Approval trials for intensive care treatments unique to Japan

Abstract

Several drugs and medical devices used in the field of intensive care in Japan are not internationally approved; the development of these drugs and devices is sometimes referred to as “Galapagosization.” The present article reviews the approval trials, including minutes of public review by regulatory authorities, for ICU treatments unique to Japan that have been approved since the 2000s. Sivelestat, a neutrophil elastase inhibitor, was approved for the treatment of ARDS in Japan in 2002. Although the initial phase Ⅲ double-blinded trial failed to demonstrate efficacy, an additional single-arm trial was conducted and the drug was approved based on the number of ventilator-free days being larger than the numbers for the initial phase Ⅲ trial and the ARDS network trials. The primary endpoint of a phase Ⅲ trial for thrombomodulin, an anticoagulant for the treatment of DIC, was the DIC resolution rate using a dichotomization of the DIC diagnostic score. Thrombomodulin was approved in 2008 because of the superiority of its DIC resolution rate on day 7, but no advantage in 28-day mortality or the DIC diagnostic score was seen. In global trials, sivelestat was inferior to a control group in terms of 180-day mortality and thrombomodulin failed to show an advantage for 28-day mortality, so neither of these drugs were approved internationally. A single-arm study of a cytokine-adsorbing hemofilter using the AN69ST membrane was conducted in patients with septic shock. The 28-day survival rate was higher than the predicted survival rate derived from the APACHE Ⅱ score, and in 2014, the hemofilter was approved as the world's first treatment for sepsis to be covered by a public insurance program. In Japanese clinical trials of drugs and medical devices, statistical analyses that are not emphasized in other countries are sometimes performed and can lead to drug or device approval, as shown by the emphasis on surrogate endpoints and single-arm trials and the de-emphasis of mortality rates.