Regulatory Aspects of Cell and Gene Therapy Products: The Japanese Perspective.

Regulations for regenerative medicine for human use, such as cell and gene therapy (CGT), have evolved in accordance with advancements in clinical experience, scientific knowledge, and social acceptance of these technologies. In November 2014, two acts, "The Act on the Safety of Regenerative Medicine" (ASRM) and the "Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act" (PMD Act), came into effect in Japan. The responsibilities of medical institutions in ensuring the safety and transparency of such medical technologies are described under ASRM. The PMD Act provides the option of a new scheme for obtaining conditional and time-limited approval for CGT products. Overall, research and development on CGT products, especially gene therapy products, is progressing. New legislative frameworks have been designed to promote the timely development of new technologies and safe and effective CGT products for Japanese patients.

Regulatory Issues: PMDA - Review of Sakigake Designation Products: Oncolytic Virus Therapy with Delytact Injection (Teserpaturev) for Malignant Glioma.

In June 2021, the Ministry of Health, Labor and Welfare approved Delytact Injection as a regenerative medical product for oncolytic virus therapy. The active substance of Delytact Injection is teserpaturev, a genetically engineered herpes simplex virus type 1 (strain F) in which the α47 gene and both copies of the γ34.5 gene have been deleted and the infected cell protein 6 (ICP6) gene has been inactivated by the insertion of the lacZ gene from Escherichia coli. Delytact Injection, when intratumorally administered to patients with malignant glioma, is expected to exert the following effects: (1) the mutant virus selectively replicates in tumor cells and destroys the infected cells through the replication process, exerting a cytocidal effect, and (2) the administration leads to induction of tumor-responsive T cells, which activates antitumor immunity and thus prolongs the survival of patients with malignant glioma. A Japanese phase II study (Study GD01) was conducted in patients with glioblastoma who had residual or recurrent tumors after radiotherapy with concomitant temozolomide. In Study GD01, however, stable disease continued for an extended period in some patients with glioblastoma. Hence, Delytact Injection is expected to be effective to a certain level. In line with this, Delytact Injection has been approved as an option for the treatment of malignant glioma, with one of the 3 approval conditions including conducting a use-results comparison survey and resubmission of the marketing authorization application within the granted time period of 7 years, under the conditional and time-limited approval scheme described in Article 23-26 of Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices.

Long-term prognosis of patients with acute myocardial infarction in the era of acute revascularization (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] registry).

BACKGROUND: The long-term prognosis of patients with acute myocardial infarction (AMI) in the contemporary acute revascularization era is not fully understood. METHODS: To clarify long-term prognosis and prognostic factors of AMI patients in a real-world setting, we consecutively registered 3021 patients with AMI (mean age 69 years, 70.7% male) who were admitted to 17 participating medical institutions and followed up prospectively. The outcome measure was death from any cause. RESULTS: Among 3021 patients, 629 patients had non-ST elevation MI (non-STEMI). During the index hospitalization, coronary angioplasty and thrombolytic therapy were performed in 58.1% and 16.3% of patients, respectively. During hospitalization, 285 patients (9.4%) died. Among 2736 patients (90.6%) who were discharged alive and followed for a median of 4.3 years (follow-up rate, 97.1%), 434 patients (15.9%) died. Among them, 250 (57.6%) died from non-cardiac causes. Compared with STEMI patients, non-STEMI patients suffered significantly more adverse outcomes. Advanced age and non-STEMI disease were associated with poorer outcomes. Multivariate analysis revealed that diabetes mellitus, acute-phase heart failure (Killip functional class ≥ 2), higher serum creatinine level (≥ 1.2 mg/dl), and advanced age (≥ 70 years and ≥ 80 years) at the onset of the AMI were independent poor prognostic factors (hazard ratios, 1.07, 2.53, 1.89, 2.50, and 6.80 respectively). CONCLUSIONS: AMI patients in the era of acute revascularization have favorable long-term prognoses, and a large proportion of late deaths are non-cardiac in nature. The establishment of an optimal management strategy for elderly AMI patients, AMI patients with diabetes, and non-ST elevation AMI patients are essential.