Genetic and clinical features of neonatal and early onset diabetes mellitus in a tertiary center cohort in Brazil.

Neonatal diabetes mellitus (NDM) is defined as the occurrence of severe hyperglycemia in infants under 6 months old and may be permanent (PNDM) or transient (TNDM). When diabetes is diagnosed at 6-12 months of age (early onset diabetes [EOD]), the etiology may be monogenic; however, most cases consist of type 1 diabetes mellitus (T1DM). Molecular diagnosis was determined in a cohort of 35 unrelated Brazilian patients with NDM or EOD based on targeted next-generation sequencing panel and/or chromosome 6q24 abnormalities. The impact of genetic testing on treatment and follow-up was evaluated. Overall, 24 patients had NDM: with 18 (75.0%) having PNDM, 5 TNDM (20.8%) and 1 case in which this information was unknown. Eleven patients had EOD. Genetic testing was positive in 20/24 patients with NDM (83.3%) and in 18.2% of cases of EOD. The commonest causes were ATP-sensitive potassium (KATP) channel genes, and GCK and IPEX mutations (37.1%, 11.4% and 5.7%, respectively). Patients with PNDM due to KCNJ11 and ABCC8 mutations transitioned successfully to sulfonylureas in almost 60% of cases, reinforcing the benefit of performing genetic testing in NDM as early as possible. This report refers to the largest series of cases of NDM (TNDM and PNDM) and EOD in Brazil in which patients were submitted to molecular investigation and in which the clinical impact of genetic diagnosis was also evaluated.

Can Patients With Metal Hypersensitivity Requiring TMJ Total Joint Prostheses be Successfully Treated With All-Titanium Alloy Mandibular Components?

PURPOSE: Patients with documented metal hypersensitivity to cobalt-chromium-molybdenum (CoCrMo) alloy with trace nickel requiring temporomandibular joint (TMJ) total joint prosthesis (TJP) may have adverse reactions to the metals in the standard TMJ Concepts TJP. This study aimed to determine if these patients can be successfully treated by eliminating CoCrMo alloy and constructing the mandibular components of all-titanium (Ti) alloy. PATIENTS AND METHODS: This retrospective cohort study evaluated metal hypersensitive patients (MHG) that received the TMJ Concepts TJP modification of all-Ti alloy mandibular components with outcome results compared to a control group (CG) of non-metal-sensitive patients that received the standard TMJ Concepts prostheses. The primary predictor variables were the 2 groups, MHG and CG. Primary variables evaluated using Likert scales included TMJ pain, headache, jaw function, diet, and disability. Maximum incisal opening and quality of life were measured. Secondary variables included: age, gender, effect of the number and type of prior TMJ surgeries. Scores for pre- and postsurgery parameters (nonparametric variables) were analyzed using a Mann-Whitney U test (α = 0.05). RESULTS: The MHG (n = 30) received the Ti alloy TJP and CG (n = 46) received the standard TJP, with statistically significant improvements in all variables in both groups and no statistically significant difference in outcome variables between the 2 groups. Patients with 0 to 1 previous TMJ surgeries had better outcomes in all parameters except maximum incisal opening compared to patients with 2 or more previous TMJ surgeries. CONCLUSIONS: Patients with documented hypersensitivity to CoCrMo alloy, requiring TMJ Concepts TJP may experience improvement in TMJ pain, headache, jaw function, diet, disability, jaw opening, and quality of life when the mandibular components are manufactured from all-Ti alloy, eliminating the CoCrMo alloy. The larger the number of previous TMJ surgeries and exposure to failed alloplastic implants, the less improvement in treatment outcomes.

Impact of Social Isolation on Physical Activity and Factors Associated With Sedentary Behavior in Older Adults During the COVID-19 Pandemic.

The objective was to analyze the impact of social isolation on moderate physical activity and factors associated with sedentary behavior of older adults during the COVID-19 pandemic. This was a cross-sectional study involving 111 older adults (aged 71.0 ± 6.87 years). The data were collected at two time points: in November 2019 and in June 2020. There was a decline in moderate physical activity when the minutes/week were compared before and during social isolation (p < .001). Sedentary behavior was associated with the condition of living alone. Older adults who lived alone were 3.29 times more likely to spend 4 hr or more in sedentary behavior than those who lived with a partner (95% confidence interval [1.01, 10.74]). Government agencies must establish PA-related health promotion strategies, especially in developing and low-income countries. Therefore, home exercises need to be encouraged to prevent the consequences of this pandemic period.

Stability-indicating method for the novel antifungal compound RI76: Characterization and in vitro antifungal activity of its active degradation product.

RI76 is a novel 2-thiazolylhydrazone compound with reported antifungal activity. In preclinical drug development, it is fundamental to know the impurity profile and to understand degradation mechanisms of the molecule. In our study, RI76 was subjected to forced degradation conditions, and a stability-indicating HPLC-DAD method was developed and validated. Separation was carried out on a C18 column (150 × 4.6 mm i.d., 5 µm) maintained at 40°C using a 1 mL/min flow rate of 2 mM ammonium acetate with 0.1% formic acid (pH 3.0) and acetonitrile in gradient mode. The method was linear in the range of 0.7-91 µg/mL for RI76 and 0.7-25 µg/mL for its degradation product PD76. The formation of a major degradation product was quickly observed when RI76 was in aqueous solution. The chemical structure of this product, named PD76, was proposed based on LC-UV-MS experiments, synthesized in-house, and confirmed by NMR spectroscopy and chromatographic analysis. In vitro antifungal activity assays demonstrated that this resultant product shows a promising activity against clinically important Candida and Cryptococcus strains, matching or surpassing the activity of its precursor and of well-established antifungal drugs.

Purity determination of a new antifungal drug candidate using quantitative 1 H NMR spectroscopy: Method validation and comparison of calibration approaches.

Quantitative nuclear magnetic resonance (qNMR) is an analytical technique that offers numerous advantages in pharmaceutical applications including minimum sample preparation and rapid data collection times with no need for response factor corrections, being a powerful tool for assaying drug content in both drug discovery and early drug development. In the present work, we have applied qNMR, using both the internal standard and the electronic reference to access in vivo concentrations 2 calibration methods, to assess the purity of RI76, a novel antifungal drug candidate. NMR acquisition and processing parameters were optimized in order to obtain spectra with intense, well-resolved signals of completely relaxed nuclei. The analytical method was validated following current guidelines, demonstrating selectivity, linearity, accuracy, precision, and robustness. The calibration approaches were statistically compared, and no significant difference was observed when comparing the obtained results and their dispersion in terms of relative standard deviation. The proposed qNMR method may, therefore, be used for both qualitative and quantitative assessments of RI76 in early drug development and for characterization of this compound.

Development and Validation of an HPLC Method for Simultaneous Determination of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochloride in Pharmaceutical Formulations.

Tuberculosis treatment consists of a fixed dose combination of rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ), and ethambutol hydrochloride (EMB). The combined treatment using various drugs is necessary for patient curing, without recrudescence, and for prevention of drug-resistant mutants, which may occur during treatment. An HPLC-diode array detector (DAD) method for the simultaneous determination of RIF, INH, PYZ, and EMB in fixed dose combination tablets was developed and validated. Chromatographic experiments were performed on an Agilent 1200 HPLC system, and the separation was carried out on a Purospher STAR RP18e (250×4.6 mm id, 5 µm, Merck) analytical column. Gradient elution was carried out with a mobile phase of 20 mM monobasic sodium phosphate buffer with 0.2% triethylamine (pH 7.0) and acetonitrile at a flow rate of 1.5 mL/min. The total run time was 12 min, and the re-equilibration time was 5 min. EMB detection was performed at 210 nm, and RIF, INH, and PYZ were detected at 238 nm, using a DAD. The method proved to be specific, linear (r2>0.99), precise (RSD<2%), accurate, and robust and may be applied to the QC analysis of pharmaceutical formulations.

Magnesium Transporter MgtA revealed as a Dimeric P-type ATPase.

