Clinical Trials In Japan Research Articles

Efficient clinical trials in Japan: Bridging studies versus participation in global clinical trials

The required number of Japanese subjects was compared between the Bridging (BG) filing strategy described in ICH-E5 for drugs approved from 1998 to 2012, in which foreign phase 3 results were used together with a BG study conducted to confirm optimum Japanese dose, and global clinical trial (GCT) strategies in which the number was simulated from the foreign phase 3 studies. The simulated number from the GCT strategy was smaller than that of the BG, suggesting that the GCT strategy could be expected to reduce Japanese clinical trial costs. However, two exceptions were found, namely for preventive drugs and drugs for children, because of the large scales of foreign phase 3 studies.

Effects of KW-2228 on the function of polymorphonuclear neutrophils in rats for the phagocytosis and killing activity and the production of active oxygen

KW-2228 is a novel derivative of a recombinant human granulocyte colony-stimulating factor (rhG-CSF) with a modification. KW-2228 has some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. In the present study, we investigated the effect of KW-2228 on phagocytic capacity and killing action of polymorphonuclear neutrophils (PMNs) obtained from normal rats which had been treated with KW-2228 using various microorganisms, such as Candida albicans, Escherichia coli and Pseudomonas aeruginosa. We also investigated the effect of KW-2228 on the production of superoxide anion using a luminol-chemiluminescence method. KW-2228 enhanced the phagocytosis and killing activity of PMNs of rats against C. albicans and E. coli. PMNs treated with KW-2228 showed some bactericidal activity against P. aeruginosa. These data obtained with PMNs treated with KW-2228 show a correlation between the bacterial susceptibility to phagocytosis and killing action and the lunimol-dependent chemiluminescence response. These results suggest the significance and the efficacy of KW-2228 used in an additional therapy to that of antibiotics in the treatment of infections diseases. KW-2228 is currently in Phase III clinical trials in Japan.

Analysis of safety reporting requirements during medical device clinical trials in Japan

Regulatory convergence in safety reporting requirements for medical device clinical trials has not yet been achieved. The Global Harmonization Task Force (GHTF) issued new guidance, GHTF/SG5/N5, on this topic in August 2012. First, we compared current reporting requirements for drug and medical devices in Japan with the international guidelines International Conference on Harmonization (ICH)-E2A/E2F and GHTF/SG5/N5. As a result, we confirmed that Japan's expedited reporting requirements are nearly the same for drugs and medical devices and that these requirements are similar to those described in ICH-E2A. We also found that GHTF/SG5/N5 differs from the ICH-E2A in several ways. We sorted these differences into three categories: reportable events, reporting time frame, and definitions of terms. Although there are several equivalent terms between the ICH and GHTF guidelines, the terms Serious Health Threat and Device Deficiency are only defined in GHTF/SG5/N5. The reporting time frame for a Serious Adverse Event is either 10 or 30days for medical devices; expedited reporting is not required according to ICH-E2A, but it is covered in the annual Development Safety Update Report in ICH-E2F. GHTF/SG5/N5 recommends substantially stricter requirements than the current requirements in Japan. Therefore, the Ministry of Health, Labour and Welfare (MHLW) seemed to have prioritized the introduction of consistent definitions of terms while maintaining the current reporting time frame, rather than introducing GHTF guidance as it is. This policy is in accordance with the draft proposal on the revision of safety reporting requirements issued by MHLW in October 2012.

