronary artery disease, increased life expectancy and the presence of residual angina after percutaneous or surgical coronary revascularisation. Therefore, new, effective, evidence-based therapies are urgently needed. In this review, we highlight the unmet clinical needs of patients with refractory angina, discuss the development of the CSR device and review the preclinical and clinical evidence base underlying CSR implantation. In addition, we discuss the current role of CSR implantation in contemporary interventional practice, highlighting knowledge gaps and discussing areas of on-going research.

This short introduction provides a historical and ethical overview of placebos and placebo controls in relation to schizophrenia research, with a focus on long-term clinical trials. Drawing on historical and philosophical scholarship, it sketches a two-level analysis of ethical issues that placebos and the placebo effect raise for the field, particularly in light of shifts in clinical trial methodologies and clinical practices.

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients\' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10-8). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10-6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10-3). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment.

Given the ever-increasing number of approved therapies for the treatment of psoriasis (PsO) and psoriatic arthritis (PsA), head-to-head (H2H) comparative studies are essential. These are aimed primarily at a comparative analysis of treatment effectiveness. In both PsO and PsA, biological disease-modifying antirheumatic drugs (bDMARD) have been shown to be superior to conventional therapies in H2H studies. In PsO interleukin 17 (IL-17) and IL-23 inhibitors proved superiority compared to tumor necrosis factor (TNF) inhibitors (etanercept and adalimumab) in several studies. Ustekinumab was more effective than etanercept, but less effective than IL-17 and IL-23 inhibitors. Only a few H2H studies have been published on the treatment of PsA. In the Spirit H2H study ixekizumab was superior to adalimumab using a combined endpoint of arthritis and psoriasis response (ACR-50 and PASI-100). When looking at arthritic symptoms only (ACR-20), secukinumab was not significantly superior to adalimumab in the EXCEED study but was superior in terms of the effect on skin involvement (PASI90). Other H2H studies focused on the treatment of enthesitis (ECLIPSA study), the efficacy of Janus kinase (JAK) inhibition (SELECT-PSA-1) or the additional administration of methotrexate to bDMARD treatment (MUST study). The H2H data have been incorporated into the treatment guidelines and have led to IL-17 and IL-23 inhibition being preferred over TNF inhibition in cases of relevant skin involvement in PsA.
UNASSIGNED: Angesichts einer immer größeren Auswahl zugelassener Therapien zur Behandlung der Psoriasis (PsO) und Psoriasisarthritis (PsA) sind direkte Vergleichsstudien unerlässlich. Diese zielen insbesondere auf eine vergleichende Analyse der therapeutischen Wirksamkeit ab. Sowohl bei der PsO als auch der PsA haben sich in Head-to-Head-Studien (H2H) biologische krankheitsmodifizierende antirheumatische Medikamente (bDMARDs) gegenüber den konventionellen Therapien überlegen gezeigt. Bei der PsO zeigten sich in mehreren Studien die IL-17- und IL-23-Inhibitoren den TNF-Inhibitoren (Etanercept und Adalimumab) überlegen. Ustekinumab war wirksamer als Etanercept, aber weniger wirksam als die IL-17- und IL-23-Inhibitoren. Zur Behandlung der PsA wurden bisher nur wenige H2H-Studien veröffentlicht. In der Spirit-H2H-Studie war bei einem kombinierten Endpunkt zum Ansprechen der Arthritis und der Psoriasis (ACR-50 und PASI-100) Ixekizumab gegenüber Adalimumab überlegen. Wenn nur die arthritischen Beschwerden betrachtet wurden (ACR-20), zeigte sich in der EXCEED-Studie Secukinumab gegenüber Adalimumab nicht signifikant überlegen, hinsichtlich der Wirkung auf die Hautbeteiligung (PASI-90) aber schon. Weitere H2H-Studien beschäftigten sich mit der Enthesitisbehandlung (ECLIPSA-Studie), der Wirksamkeit von JAK-Inhibition (SELECT-PSA-1) oder von zusätzlichem Methotrexat bei bDMARD-Therapie (MUST-Studie). Die H2H-Daten finden Eingang in die Therapieleitlinien und haben zu einer bevorzugten Empfehlung von IL-17- und IL-23-Inhibition gegenüber TNF-Inhibition bei relevanter Hautbeteiligung bei der PsA geführt.

Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence. We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued. Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes. Third, studies should have multiple illness comparator cohorts for IACCIs such as Myalgic Encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses. Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity. Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel.