Global Medical Device Clinical Trials Involving Both the United States and Japan: Key Considerations for Development, Regulatory Approval, and Conduct.

As medical device development becomes increasingly global, the opportunities and potential advantages offered by international clinical trial and regulatory approval strategies are also growing. In particular, medical device clinical trials involving sites in both the United States and Japan and intended to support marketing in both countries may warrant particular consideration, given the similarities in their regulatory systems, patients and clinical practice patterns, and market sizes. Since 2003, the US-Japan Harmonization By Doing (HBD) initiative has been focused on identifying and addressing clinical and regulatory barriers to medical devices access in both countries via collaboration between governmental, academic, and industry stakeholders. Through the efforts of HBD participants, US-Japanese clinical trials have been conducted and the resulting data have supported regulatory approval for marketing in both countries. Based on these experiences, this paper outlines some of the key factors to consider when developing a global clinical trial involving US and Japanese participation. These considerations include the mechanisms for consultation with regulatory authorities on clinical trial strategies, the regulatory framework for clinical trial notification and approval, recruitment and conduct of clinical sites, and lessons learned from specific US-Japanese clinical trial experiences. The goal of this paper is to promote global access to promising medical technologies by assisting potential clinical trial sponsors in understanding when an international strategy may be appropriate and successful.

A long-term survival case of Erdheim-Chester disease on maintenance hemodialysis.

Erdheim-Chester disease, a rare non-Langerhans histiocytosis, involves multiple organs, including kidney. Renal dysfunction sometimes occurs, and is attributed to ureteral obstruction and renal artery stenosis by histiocytic infiltration. However, to our knowledge, case reports of end-stage renal disease requiring renal replacement therapy due to Erdheim-Chester disease are very few. Here, we report a 69-year-old woman who was diagnosed with Erdheim-Chester disease 10 years ago. She had multiple organ involvement, such as bone, skin, heart, pituitary gland, kidney, and retroperitoneum. She had been treated with interferon-alpha, but discontinued after 2 years due to depression and repeated infection. She did not desire treatment with other drugs, so we continued supportive care. Her renal function gradually deteriorated, and hemodialysis was initiated 4 years ago. Subsequently, she is still doing well without any major symptoms. This report describes an unusual case of Erdheim-Chester disease requiring maintenance hemodialysis that longer prognosis than expected was obtained regardless of multiple organ involvement and no specific treatment after interferon-alpha cessation.

Nephrotic syndrome with acute kidney injury due to focal segmental glomerulosclerosis following long-term treatment with minodronate.

Although bisphosphonates are well known to cause kidney disease, there are very few published cases of focal segmental glomerulosclerosis (FSGS) following treatment with minodronate. Here we report the case of an 86-year-old woman who developed acute kidney injury and nephrotic syndrome after receiving monthly oral minodronate for 24 months. Kidney biopsy revealed cellular variant FSGS. Treatment was initiated with the discontinuation of minodronate followed by intravenous methylprednisolone pulse and prednisolone at 35 mg/day. Subsequently, the patient's renal function gradually worsened, requiring initiation of hemodialysis. However, renal function and proteinuria improved markedly and hemodialysis was withdrawn 1 month after the initiation of steroid therapy. This is, to our knowledge, the first published case of FSGS induced by long-term use of minodronate, and also the first case of cellular variant FSGS induced by bisphosphonates although collapsing variant of FSGS is commonly caused by bisphosphonates. Our study indicates that patients on bisphosphonates should be closely monitored for proteinuria and renal impairment, regardless of the type of bisphosphonate.

Long-Term Prognosis of Hyperferritinemia Induced by Intravenous Iron Therapy in Patients Undergoing Maintenance Hemodialysis: A 10-Year, Single-Center Study.

Optimal ferritin level in hemodialysis patients between Japan and other countries is controversial. Long-term side effects of iron supplementation in these patients remain unclear. We aimed to elucidate whether past hyperferritinemia in hemodialysis patients was associated with high risk of death and cerebrovascular and cardiovascular diseases (CCVDs). This small retrospective cohort study included approximately 44 patients unintentionally supplemented with excessive intravenous iron. A significantly higher risk of CCVDs was observed in patients with initial serum ferritin levels ≥1000 ng/mL than in the remaining patients. High ferritin levels slowly decreased to <300 ng/mL in a median of 24.2 (10.5-46.5) months without treatment. However, compared with the remaining patients, only patients whose ferritin levels did not decrease to <300 ng/mL steadily had a significantly higher risk of all-cause death (hazard ratio, 9.6). Long-term hyperferritinemia due to intravenous iron therapy is a risk factor for death in maintenance hemodialysis patients. For a prolonged better prognosis, intravenous iron should be carefully administered so as to avoid hyperferritinemia in patients with hemodialysis.

Development of Antibody-Oligonucleotide Complexes for Targeting Exosomal MicroRNA.

MicroRNAs in exosomes (exosomal miRNAs) are considered as significant targets for cancer therapy. Anti-miR oligonucleotides are often used for the functional inhibition of miRNAs; however, there are no studies regarding the regulation of exosomal miRNA functions. In this study, we attempted to develop a novel drug delivery system using anti-exosome antibody-anti-miR oligonucleotide complexes (ExomiR-Tracker) to hijack exosomes to carry anti-miR oligonucleotides inside exosome-recipient cells. We found that ExomiR-Tracker bound to the exosomes, and then the complexes were introduced into the recipient cells. We also found that anti-miR oligonucleotides introduced into the recipient cells can exhibit inhibitory effects on exosomal miRNA functions in vitro and in vivo. We believe that our strategy would be a promising one for targeting exosomal miRNAs.

Turing pattern formation by the CIMA reaction in a chemical system consisting of quaternary alkyl ammonium cationic groups.

For the spontaneous generation of a Turing pattern, two intermediate species, an activator and an inhibitor, should be generated with the diffusion coefficient of the activator smaller than that of the inhibitor. The chlorite-iodide-malonic acid (CIMA) reaction that generates the activator, I(-), and inhibitor, ClO(2-), was performed in an open gel reactor. In order to lower the effective diffusivity of I(-), micelles of quaternary alkyl ammonium cationic amphiphiles and polymers having a quaternary alkyl ammonium cationic side chain were combined in the CIMA reaction system in an open gel reactor. A Turing pattern formation was observed with the addition of n-dodecyltrimethylammonium bromide. Employing the gel reactor prepared by the polymerization of a monomer having quaternary alkyl ammonium cationic side chains also leads to the generation of a Turing pattern. The micelles and polymers are believed to trap I(-) in their vicinity as a counterion to lower the effective diffusivity.