Comparison of the Speed of Enrollment for Clinical Trials Conducted by Japanese and Global Pharmaceutical Companies.

Since the establishment of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), many countries in the world have rapidly improved their clinical trial performance, and the era has come to compare the clinical trial performance of each country. Japan's clinical trials are considered excellent quality, but costly and slow. In this study, we examined the speed of enrollment period in clinical trials. We surveyed clinical trials from January 1, 2010, to December 31, 2019, covering the top 10 pharmaceutical companies in each global sales ranking (Global 10) and the Japanese sales ranking (Japan 10). Clinical trial data were obtained from ClinicalTrials.gov, a clinical trial registration information database, and the speed of participant enrollment (cases/month) was compared for each phase of the trials. The number of clinical trials conducted during the 10 years was 8938 trials for Global 10 and 1439 trials for Japan 10. Comparing the speed of participant enrollment by phase, Japan 10 was significantly faster in phase 1 for both healthy subjects and oncology patients. [Japan 10: Global 10; 15.1 : 12.0 cases/month (healthy subjects) and 5.5 : 1.8 cases/month (oncology), respectively. p < 0.001]. Global 10 was also significantly faster in phase 3. [Japan 10: Global 10; 12.4: 36.9 cases/month, p < 0.001). No significant difference was observed in phase 2 and phase 4. There was a possibility that the speed of enrollment differed by phase between global companies and Japanese domestic companies.

Subvisible Particles Derived by Dropping Stress Enhance Anti-PEG Antibody Production and Clearance of PEGylated Proteins in Mice.

Bioconjugation with polyethylene glycol (PEG) is important for protein drug development as it has improved biological stability. In contrast, proteins including PEGylated ones are susceptible to physicochemical stresses. Particularly, protein drugs in solution may form aggregates or subvisible particles if they are exposed to dropping stress during transportation. However, many PEGylation studies have focused on its usefulness, such as the extension of half-life in blood, and changes in the physical properties or biological responses of PEGylated proteins under dropping stress remain unexplored. Here, we prepared four PEGylated ovalbumin (PEG-OVA) molecules conjugated with different lengths (5 or 20 kDa) and numbers (large [L] or small [S]) of PEG, analyzed the formation of subvisible particles under dropping stress, and examined their impact on antibody production and clearance. Under dropping stress, the aggregated particle concentration of 20 kDa PEG-OVA (S) and (L) solutions was approximately 3-fold that of the OVA solution. Moreover, administration of 20 kDa PEG-OVA with dropping stress induced anti-PEG antibody production and clearance of PEG-OVA. As a mechanism, dropping stress could enhance the uptake of 20 kDa PEG-OVA (L) by macrophages. These findings could provide insights into proper transportation conditions to ensure the quality of PEGylated protein drugs.

Assessment of Drugs Approved by Public Knowledge-Based Applications (Kouchi-shinsei) During the Last Two Decades in Japan.

Public knowledge-based application ("Kouchi-shinsei" in Japanese) is unique to Japan, implemented to eliminate the off-label use of unapproved indications, dosages, and administrations because of drug lag. The guidance for public knowledge-based application was issued in 1999. This study comprehensively investigated the trends of items approved by public knowledge-based application in Japan during the last 2 decades. Prescription drugs approved from January 2000 to December 2019 were surveyed. In Japan, 1,855 drugs were approved within the target survey period. Among them, 219 (11.8%) were approved by public knowledge-based application. Considering the changes in the number of items approved by public knowledge-based application over the years, the number of items approved in 2000 was 7, reaching a maximum of 34 items in 2011, and decreased after that, 8 items were approved in 2019. The regulatory characteristics of drugs approved by public knowledge-based application and those of other drugs were compared. By public knowledge-based application, more anticancer and pediatric drugs were approved (P < 0.001), and only one drug for orphan diseases was approved (P < 0.001). In addition, the review time of public knowledge-based applications was significantly shorter than that of normal applications regardless of time point. The approval system using public knowledge-based application began in 2000, following issuance of the "Guidance for off-label use of prescription drugs." Furthermore, the approved items were mostly drugs for cancer, infectious diseases, and pediatric drugs. We anticipate the promotion of public knowledge-based application to accommodate the approval of drugs for orphan diseases.

Prostaglandin E2 receptor EP4-selective antagonist inhibits lipopolysaccharide-induced cervical ripening in rabbits.

BACKGROUND: The purpose of this study was to examine whether EP4 as prostaglandin (PG) E2 receptor is involved in lipopolysaccharide (LPS)-induced cervical ripening. METHODS: New Zealand White non-pregnant rabbits were randomly allocated to 4 equal groups and treated with vaginal suppositories containing LPS with various concentrations of EP4-selective antagonist once daily for 3 days, and then sacrificed for analysis. Analysis was performed in order to examine the inhibitory effect of EP4 antagonist on LPS-induced cervical ripening. The expression of EP4 in a cervix treated with LPS was examined immunohistochemically. The percent of cervical extensibility in the segment of cervix as the tensile strength was determined with 5.8 g of constant perpendicular stretching. The ripening area of the cervix with edematous changes in H&E sections was calculated by a microscopic system with a computer-assisted digital analyser. Type-1 collagenase activity was determined in cervical tissue using FITC-labelled type-1 collagen. RESULTS: Immunohistochemical study shows the positive staining of EP4 at the interstitial cells in the cervix treated with LPS. The extensibility, cervical edematous area and type-1 collagenase activity are significantly reduced in the cervix treated with LPS in the presence of EP4 antagonist compared with that treated with LPS alone. CONCLUSIONS: These data implicates the EP4 as the PGE2 receptor involved in LPS-induced cervical ripening.