Magnesium (Mg2+) uptake systems are present in all domains of life given the vital role of this ion. Bacteria acquire Mg2+ via conserved Mg2+ channels and transporters. The transporters are required for growth when Mg2+ is limiting or during bacterial pathogenesis, but, despite their significance, there are no known structures for these transporters. Here we report the first structure of the Mg2+ transporter MgtA solved by single particle cryo-electron microscopy (cryo-EM). Using mild membrane extraction, we obtained high resolution structures of both a homodimeric form (2.9 Å), the first for a P-type ATPase, and a monomeric form (3.6 Å). Each monomer unit of MgtA displays a structural architecture that is similar to other P-type ATPases with a transmembrane domain and two soluble domains. The dimer interface consists of contacts between residues in adjacent soluble nucleotide binding and phosphotransfer regions of the haloacid dehalogenase (HAD) domain. We suggest oligomerization is a conserved structural feature of the diverse family of P-type ATPase transporters. The ATP binding site and conformational dynamics upon nucleotide binding to MgtA were characterized using a combination of cryo-EM, molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and mutagenesis. Our structure also revealed a Mg2+ ion in the transmembrane segments, which, when combined with sequence conservation and mutagenesis studies, allowed us to propose a model for Mg2+ transport across the lipid bilayer. Finally, our work revealed the N-terminal domain structure and cytoplasmic Mg2+ binding sites, which have implications for related P-type ATPases defective in human disease.

Effect of Degradation on the Physicochemical and Mechanical Properties of Extruded Films of Poly(lactic acid) and Chitosan.

This study addresses the fabrication of extruded films using poly(lactic acid) (PLA) and chitosan, with and without maleic anhydride as a compatibilizing agent, for potential applications in disposable food packaging. These films underwent controlled conditions of UV irradiation, water condensation, and temperature variations in an accelerated weathering chamber. The investigation analyzed the effect of different exposure periods on the structural, morphological, mechanical, and thermal properties of the films. It was observed that PLA films exhibited a lower susceptibility to degradation compared to those containing chitosan. Specifically, the pure PLA film showed an increase in elastic modulus and strength during the initial 144 h of exposure, associated with cross-linking induced by UV radiation. On the other hand, film Q2 composed of PLA, chitosan, and maleic anhydride and Q1 without maleic anhydride experienced a tensile strength loss of over 50% after 244 h of exposure. The Q2 film exhibited greater homogeneity, leading to increased resistance to degradation compared to that of Q1. As the degradation time increased, both the Q1 and Q2 films demonstrated a decline in thermal stability. These films also exhibited alterations in crystallinity attributed to the chemo-crystallization process, along with fluctuations in the glass transition temperature and crystallization, particularly at 288 h.

Regulatory Pathways Supporting Expedited Drug Development and Approval in ICH Member Countries.

Regulators and pharmaceutical companies across the world are intensifying efforts to get increasingly complex and innovative drugs to patients with high unmet medical need in the shortest possible time frame. This article reviews pathways to expedite drug development and approval available in member countries of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Australia. It is concluded that the increasing availability of expedited regulatory pathways and associated modernisation of regulatory systems changes the current regulatory paradigm and requires sponsors to rethink drug development and regulatory strategy. A transformation of the current sequence of regulatory submissions, favouring those countries/collaborations that are best regulatory equipped to make innovative medical need drugs available to patients in the shortest time frame is imminent.

Assessing the Effect of Cellulose Nanocrystal Content on the Biodegradation Kinetics of Multiscale Polylactic Acid Composites under Controlled Thermophilic Composting Conditions.

This work studied the effect of cellulose nanocrystal (NCC) content on the biodegradation kinetics of PLA-based multiscale cellulosic biocomposites (PLAMCBs). To facilitate biodegradation, the materials were subjected to thermo-oxidation before composting. Biodegradation was carried out for 180 days under controlled thermophilic composting conditions according to the ASTM D 5338 standard. A first-order model based on Monod's kinetics under limiting substrate conditions was used to study the effect of cellulose nanocrystal (NCC) content on the biodegradation kinetics of multiscale composite materials. It was found that thermo-oxidation at 70 °C for 160 h increased the biodegradability of PLA. Also, it was found that the incorporation of cellulosic fibrous reinforcements increased the biodegradability of PLA by promoting hydrolysis during the first stage of composting. Likewise, it was found that partial substitution of micro cellulose (MFC) by cellulose nanocrystals (NCCs) increased the biodegradability of the biocomposite. This increase was more evident as the NCC content increased, which was attributed to the fact that the incorporation of cellulose nanocrystals facilitated the entry of water into the material and therefore promoted the hydrolytic degradation of the most recalcitrant fraction of PLA from the bulk and not only by surface erosion.

