Pharmaceuticals and Medical Devices Agency

ABSTRACT Pyrimethanil [PMT] is one of the most preferred fungicides for controlling grey mould, wilt, leaf scab, and blight diseases in fruits and vegetables. A disposable, inexpensive, simple, and sensitive modified silver nanoparticles/poly-L-cysteine pencil graphite electrode [AgNPs/poly(L-cys)/PGE] was developed using an electrodeposition technique to study the electrochemical behaviour and determination of the PMT in pH 4.0 phosphate-citric acid buffer solution. The surface morphology and surface area of the sensor were elucidated using scanning electron microscope [SEM] and cyclic voltammetry [CV], respectively. To study the electrochemical behaviour and quantitative determination of PMT by square wave voltammetry [SWV] on AgNP/poly(L-cys)/PGE, parameters such as pH, frequency, step potential, and pulse amplitude, which have significant effects on the current and potential, were optimised separately at first time. Under optimum experimental conditions, the linear dynamic range [LDR] was 20.0–500.0 μg/L, and the limit of detection [LOD] and limit of quantification [LOQ] values were highly sensitive at 20.24 μg/L and 67.47 μg/L, respectively. Additionally, the interference effects of some pesticides were studied, and PMT was analysed with high recovery and low relative error. Finally, the analytical application of the proposed method and modified AgNPs/poly(L-cys)/PGE was successfully demonstrated in real samples, such as the commercial drug Mythos® and tap water. Accordingly, 3.0 µM PMT prepared from MYTHOS® drug was found to be 2.98 ± 0.03 µM at 95% confidence level (n = 3) and was determined with 99.56% recovery, 0.39% relative standard deviation and ̶ 0.43% relative error. Ultimately, a fully validated, simple, inexpensive, sensitive, reproducible, environmentally friendly, miniature, and disposable nanosensor for the determination of PMT was developed.

ABSTRACTIndividual predictions of long‐term chronic disease progression from data of limited duration provide valuable insights into estimating patient outcomes and therapeutic needs. Statistical Restoration of Fragmented Time course (SReFT) was developed to address this challenge, yet it is computationally too intensive for large‐scale datasets. Although diabetes is a representative chronic disease with significant medical needs, it has been challenging to analyze long‐term changes using large‐scale patient data due to this limitation. In this study, we aimed to develop a new method (SReFT‐machine learning, SReFT‐ML) by applying machine learning to the concept of SReFT, and to confirm its performance using synthetic data and the data from a clinical trial, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 10,251). SReFT‐ML has successfully analyzed both synthetic and clinical data, and reconstructed biomarker trajectories over a 30‐year period in patients with diabetes. Decreases in diastolic blood pressure and renal function may be important indicators of disease progression. Furthermore, although age and mortality data were not included in the model, survival analysis demonstrated a clear trend of hazard increases in mortality and diabetes‐related outcomes with disease progression. This study introduced machine learning to enhance long‐term disease progression modeling. The resulting model characterized a 30‐year trajectory of disease risk in diabetes. The results provide a clinically meaningful hypothesis that incorporating systemic factors such as renal function and blood pressure, in addition to classic glycemic control, may enhance comprehensive diabetes care.Trial Registration:ClinicalTrials.gov number: NCT00000620

A biowaiver generally refers to the request to waive an in vivo bioequivalence study. A biowaiver may be granted not only based on the Biopharmaceutics Classifications System (BCS) but also for many immediate-release dosage forms based on pre-defined criteria. The current paper summarises the results from a survey of the biowaiver requirements for cutaneous/topical products (topical solutions, gels, suspensions, ointments, and creams), ear/otic and ophthalmic solutions and suspensions, enemas in solution and suspension, and vaginal solid dosage forms and suppositories defined by the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the results from the survey indicates that there is a trend towards convergence when the dosage forms are less complex; however, the most common approach used by each of the participants was a case-by-case approach given that most participants do not have well-defined guidelines to support all possible scenarios. Notwithstanding the differences, disseminating information is the first step towards regulatory convergence regarding biowaivers for certain dosage forms and will be useful for pharmaceutical companies currently developing generic medicinal products for countries represented by IPRP participants.