A Survey of Physicians^|^apos; Understanding of the Regulatory Systems for Clinical Trials in Japan

A Survey of Physicians^|^apos; Understanding of the Regulatory Systems for Clinical Trials in Japan

Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines

Hepatitis C virus (HCV) infection is a serious health problem leading to cirrhosis, liver failure and hepatocellular carcinoma. The recent introduction of telaprevir, which was approved in November 2011, in combination with peg-interferon and ribavirin is expected to markedly improve the eradication rate of the virus. However, side effects of triple therapy may be severe. In a phase three III clinical trial, 2250 mg of telaprevir, which is the same dosage used in clinical trials in Western countries, was given to Japanese patients. As this dosage is considered to be relatively high for Japanese patients, who typically have lower weight than patients in Western countries, reduction of telaprevir is recommended in the 2012 revision of the guidelines established by the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis published by the Ministry of Health, Labour and Welfare of Japan. Other protease inhibitors with fewer side effects are now in clinical trials in Japan. Alternatively, treatment of patients with combination of direct acting antivirals without interferon has been reported. In this review we summarize current treatment options in Japan and discuss how we treat patients with chronic HCV infection.

SY4-6 - Required Capabilities and Infrastructure for Japanese Phase I Institutes: From the Experience of Early Phase Drug Development Operation at Phase I Centers in United States

ABSTRACT Despite Japanese leadership in basic research and discovery, its prominence in early phase oncology drug development is less established, and frequently, separate trials have been required because of the differing pharmacology of drugs in Asian patients. To date, relatively few first-in-human studies have been conducted in Japan, for the reasons described above with the majority using data from first-in-human studies from other countries to support starting doses. Many first-in-human studies of anticancer drugs are conducted in two sites in different countries, usually in North America (United States or Canada) and the other in Europe. Additional phase I studies including Japanese patients are often required for later marketing approvals in Japan. A number of major initiatives have been implemented since 2004 involving the Pharmaceuticals and Medical Devices Agency (PMDA), and Ministry of Health, Labor and Welfare (MHLW), including initiatives to improve the infrastructure for clinical trials in Japan by supporting clinician researchers (investigators) and medical institutions in conducting clinical trials and developing clinical trial networks. Remarkably, as a new measure to promote early phase clinical studies, the MHLW has been creating infrastructure for early-stage and exploratory clinical trials in Japan since 2011. Given the fact that most Japanese phase I institutes are not sufficiently equipped with effective infrastructures to conduct a fair number of ‘novel’ first-in-human studies, urgent improvements are currently required to strengthen their capabilities. Based on the experience of the phase I operation at START (South Texas Accelerated Research Therapeutics, San Antonio, TX, USA) phase I center, this session will involve discussion of required capabilities for Japanese Phase-I institutes, in addition to introduction of the exemplary Phase-I operation system of US phase I centers.

Bone and calcium update; diagnosis and therapy of metabolic bone disease update. Advances in clinical trials for osteoporosis in Japan

Microdensitometry of the metacarpal bone on radiograph was first set up as the endpoint of the treatment in clinical trials in Japan in 1980s. Then, radial bone mineral content obtained by single photon absorptiometry was used. In 1990s, lumbar spine BMD measured by DXA became the major endpoint of the study which was designed as prospective, randomized, double-blind, controlled trial. In 2000s, assessments on the incidences of the vertebral fractures have become mandatory as the primary endpoint of the placebo-controlled trial. The numbers of the subjects required in the study are getting larger and the subtleties in the study including adverse events more important along the progress of evidence-based medicine.

Fibroblast Growth Factor‐2 Stimulates Periodontal Tissue Regeneration

Introduction: An ideal goal of periodontal therapy is to achieve the complete regeneration of periodontal tissue destroyed by the progression of periodontal diseases. The use of recombinant cytokines is one of the physiologically efficient procedures to stimulate periodontal tissue regeneration. Recently, the safety and efficacy of topical application of basic fibroblast growth factor (FGF‐2) to regenerate 2‐ or 3‐walled vertical bone defects was evaluated in Phase 2 multicenter clinical trials in Japan. The results revealed a significant difference in the percentage of increase in alveolar bone height at 36 weeks after administration between the placebo group and the 0.3% FGF‐2 group.Case Presentation: Two cases of intraosseous bone defects, which were treated with a topical application of FGF‐2, are presented. To our knowledge, this is the first case report of FGF‐2‐induced periodontal tissue regeneration. The flap operation was conducted in accordance with the modified Widman procedure, and recombinant human FGF‐2 with 3% hydroxypropylcellulose was used as a vehicle and topically applied to the vertical bone defects. A standardized dental radiograph revealed a considerable increase in radiopacity at the bone defects 36 weeks after administration; also, no serious adverse events attributable to the drug were identified in either case.Conclusion: These results strongly suggest that topical application of 0.3% FGF‐2 can be efficacious in an increase in the height of alveolar bone that has been destroyed by periodontitis.