The performance of the MODY calculator in a non-Caucasian, mixed-race population diagnosed with diabetes mellitus before 35 years of age.

BACKGROUND: A maturity-onset diabetes of the young (MODY) calculator has been described and validated for use in European Caucasians. This study evaluated its performance in Brazilians diagnosed with diabetes mellitus (DM) before 35 years of age. METHODS: The electronic records of 391 individuals were reviewed in 2020 at the diabetes clinic of a quaternary hospital in São Paulo were analyzed: 231 with type 1 DM (T1DM), 46 with type 2 (T2DM) and 114 with MODY. The MODY calculator was applied to the three groups. A receiver operating characteristic curve was calculated to obtain cut-off points for this population. RESULTS: The principal differences between the MODY and the T1DM and T2DM groups were body mass index, a positive family history of diabetes and mean HbA1c level. Age at diagnosis in the MODY group was only significantly different compared to the T2DM group. Specificity and sensitivity were good for the cut-off points of 40%, 50% and 60%, with the accuracy of the model for any of these cut-off points being > 95%. CONCLUSION: The capacity of the calculator to identify Brazilian patients with MODY was good. Values ≥ 60% proved useful for selecting candidates for MODY genetic testing, with good sensitivity and specificity.

Ballistic Behavior of Bioinspired Nacre-like Composites.

In this paper, the ballistic performance of a multilayered composite inspired by the structural characteristics of nacre is numerically investigated using finite element (FE) simulations. Nacre is a natural composite material found in the shells of some marine mollusks, which has remarkable toughness due to its hierarchical layered structure. The bioinspired nacre-like composites investigated here were made of five wavy aluminum alloy 7075-T651 (AA7075) layers composed of ~1.1-mm thick square tablets bonded together with toughened epoxy resin. Two composite configurations with continuous layers (either wavy or flat) were also studied. The ballistic performance of the composite plates was compared to that of a bulk monolithic AA7075 plate. The ballistic impact was simulated in the 300-600 m/s range using two types of spherical projectiles, i.e., rigid and elastoplastic. The results showed that the nacre plate exhibited improved ballistic performance compared to the bulk plate and the plates with continuous layers. The structural design of the nacre plate improved the ballistic performance by producing a more ductile failure and enabling localized energy absorption via the plastic deformation of the tablets and the globalized energy dissipation due to interface debonding and friction. All the plate configurations exhibited a better ballistic performance when impacted by an elastoplastic projectile compared to a rigid one, which is explained by the projectile plastic deformation absorbing some of the impact energy and the enlarged contact area between the projectile and the plates producing more energy absorption by the plates.

Anacardium occidentale L. (cajueiro) in the healing of skin wounds: an experimental study in rats.

PURPOSE: To analyze the effects of Anacardium occidentale Linn on the healing of skin wounds. METHODS: Twenty Wistar male rats were distributed into four groups (with five animals each one): negative control group (NCG), treated with saline solution; cashew tree group (CG), treated with hydroalcoholic extract of the bark of A. occidentale Linn; manipulated cashew tree group (MCG), with the ointment of extract of the bark of A. occidentale Linn; positive control group (PCG), treated with sunflower oil. All animals were examined daily, observing the macroscopic aspects of the surgical wound. Hematoxylin-eosin staining was used for tissue morphology analysis and Masson's trichrome for better collagen fiber characterization. RESULTS: On day 7, the MCG group had the expansion of the surgical wound covered by crust, exceeding the initial limits. On day 21, the wounds were observed to be completely closed and epithelialized in the NCG and CG groups. PCG and MCG still had remnants of crusts on the wound. The NCG was the only one not to present an abscess in histopathological analysis. CONCLUSIONS: There was a prolongation of the healing phase of the animals treated with the extract, and the animals in the NCG showed a better outcome by histological analysis.

Preparation and Characterization of Extruded PLA Films Coated with Polyaniline or Polypyrrole by In Situ Chemical Polymerization.

