Using a Quality Management System and Risk-based Approach in Observational Studies to Obtain Robust Real-World Evidence.

The results of observational studies using real-world data, known as real-world evidence, have gradually started to be used in drug development and decision-making by policymakers. A good quality management system-a comprehensive system of process, data, and documentation to ensure quality-is important in obtaining real-world evidence. A risk-based approach is a common quality management system used in interventional studies. We used a quality management system and risk-based approach in an observational study on a designated intractable disease. Our multidisciplinary team assessed the risks of the real-world data study comprehensively and systematically. When using real-world data and evidence to support regulatory decisions, both the quality of the database and the validity of the outcome are important. We followed the seven steps of the risk-based approach for both database selection and research planning. We scored the risk of two candidate databases and chose the Japanese National Database of designated intractable diseases for this study. We also conducted a quantitative assessment of risks associated with research planning. After prioritizing the risks, we revised the research plan and outcomes to reflect the risk-based approach. We concluded that implementing a risk-based approach is feasible for an observational study using real-world data. Evaluating both database selection and research planning is important. A risk-based approach can be essential to obtain robust real-world evidence.

Phase II Study of a Multi-center Randomized Controlled Trial to Evaluate Oral Vitamin B12 Treatment for Vitamin B12 Deficiency After Total Gastrectomy in Gastric Cancer Patients.

BACKGROUND/AIM: This prospective multi-central randomized phase II trial evaluated the efficacy and safety of oral Vitamin B12 500 µg/day replacement compared with oral Vitamin B12 1,500 µg/day in patients with Vitamin B12 deficiency after total gastrectomy for gastric cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive oral Vitamin B12 500 µg/day or Vitamin B12 1,500 µg/day in a 1:1 ratio with a minimization method. The primary endpoint was the incidence of a normal serum Vitamin B12 level at three months after treatment. RESULTS: From January 2018 to December 2021, 3 institutions collaborated with the present study, and 74 patients were registered from these 3 institutions. The study was prematurely closed due to poor accrual after reaching almost 50% of its goal. Among the 74 recruited patients, 36 were allocated to the Vitamin B12 500 µg/day arm and 38 to Vitamin B12 1,500 µg/day arm. The incidences of patients with a normal Vitamin B12 level at 3 months (serum Vitamin B12 level >200 pg/ml) were 91.7% (33/36) in the Vitamin B12 500 µg/day arm and 100% (38/38) in the Vitamin B12 1,500 µg/day arm (p=0.3587). The types of clinical symptoms with Vitamin B12 deficiency that improved with Vitamin B12 treatment and the degree of improvement were also similar. CONCLUSION: Although the primary endpoint of the present study was not met, it was found that oral Vitamin B12 500 µg/day replacement is as effective and safe as oral Vitamin B12 1,500 µg/day replacement for Vitamin B12 deficiency.

Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.

Objective: There is scarce evidence regarding the long-term persistence of neutralizing antibodies among coronavirus disease 2019 (COVID-19) survivors. This study determined neutralizing antibody titers (NT50) and antibodies against spike protein (SP) or nucleocapsid protein (NP) antigens approximately 6 months after the diagnosis of COVID-19. Methods: COVID-19 survivors in Japan were recruited. Serum samples and data related to patients' characteristics and COVID-19 history were collected. NT50 and titers of antibodies against NP and SP antigens were measured at 20-32 weeks after the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results. Factors associated with NT50 were identified using the multivariable linear regression and the correlations among NT50 and titers of immunoglobulin G (IgG) and total immunoglobulins (Igs) against NP and SP were assessed by Spearman's correlation. Results: Among 376 participants (median [range] days after testing positive for SARS-CoV-2, 180 (147-224); median [range] years of age, 50 (20-78); 188 [50%] male), most tested positive for NT50 (n = 367, 98%), SP-IgG (n = 344, 91%), SP-total Ig (n = 369, 98%), NP-IgG (n = 314, 84%), and NP-total Ig (n = 365, 97%). Regression analysis indicated that higher BMI, fever, and the requirement of mechanical ventilation or extracorporeal membrane oxygenation were significantly associated with higher NT50. Anti-SP antibodies correlated moderately with NT50 (Spearman's correlation: 0.63 for SP IgG; 0.57 for SP-total Ig), while the correlation was weak for anti-NP antibodies (0.37 for NP IgG; 0.32 for NP-total Ig). Conclusions: Most COVID-19 survivors had sustained neutralizing antibodies and tested positive for SP-total Ig and NP-total Ig approximately 6 months after infection.

Purification and characterization of a new platelet aggregation inhibitor with dissociative effect on ADP-induced platelet aggregation, from the venom of Protobothrops elegans (Sakishima-habu).

A platelet aggregation inhibitor, named snake venom platelet aggregation dissociator (SV-PAD)-1, with a dissociative reaction of ADP-induced platelet aggregation, was purified from the venom of Protobothrops elegans (Sakishima-habu) by gel-filtration employing Sephadex G-100, and ion-exchange chromatographies using DEAE-Sepharose Fast Flow, CM-Sepharose Fast Flow, and Mono S. By this procedure, about 1.5mg of purified protein was obtained from 1.0g of P. elegans venom. The purified protein showed a single protein band and the molecular weight was about 110kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. The pI of purified protein showed four-bands of 7.7, 7.8, 7.95, and 8.15. This protein strongly inhibited ADP-induced platelet aggregation in rabbit platelet-rich plasma (PRP), and its IC(50) was about 58nM. It inhibited ristocetin-induced platelet aggregation in rabbit PRP (IC(50): 100nM), but hardly blocked collagen-induced platelet aggregation. This protein promptly dissociated platelet aggregation in rabbit PRP stimulated by high-concentration ADP.