Limited accessibility to designs and results of Japanese large-scale clinical trials for cardiovascular diseases.

BackgroundClinical evidence is important for improving the treatment of patients by health care providers. In the study of cardiovascular diseases, large-scale clinical trials involving thousands of participants are required to evaluate the risks of cardiac events and/or death. The problems encountered in conducting the Japanese Acute Myocardial Infarction Prospective (JAMP) study highlighted the difficulties involved in obtaining the financial and infrastructural resources necessary for conducting large-scale clinical trials. The objectives of the current study were: 1) to clarify the current funding and infrastructural environment surrounding large-scale clinical trials in cardiovascular and metabolic diseases in Japan, and 2) to find ways to improve the environment surrounding clinical trials in Japan more generally.MethodsWe examined clinical trials examining cardiovascular diseases that evaluated true endpoints and involved 300 or more participants using Pub-Med, Ichushi (by the Japan Medical s Society, a non-profit organization), websites of related medical societies, the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, and clinicaltrials.gov at three points in time: 30 November, 2004, 25 February, 2007 and 25 July, 2009.ResultsWe found a total of 152 trials that met our criteria for 'large-scale clinical trials' examining cardiovascular diseases in Japan. Of these, 72.4% were randomized controlled trials (RCTs). Of 152 trials, 9.2% of the trials examined more than 10,000 participants, and 42.8% examined between 1,000 and 10,000 participants. The number of large-scale clinical trials markedly increased from 2001 to 2004, but suddenly decreased in 2007, then began to increase again. Ischemic heart disease (39.5%) was the most common target disease. Most of the larger-scale trials were funded by private organizations such as pharmaceutical companies. The designs and results of 13 trials were not disclosed.ConclusionsTo improve the quality of clinical trials, all sponsors should register trials and disclose the funding sources before the enrolment of participants, and publish their results after the completion of each study.

Japan lags behind the UK in neurological drug approvals

Japan lags behind the UK in neurological drug approvals

Treatment of diffuse diabetic macular oedema using steroid eye drops

To evaluate the efficacy of treatment of diffuse diabetic macular oedema (DME) with difluprednate ophthalmic emulsion 0.05% (Durezol™) in eyes before vitrectomy. This study enrolled patients with diffuse DME for whom more than 3 months had passed since prior treatment. Nineteen eyes in 15 subjects were treated with difluprednate ophthalmic emulsion 0.05% four times daily for the first month and then twice daily for 2 months (treatment group). As a control group, 22 eyes in 11 subjects with DME were selected from subjects who underwent the steroid responder test. In the treatment group, the mean visual acuity (VA) (±SD) was 0.38 ± 0.25 logMAR and mean retinal thickness was 461.1 ± 109.9 μm at baseline. After 1 month of treatment, the mean VA had improved to 0.29 ± 0.25 (Wilcoxon rank-sum test, p = 0.30), while mean retinal thickness had decreased to 372.1 ± 70.0 μm (p = 0.006). The rate of effective improvement in retinal thickness was 42% and that of VA was 26%. In the control group, changes in neither VA nor retinal thickness were significant. Eye drop therapy using difluprednate ophthalmic emulsion 0.05% is a useful and effective treatment modality without surgical intervention or severe side-effects.

