Comparative analysis of GMO regulatory requirements for AAV vectors in the EU and Japan focusing on the shedding data and containment measures.

INTRODUCTION: Recombinant viral-based gene therapy products, such as those incorporating adeno-associated viruses (AAVs), fall under the category of genetically modified organisms (GMOs). The European Union (EU) countries and Japan must obtain environmental risk assessment (ERA) approval for the use of GMOs before starting any clinical trials. It has been reported that the development of GMO-containing products in these two regions encounters several regulatory obstacles due to the longer regulatory procedures and document preparation for ERA. AREAS COVERED: In this article, we comparatively analyzed the ERA document requirements in the EU and Japan for AAV-based recombinant medicinal products to highlight the differences in the context of potential future attempts of convergence. Additionally, we analyzed non-clinical and clinical shedding data requirements, which are key components of ERA reviews in the EU and Japan. Lastly, we compared the containment measures to minimize the spread of GMOs in the environment in the EU and Japan. EXPERT OPINION: Based on our comparative analysis, we present several policy recommendations of standardizing and simplifying the application materials and procedures for the ERA regulations on GMOs in the EU and Japan in the mid-, and long-term timeframe to achieve global regulatory convergence.

Non-clinical, quality and environmental impact assessments of cell and gene therapy products: Report on the 5th Asia Partnership Conference of Regenerative Medicine - April 7, 2022.

The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.

Bortezomib-thalidomide-dexamethasone-cisplatin-doxorubicin-cyclophosphamide-etoposide as a Salvage and Bridging Regimen before Hematopoietic Stem Cell Transplantation for Relapsed or Refractory Multiple Myeloma.

Objective Currently, treatment of relapsed or refractory multiple myeloma is challenging. Although bortezomib-thalidomide-dexamethasone-cisplatin-doxorubicin-cyclophosphamide-etoposide (VTD-PACE), a potent combination of a proteasome inhibitor, immunomodulatory drug, and conventional chemotherapeutics, is a widely used regimen, its efficacy and safety are unclear. Methods We retrospectively analyzed the clinical data of 35 patients treated with VTD-PACE. Results The overall response rate was 65.7% (complete response, 5.7%). The median progression-free survival (PFS) and overall survival (OS) were 8.0 [95% confidence interval (CI), 0.9-15.0] and 20.0 (95% CI, 17.5-22.5) months, respectively. Twenty-two (62.9%) patients developed grade 3-4 infections, and no therapy-related deaths occurred. Sixteen of 25 patients (64%) underwent stem cell harvest successfully with more than 2.0×106/kg of CD34 cells after VTD-PACE. Twenty-two patients underwent autologous or allogeneic stem cell transplantation (SCT). The response and survival durations were short in patients without SCT after VTD-PACE [median PFS: 4.0 (95% CI, 2.7-5.3) months; OS: 14.0 (6.9-21.0) months]; however, these responses significantly improved with SCT following VTD-PACE. The PFS was 8.0 (NA) months (p=0.024), and the OS was 21.0 (19.1-22.8) months (p=0.019). Conclusion VTD-PACE is an effective and tolerable salvage regimen and feasible bridging therapy for SCT.

Contamination of lenalidomide on blister packages after administration and its exposure countermeasures.

BACKGROUND: Reliable exposure control measures are needed to avoid occupational exposures from hazardous drugs. However, there is little information on blister packages concerning exposure. We investigated the contamination and exposure control methods of lenalidomide. MATERIALS AND METHODS: Nine facilities involved with the RevMate program (the Japanese REMS program) participated in this study. Blister packages (10 capsules/ sheet, no cuts) were collected from each institution after the administration of 5-mg Revlimid capsules. Additionally, the safety performance of different gloves was tested. RESULTS: A total of 18 samples were analyzed and the results revealed that all samples were contaminated with lenalidomide. Our questionnaire revealed that all pharmacists handled the blister packages with their bare hands when they were checking the remaining capsules of lenalidomide. We analyzed gloves made from four different materials (nitrile, polyvinyl chloride, latex, and polyethylene) and found no permeability in any glove type. CONCLUSION: We conclude that the spent blister package is a potential source of exposure to lenalidomide. All medical staff and caregivers should wear gloves when they handle lenalidomide.

Investigation of prognostic factors affecting efficacy in carboplatin- and paclitaxel-based first-line chemotherapies for advanced non-small-cell lung cancer.

AIMS AND BACKGROUND: First-line chemotherapies for advanced non-small-cell lung cancer (NSCLC) are platinum-based regimens. An analysis of efficacy outcomes has not yet been systematically performed and fully evaluated using large patient cohorts in each of the platinum-based chemotherapies. The present meta-analysis aims to investigate prognostic factors affecting overall survival (OS), progression-free survival (PFS) or time to progression (TTP), and overall response rate (ORR) in carboplatin and paclitaxel-based first-line chemotherapies for advanced NSCLC. METHODS: We performed a literature search in PubMed for randomized phase II and III clinical trials in patients with NSCLC treated with carboplatin and paclitaxel as first-line chemotherapy published from January 2000 to December 2013 to investigate prognostic factors affecting OS, PFS or TTP, and ORR by linear regression analysis and logistic regression analysis. RESULTS: We identified 61 treatment arms in 53 phase II and III clinical trials for the analysis. Asian region was found to be a prognostic factor that affects longer OS in treatment with carboplatin and paclitaxel as first-line chemotherapy. In addition, we identified weekly administration schedule of paclitaxel, Asian region, and lower percentage of patients with adenocarcinoma as factors affecting higher ORR. CONCLUSIONS: Our findings of prognostic factors affecting ORR and OS in carboplatin and paclitaxel-based chemotherapies as first-line therapy should be considered in the interpretation of efficacy results in global phase II and III clinical trials.

Characterization of Smubp-2 as a mouse mammary tumor virus promoter-binding protein.

A cDNA encoding a rat Smubp-2 has been cloned from a lambdagt11 library by South-Western blot screening using a 50-bp tannic acid responsive element [J. Biol. Chem. 273 (1998) 12499] of the mouse mammary tumor virus (MMTV) promoter region as a probe. The full-length cDNA encodes a protein with a predicted size of 108 kDa. Northern blot analysis revealed that the gene expression of Smubp-2 is comparatively high in testis, moderate in brain, and low in other tissues. The recombinant Smubp-2 protein was expressed as a GST- or Trx-fusion protein in Escherichia coli and purified by affinity column chromatography. Gel mobility shift competition analysis indicated that the recombinant Smubp-2 protein binds to region II (containing the ACTG-motif) in the 50-bp element in the MMTV promoter. A transient transfection assay of the Smubp-2 expression vector with MMTV promoter-containing Luciferase (Luc) reporter plasmids into mouse cells suggested that Smubp-2 is a negative transcription factor. Furthermore, the MMTV promoter activity was suppressed in cells expressing high levels of Smubp-2. Insertion of the 50-bp element upstream of the SV40 promoter negatively responded to the induced expression of Smubp-2. These results suggest that the negative transcriptional effect of Smubp-2 arises from its binding to the 50-bp element located in the MMTV promoter region.