Conductive polymers, such as polypyrrole and polyaniline, have been extensively studied for their notable intrinsic electronic and ionic conductivities, rendering them suitable for a range of diverse applications. In this study, in situ chemical polymerization was employed to coat extruded PLA films with PPy and PANi. Morphological analysis reveals a uniform and compact deposition of both polyaniline and polypyrrole after polymerization periods of 3 and 1 h, respectively. Furthermore, the PLA-PANi-3h and PLA-PPy-1h composites exhibited the highest electrical conductivity, with values of 0.042 and 0.022 S cm-1, respectively. These findings were in agreement with the XPS results, as the polyaniline-coated film showed a higher proportion of charge carriers compared to the polypyrrole composite. The elastic modulus of the coated films showed an increase compared with that of pure PLA films. Additionally, the inflection temperatures for the PLA-PANi-3h and PLA-PPy-1h composites were 368.7 and 367.2 °C, respectively, while for pure PLA, it reached 341.47 °C. This improvement in mechanical and thermal properties revealed the effective interfacial adhesion between the PLA matrix and the conducting polymer. Therefore, this work demonstrates that coating biopolymeric matrices with PANi or PPy enables the production of functional and environmentally friendly conductive materials suitable for potential use in the removal of heavy metals in water treatment.

Clinical and genetic characterization and long-term evaluation of individuals with maturity-onset diabetes of the young (MODY): The journey towards appropriate treatment.

AIMS: To describe the clinical and genetic characteristics and long-term follow-up of a cohort with maturity-onset diabetes of the young (MODY), and to evaluate how molecular diagnosis impacted on treatment. METHODS: A large observational, retrospective, cohort study included individuals referred to the University of São Paulo's Monogenic Diabetes Unit between 2011 and 2020. Comprehensive clinical and genetic evaluations were performed. RESULTS: Overall, 228 individuals (190 GCK-MODY and 38 HNF1A-MODY) were enrolled. Sixty-two different GCK gene mutations (5 novel) and 17 HNF1A gene mutations (2 novel) were found. Data were available on treatment status for 76 index individuals with GCK-MODY. Before molecular diagnosis, nutritional intervention alone was used in 41 cases (53.9%). After molecular diagnosis, this number increased to 72 (94.8%). Glycated haemoglobin (HbA1c) remained stable over the 6-year follow-up period: 6.5% (47 mmol/mol) at the first and 6.3% (45 mmol/mol) at the final visit (p = 0.056). Prior to molecular diagnosis, 7/21 (33.3%) HNF1A-MODY individuals were using sulfonylurea compared to 17/21 (81%) after testing. After a median of 5 years on sulfonylureas, HbA1c values improved from 7.5% (58 mmol/mol) to 6.5% (48 mmol/mol) (p = 0.006). CONCLUSIONS: Molecular diagnosis resulted in appropriate adjustment of treatment in approximately 80% of participants with GCK-MODY or HNF1A-MODY.

Tensile Behavior of 3D Printed Polylactic Acid (PLA) Based Composites Reinforced with Natural Fiber.

Natural fiber-reinforced composite (NFRC) filaments for 3D printing were fabricated using polylactic acid (PLA) reinforced with 1-5 wt% henequen flour comprising particles with sizes between 90-250 µm. The flour was obtained from natural henequen fibers. NFRCs and pristine PLA specimens were printed with a 0° raster angle for tension tests. The results showed that the NFRCs' measured density, porosity, and degree of crystallinity increased with flour content. The tensile tests showed that the NFRC Young's modulus was lower than that of the printed pristine PLA. For 1 wt% flour content, the NFRCs' maximum stress and strain to failure were higher than those of the printed PLA, which was attributed to the henequen fibers acting as reinforcement and delaying crack growth. However, for 2 wt% and higher flour contents, the NFRCs' maximum stress was lower than that of the printed PLA. Microscopic characterization after testing showed an increase in voids and defects, with the increase in flour content attributed to particle agglomeration. For 1 wt% flour content, the NFRCs were also printed with raster angles of ±45° and 90° for comparison; the highest tensile properties were obtained with a 0° raster angle. Finally, adding 3 wt% content of maleic anhydride to the NFRC with 1 wt% flour content slightly increased the maximum stress. The results presented herein warrant further research to fully understand the mechanical properties of printed NFRCs made of PLA reinforced with natural henequen fibers.

Essential oils of Taxandria fragrans and Melaleuca alternifolia have effective antidermatophytic activities in vitro and in vivo that are antagonised by ketoconazole and potentiated in gold nanospheres.