国際共同治験における用量差とエビデンス

Recent breakthroughs in science and technology have the potential to transform our ability to prevent, diagnose and treat disease. Global clinical trials are expanding. A number of difficulties emerged in conducting global clinical trials in Japan. Ethnic factors in multinational clinical trials have been apparent to determine drug dosing. Regulatory science is the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance. It is important to promote regulatory science for establishment of evidence-based medicine.

Medical device development in crisis: A movement for technology innovation in health and medicine in Japan

Japan is currently confronting a serious decline in medical device innovation. We identified some of the many barriers posed by the current clinical development system in Japan, as they relate to academia, industry and regulatory agencies: a scarcity of medical engineering and bioengineering scientists, two separate categories of clinical trials in Japan, a high level of uncertainty in any R&D schedule, leading to stagnation in the development of medical devices. We propose a new clinical development system (CDS) to stimulate medical device development in Japan, with a central body to facilitate the CDS process with appropriate coordination of interdisciplinary and translational research, and through rational public funding arrangements. With the recommendations, a new organization (Council on Health Research Promotion) has been established in the cabinet of office of Japan, and is expected to work in an effective and efficient manner.

Japanese Lung Cancer Registry Study: First Prospective Enrollment of a Large Number of Surgical and Nonsurgical Cases in 2002

To investigate prognoses of lung cancer patients prospectively enrolled in the Japan Lung Cancer Registry Study. Patients newly diagnosed as having lung cancer exclusively in 2002 were enrolled. Follow-up surveys were performed twice, in 2004 and 2009, and the final follow-up data with prognoses were analyzed for 14,695 patients (79%). Clinical stages were defined according to the sixth edition of the International Union Against Cancer--tumor, node, metastasis classification (2002). The mean age was 67.1 years (range, 18-89 years), and there were 10,194 men (69.3%) and 4315 women (29.7%). The most frequent histology was adenocarcinoma (n = 8325, 56.7%), followed by squamous cell carcinoma (n = 3778, 26%) and small cell carcinoma (n = 1345, 9.2%). The distribution of clinical stages was as follows: IA, 4245 cases (29.3%); IB, 2248 (14.5%); IIA, 208 (1.4%); IIB, 918 (6.3%); IIIA, 1700 (11.8%); IIIB, 2110 (16.3%); and IV, 3037 (21.0%). The 5-year survival rates were 44.3% for all patients, 46.8% for those with non-small cell lung cancer, and 14.7% for those with small cell lung cancer. According to the clinical stage of non-small cell lung cancer and small cell lung cancer, the 5-year survival rates were 79.4 and 52.7% for stage IA, 56.9 and 39.3% for IB, 49.0 and 31.7% for IIA, 42.3 and 29.9% for IIB, 30.9 and 17.2% for IIIA, 16.7 and 12.4% for IIIB, and 5.8 and 3.8% for IV, respectively. Analysis of a large cohort in the Japanese registry study found that stage-specific prognosis was within a range similar to other reports. The data presented should provide an important reference for future clinical trials in Japan.

One Year Efficacy and Safety of Lanthanum Carbonate for Hyperphosphatemia in Japanese Chronic Kidney Disease Patients Undergoing Hemodialysis

Lanthanum carbonate is a non-calcium-based phosphate binder for hyperphosphatemia in patients with chronic kidney disease (CKD). The efficacy and safety of lanthanum carbonate (LaC) on hyperphosphatemia in patients has been well documented in clinical trials in Western countries and recent relatively short-term clinical trials in Japan. Evidence supporting its safety and efficacy in Japanese patients for longer-term treatment is now desired for clinical practice. A non-controlled, open-label, multicenter, one year study of LaC to assess safety and its effect on the levels of serum phosphate, serum calcium and parathyroid hormone was performed with Japanese dialysis patients. Lanthanum carbonate was administered to patients at variable doses for a period of 46-52 weeks. Evaluation of the safety and efficacy of LaC in reducing serum phosphate was performed, in addition to extensive and systematic monitoring of the laboratory parameters related to bone turnover and cardiac health. A significant reduction in the serum phosphate level was demonstrated throughout the treatment period (P < 0.05), without any increase in the frequency or severity of drug-related adverse events such as vomiting, nausea, and stomach discomfort. There was no clinically relevant change in vital signs, or electrocardiograms for a period. The profiles for parathyroid hormone, bone alkaline phosphates, and osteocalcin were stable in the patients concomitantly treated with vitamin D. This study provides further evidence that the administration of LaC over a period of one year is safe and effective for the reduction of serum phosphate levels in CKD patients undergoing hemodialysis.

