Characteristics of drugs approved in Japan without conducting confirmatory clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Drug development is generally a long and expensive process. Regulatory authorities have established several expedited regulatory pathways, such as accelerated approval designation in the United States (1992) and conditional approval regulation in Japan (2017). In Japan, prior to 2017, the Pharmaceutical and Medical Device Agency (PMDA) granted marketing approval without requesting the results of confirmatory clinical trials case by case basis, and even after 2018, only three drugs have been approved via the conditional approval pathway, although many drugs without confirmatory clinical trials have been approved without this pathway; therefore, it is difficult to predict the circumstances under which confirmatory clinical trials may be waived. The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict a waiver of confirmatory clinical trials. METHODS: Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. RESULTS AND DISCUSSION: Categorization of drugs as antineoplastic agents, use of the cost accounting method in the drug pricing system, "orphan" designation and accelerated approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (p ≤ 0.05). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.8) and specificity (0.8) and high accuracy for newly approved drugs. WHAT IS NEW AND CONCLUSION: The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally.

The yliA, -B, -C, and -D genes of Escherichia coli K-12 encode a novel glutathione importer with an ATP-binding cassette.

Glutathione protects cells and organisms from oxygen species and peroxides and is indispensable for aerobically living organisms. Moreover, it acts against xenobiotics and drugs by the formation and excretion of glutathione S conjugates. In this study, we show that the yliA, -B, -C, and -D genes of Escherichia coli K-12 encode a glutathione transporter with the ATP-binding cassette. The transporter imports extracellular glutathione into the cytoplasm in an ATP-dependent manner. This transporter, along with gamma-glutamyltranspeptidase, has an important role in E. coli growth with glutathione as a sole sulfur source.

Use of bacterial gamma-glutamyltranspeptidase for enzymatic synthesis of gamma-D-glutamyl compounds.

An enzymatic method for synthesizing various gamma-D-glutamyl compounds efficiently and stereospecifically involving bacterial gamma-glutamyltranspeptidase (EC 2.3.2.2) with D-glutamine as a gamma-glutamyl donor was developed. With D-glutamine as a gamma-glutamyl donor instead of L-glutamine in gamma-glutamyltaurine synthesis, by-products such as gamma-glutamylglutamine and gamma-glutamyl-gamma-glutamyltaurine were not synthesized and the yield of gamma-glutamyltaurine dramatically increased from 25 to 71%. It was also shown that the purification could be simplified without these gamma-glutamyl by-products. The possibility of synthesizing various gamma-D-glutamyl compounds was also shown.