In recent years, introducing virtual control groups (VCGs) into toxicology studies is increasingly discussed because of the 3Rs and non-human primate (NHP) supply issues. Evaluating toxicology study results using historical control data is not new; however, introducing a VCG means replacing the concurrent control group in a toxicology study with a VCG, thereby reducing the number of animals used by approximately 30%. While it may be possible to conduct a toxicology study of a developmental compound in which the concurrent control group is replaced with a VCG, the scientific appropriateness of introducing a VCG and its regulatory acceptability needs to be considered. Therefore, we identified the following five issues that may arise when implementing a VCG: 1) regulatory requirements, 2) common issues when introducing a VCG, 3) issues related to histopathological examinations when introducing a VCG, 4) statistical analysis when introducing a VCG, and 5) facility monitor (sentinel) animals. Current regulatory guidelines require a concurrent control group for a pivotal toxicology study, whose results, if do not meet the requirements of these guidelines, cannot be used for new drug approval applications. Even if the use of VCGs is justified from animal welfare and scientific points of view, it is critical that the industry work with health authorities to ensure that data from these studies are accepted. The Japan Pharmaceutical Manufacturers Association will continue to hold necessary discussions with key stakeholders to accelerate efficient and effective new drug development pertaining to the use of VCGs.

Medication history is a series of data for each patient recorded by pharmacists in daily clinical practice in Japanese pharmacies. This real-world data potentially contains useful information on various risks induced by drugs; however, this information has rarely been used. Therefore, we aimed to verify whether medication histories can be used for drug-induced risk assessment by comparing them with known events as references. To this end, we chose previously reported large-scale trials indicating that anticholinergic drugs for overactive bladder (OAB) are associated with the risk of inducing dementia. We referred to these studies and conducted a retrospective study based on the medication histories of 172,958 patients aged 55 years or older visiting a community pharmacy. Six drugs for OAB (oxybutynin, propiverine, tolterodine, fesoterodine, solifenacin, and imidafenacin) were tested for their risk of inducing dementia, which was determined at the start of using one of the four drugs for dementia (donepezil, galantamine, rivastigmine, and memantine). The association between OAB medications and dementia was assessed using odds ratios (ORs) and 95% confidence intervals (95% CIs). The analysis included 2,634 patients in the case group and 170,324 patients in the control group. A significant difference was observed between the case and control groups (OR, 2.12; 95% CI, 1.66–2.67), indicating that anticholinergic drugs increased the risk of developing dementia. The results were equivalent to those of the referenced large-scale clinical trials, suggesting that medication histories are useful for drug-induced risk assessment.

The effectiveness of vaccines in preventing infection from specific pathogens is closely related to the magnitude of the antigen-specific T cell and antibody responses induced by the vaccine. These responses depend on the immune states of the individual, which is shaped by genetic and environmental factors. Recent studies using omics technologies identified immune cells, genes, and gut microbial species and metabolic pathways at baseline or during early vaccine responses as correlates of vaccine responses. These findings shed light on the molecular and cellular mechanisms underlying the inter-individual differences in vaccine responses. In this review, we provide an overview of correlates of recently developed COVID-19 mRNA vaccine-induced adaptive immune responses.

Macrophages infiltrate lesions in diseases such as inflammation, tumors, and fibrotic tissues. Once recruited to the lesion sites, macrophages are activated and acquire diverse phenotypes depending on the stimuli in the microenvironment. Activated macrophages contribute to disease progression and are crucial targets in disease therapy because of their significant impact on immune responses through various effector functions, such as cytokine production, phagocytosis, and antigen presentation. Various approaches, including the regulation of macrophage recruitment, activation, and cancer suppression, have been demonstrated to have therapeutic effects. The challenge in modulating macrophages is that therapies aimed at regulating one aspect of macrophage properties may have unintended effects on another, potentially causing adverse effects. This review describes a therapeutic approach for regulating macrophages, focusing on FROUNT, a novel target molecule that induces macrophage migration and activation of regulatory molecules. FROUNT promotes signaling via chemokine receptors CCR2 and CCR5, modulating the intensity of chemokine signaling responses; thus, becoming a promising target for modulating macrophage function and safely controlling cancer and inflammation. By disrupting the interaction between FROUNT and chemokine receptors, we selectively regulated chemokine receptor signals mediated by FROUNT, suppressed the infiltration and activation of macrophages at lesion sites, and mitigated the pathogenesis of macrophage-related conditions such as nephritis and cancer. Targeting molecules that promote chemokine receptor–signaling could be a next-generation macrophage-targeted therapy with fewer side effects and higher efficacy than existing drugs for cancer and inflammation.