The investigation of the effects of three essential oils (EOs) from Taxandria fragrans (FRA), Melaleuca alternifolia (TTO) and Boswellia serrata (IF), alone and combined with ketoconazole (KTZ), and their functionalised gold nanoparticles (AuNP) against Trichophyton interdigitale both in vitro and in vivo indicated that EOs presented activity against T. interdigitale. The combination of EOs and KTZ was antagonistic. FRA, TTO, gold nanoparticles capped with T. fragrans (AuNPFRA) and gold nanoparticles capped with M. alternifolia (AuNPTTO) presented antidermatophytic activity in vivo, with the capacity to reduce fungal burden and to preserve tissue architecture; however, combination treatment with KTZ increased fungal burden and caused tissue damage. The combination of EO with KTZ exhibited antagonistic activity and was histologically harmful. In contrast, FRA, TTO, AuNPFRA and AuNPTTO are promising treatments for dermatophytosis.

Electrochemical evidence of nitrate release from the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid and its antinociceptive and anti-inflammatory activities in mice.

Considering the many biological activities of nitric oxide (NO), some lines of research focused on the modulation of these activities through the provision of this mediator by designing and synthesizing compounds coupled with an NO donor group. Thus, the objectives of the present study were to carry out an electrochemical investigation of the nitrooxy compound 4-((nitrooxy) methyl)-3-nitrobenzoic acid (1) and evaluate its activities and putative mechanisms in experimental models of pain and inflammation. Voltammetric studies performed in aprotic medium (mimetic of membranes) showed important electrochemical reduction mechanisms: nitroaromatic reduction, self-protonation, and finally reductive elimination, which leads to nitrate release. Systemic administration of the nitrooxy compound (1) inhibited the nociceptive response induced by heat and the tactile hypersensitivity and paw edema induced by carrageenan in mice. The activities in the models of inflammatory pain and edema were associated with reduced neutrophil recruitment and production of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and CXCL-1, and increased production of IL-10. Concluding, electrochemical analysis revealed unequivocally that electron transfer at the nitro group of the nitrooxy compound (1) results in the cleavage of the organic nitrate, potentially resulting in the generation of NO. This electrochemical mechanism may be compared to a biochemical electron-transfer mediated nitrate release that, by appropriate in vivo bioreduction (enzymatic or not) would lead to NO production. Compound (1) exhibits activities in models of inflammatory pain and edema that may be due to reduced recruitment of neutrophils and production of inflammatory cytokines and increased production of IL-10. These results reinforce the interest in the investigation of NO donor compounds as candidates for analgesic and anti-inflammatory drugs.

Mechanical Properties of Natural Fiber Reinforced Foamed Concrete.

The mechanical characterization of plain foamed concrete (PFC) and fiber-reinforced foamed concrete (FRFC) with a density of 700 kg/m3 was performed with compression and tension tests. FRFC was reinforced with the natural fiber henequen (untreated or alkaline-treated) at volume fractions of 0.5%, 1% and 1.5%. Polypropylene fiber reinforcement was also used as a reference. For all FRFCs, the inclusion of the fibers enhanced the compressive and tensile strengths and plastic behavior, which was attributed to the increase of specimen integrity. Under compressive loading, after the peak strength, there was no considerable loss in strength and a plateau-like regime was observed. Under tensile loading, the fibers significantly increased the tensile strength of the FRFCs and prevented a sudden failure of the specimens, which was in contrast to the brittle behavior of the PFC. The tensile behavior enhancement was higher when treated henequen fibers were used, which was attributed to the increase in the fiber-matrix bond produced by the alkaline treatment. The microscopic characterization showed that the inclusion of fibers did not modify the air-void size and its distribution. Higher energy absorption was observed for FRFCs when compared to the PFC, which was attributed to the enhanced toughness and ductility by the fibers. The results presented herein warrant further research of FRFC with natural henequen fibers for engineering applications.

Clinical Development and Initial Approval of Novel Immune Checkpoint Inhibitors in Oncology: Insights From a Global Regulatory Perspective.

Immune checkpoint inhibitors (ICI) have demonstrated meaningful patterns of clinical efficacy across various cancers. During their development, novel regulatory strategies and clinical design approaches were explored. This metrics-based narrative review examines submission strategies and clinical evidence expectations of the US, European, and Japanese drug agencies, as well as their impact on approval and overall development times. Also discussed is the role of emerging clinical science and biomarker evaluation to get the first six ICI initially approved.