This perspective focuses on the current and future regulatory landscape in Japan regarding food effect studies of orally administered drugs. Our study of new drugs shows that the drugs classified as Biopharmaceutics Classification System (BCS) Class I exert minimal food effects on systemic pharmacokinetics (Cmax and AUC). This work will facilitate discussions to refine drug development and regulatory frameworks regarding the waiver of food effect studies using final formulations.

Information on biosimilars was rarely disseminated on the Pharmaceuticals and Medical Devices Agency (PMDA) website of the Japanese Regulatory Agency until the fiscal year (FY) 2022. Therefore, the PMDA website for biosimilars was created in FY 2023. This study confirmed the PMDA website for biosimilars and surveyed information about the approval fiscal year, brand name, indications at the initial approval, type of biopharmaceuticals, and disease area at the initial approval based on review reports and the "List of Approved Products." The PMDA website for biosimilars provides information on the definition of biosimilar, approved biosimilar products, related guidelines and notifications, learning videos, presentation material, and publication articles. As of March 2024, 35 biosimilars were approved in Japan based on the following 18 active pharmaceutical ingredients: somatropin, epoetin-alfa, filgrastim, infliximab, insulin glargine, rituximab, etanercept, trastuzumab, agalsidase beta, bevacizumab, teriparatide, darbepoetin-alfa, insulin lispro, adalimumab, insulin aspart, ranibizumab, pegfilgrastim, and ustekinumab. The disease area comprised nine patterns: rheumatology, oncology, hematology, gastroenterology, dermatology, endocrinology, ophthalmology, bone, and inborn errors represented in numbers and percentages for each pattern: 12 (23.1%), 9 (17.3%), 8 (15.4%), 7 (13.5%), 7 (13.5%), 5 (9.6%), 2 (3.8%), 1 (1.9%), and 1 (1.9%), respectively. This website provides various information regarding biosimilars in Japan. It will be more important to effort the understanding and education for the healthcare providers and patients on biosimilar regulations. Moreover, information should be disseminated through the PMDA website of biosimilars to accelerate and ensure transparency regarding regulatory approvals and biosimilar regulations.

Background To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis. Method We conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/μL) or grade 3 (neutrophil count < 1,000/μL) neutropenia. Results Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27–2.51) for grade 2 and 0.40 (0.02–7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28–2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62–24.48) for grade 2 and 0.43 (0.02–11.63) for grade 3 neutropenia. Conclusion No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.

The Japanese biosimilar guideline requires that the sponsors conduct clinical studies such as comparative pharmacokinetic (PK), pharmacodynamic (PD), or efficacy studies. In each biosimilar development, the sponsors consider the clinical data package, and thus clinical data packages vary among biosimilar developments. The aim of this study was to elucidate the clinical data packages for the biosimilars approved in Japan. The details of clinical data packages and sample size for the regulatory approvals of biosimilars in Japan was reported. We surveyed the clinical data packages and sample size based on the Pharmaceuticals and Medical Devices Agency (PMDA) website review reports between 2009 and 2023. Twenty-four biosimilars have been approved based on the comparative PK and efficacy studies, 10 biosimilars have been approved based on the comparative PK/PD study, and one biosimilar has been approved based on the comparative efficacy study. Regarding the sample size, comparative PK studies were conducted in healthy volunteers or patients for up to 300 cases, although the majority enrolled only 1-100 cases (68.1%, 32/47). Comparative PD studies enrolling 1-30, 31-60, and 61-90 cases totaled 4, 7, and 4 cases, respectively. Finally, comparative efficacy studies enrolling 1-300, 301-600, and 601-900 totaled 6, 10, and 11 cases, respectively. In particular, the oncology and rheumatology areas were the first and second disease areas recruiting 601-900 patients. Large numbers of patients were enrolled to conduct a comparative efficacy study. Efficient biosimilar development should be considered on the basis of the accumulation of scientific understanding of comparable features of biosimilars and their development.