Clinical Trials and Good Clinical Practice

To analyze the quality of clinical trials in Japan for new applications of pharmaceuticals, compliance with the Good Clinical Practice (GCP) inspection was studied using Review Reports for approvals from fiscal year (FY)1999 to FY2008. Guidelines for GCP in Japan were harmonized with those of other countries at the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Both to protect human rights, safety and welfare and to perform clinical trials scientifically and ethically, ensuring conformity with GCP is necessary when evaluating the safety and efficacy of the clinical data in common technical documents (CTD). In the conformity audit service of the Office of Conformity Audit of Pharmaceuticals and Medical Devices Agency (PMDA), the conformity of the studies and the documents between application materials of CTD attached to application forms for approval and case report forms (CRFs) is reviewed by document-based conformity inspection, and the conformity between medical records and CRFs is reviewed by on-site GCP inspection including oversea inspection. The GCP inspection includes both the on-site GCP inspection and the document-based conformity inspection. The importance of the GCP inspection by the Office of Conformity Audit to protect human rights, safety and welfare is summarized in this study. In conclusion, GCP inspection is conducted in accordance with the latest GCP, and the quality of clinical trials in Japan meets the Review Process by PMDA for marketing authorization. I hope that the GCP inspection protects human rights and improves the GCP conformity of clinical trials in Japan.

日本の大規模臨床試験に基づく心房細動の理想的薬物療法

日本の大規模臨床試験に基づく心房細動の理想的薬物療法

Summary analysis of the pre-clinical and clinical results of brain tumor patients treated with pritumumab

Pritumumab is a human IgG1 kappa antibody that has been derived from a B-cell isolated from a regional draining lymph node of a patient with cervical carcinoma. Specificity analysis of the antibody with human tissues showed the antigen, altered tumor-associated vimentin, to be highly restricted to various cancers and not normal cells and tissues. In various clinical trials in Japan 249 patients with brain cancer were treated with pritumumab. The overall response rate was between 25-30% with several survivors beyond 5-years post-treatment. The patients were on a low dose regimen of 1mg given twice a week for a course of 24 weeks for a total dose of 48 mgs per course. Pritumumab appears to be a safe and effective therapy in patients with malignant gliomas.

Key Performance Indicators of Clinical Trials in Japan

Background: In Japan, the launch of new drugs is often delayed compared with other major regions, including the US and European countries. This so-called ‘drug lag’ is a significant problem because patients are being denied access to new and potentially life-saving therapies.

Industry Watch

University of Queensland and Life Technologies (LIFE) Collaborate on Landmark Cancer Research Studies in Australia. Hexima Collaborates with Pioneer Hi-Bred in MGEV Research Licence. Surpassing 50 Successful Implants for Miniaturized Heart Pump under Clinical Trial. Pfizer in Partnership with Shanghai Institutes for Biological Sciences for Drug Discovery Activities. Cryo-Cell Signs Exclusive Licensing Deal with Chinese Stem Cell Firm. AlphaRx and Venturepharm Collaborate in Drug Development. Sanofi Acquires Shantha Biotechnics. Siemens Introduces Liver Elastography Technology in India. A New Plant-based Antiviral for H1N1 Virus? WebHeart® in a Cardiovascular Study Solidifies New Force in Clinical Trials in Japan and Asia. Astellas to Build Fermentation Tech Research Center. A*STAR and Swiss Institute Collaborate to Boost Microfluidics Technology.