Katsura Tsukamoto

Development of Novel Pharmaceutical Agents for Alzheimer's Disease: The Impact of Regulatory Initiatives in Japan and the United States

PURPOSE The incidence of Alzheimers disease (AD) has been steadily increasing worldwide. AD is a serious disease that has both societal and economic impacts. The greatest risk factor for AD is aging. Thus, because of the rapidly aging population in Japan, the development of new, effective drugs for AD is urgently needed. The goal of the present article was to analyze the status, clarify the problems, and discuss the scientific and political challenges of disease-modifying drug development for AD. METHODS Public data, official documents, literature, and news releases were surveyed and discussed. FINDINGS Compared with diabetes mellitus drugs, there is a lack of quantitative surrogate end points among AD drugs. Much AD drug development has focused on amyloid-β and its associated pathways; however, these drugs have not shown efficacy in Phase III clinical trials. Thus, the US Food and Drug Administration has appealed for a new draft industrial guidance for the development of AD drugs, including those for early-stage AD. In Japan, the Minister of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency have also taken action, including the publication of potential new guidelines for clinical evaluation and development of new AD therapeutics, including drugs. Moreover, scientific initiatives to develop novel AD drugs are ongoing. IMPLICATIONS The development of quantitative surrogate end points remains necessary to improve the development of AD drugs. Therefore, collaboration among industry, government, and academia should be encouraged. Following the principles of regulatory science, strategies to develop drugs for illnesses with unmet needs can be framed by investigating the effects of past, current, and future AD drug development initiatives.

Influence of Expedited Programs in the United States on Oncology Drug Development in Japan

Background: Recent trends in globalization and the complexity of drug development have resulted in the possibility that expedited programs in one country may now influence drug development in another. We examined the effects of expedited programs in the United States on the development of oncology drugs in Japan. Methods: Among oncology drugs approved in Japan between 2007 and 2016, we analyzed those that were approved in both the United States and Japan. The development period was calculated by subtracting the start date of the first clinical study or the investigational new drug application date from the drug approval date in the respective country. All data were obtained from publicly disclosed information. Results: We analyzed a total of 108 approvals for oncology drugs. The difference in the development start date between the United States and Japan for drugs granted Breakthrough Therapy designation was smaller than that for drugs without this designation (P < .01). The development period in Japan for drugs granted Breakthrough Therapy, Accelerated Approval or Fast Track designations was significantly shorter than that for drugs without these designations (P < .05). In addition, the development period of oncology drugs in Japan tended to be significantly shorter as the number of expedited program designations increased (P < .006 for trend). Conclusions: The characteristics and the target disease of the drug that could be eligible for expedited program(s) in the United States, which was supported by the designation, were one of the factors influencing the development of oncology drugs in Japan.

Evaluation of the Microbiological Efficacy of a Single 2-Gram Dose of Extended-Release Azithromycin by Population Pharmacokinetics and Simulation in Japanese Patients with Gonococcal Urethritis

ABSTRACT The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the Neisseria gonorrhoeae isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated N. gonorrhoeae in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an N. gonorrhoeae eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain.

Future Perspectives for the Treatment of Diabetes: Importance of a Regulatory Framework

Background: The number of diabetes patients is steadily increasing worldwide. Consequently, the social burden of diabetes is huge, requiring urgent countermeasures. We performed an intensive survey of antidiabetic drugs approved in Japan, the United States, and the European Union. Methods: Information about approved antidiabetic drugs was obtained by searching databases of regulatory authorities in the 3 regions. Other relevant information was also obtained from publicly available literature and documents. Results: No difference in the total number and types of approved drugs among the 3 regions was found (P = .173 by log-rank test). However, the numbers of approved dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in Japan were almost double of those in the other regions. The average sample size in clinical trials used for antidiabetic drug approval in Japan (1134 patients) was much smaller than that in the other regions (P < .001 by analysis of variance repeated measures test adjusted by the Holm method). Currently, 6 drugs with known modes of action are being developed for type 1 diabetes in Japan, whereas at the end of 2016, nearly 7-fold more products with novel modes of action were in clinical development in the United States. Conclusion: Antidiabetic drug development in Japan costs less than that in the other regions, although novel development is less active because of regulatory differences. To achieve better pharmacotherapy for diabetes, the regulatory framework requires careful consideration.

Health Technology Assessment in Japan: A Pharmaceutical Industry Perspective

Background: Japan has been preparing to implement a Health Technology Assessment (HTA) process in 2018. Through a 2-year pilot program implemented in 2016, the government examined the criteria for applicable products and the necessary infrastructure to review both the content and quality of the data and to conduct cost-effectiveness assessments to be incorporated into the current Japanese reimbursement and pricing scheme. A survey of the pharmaceutical industry was conducted to understand the current landscape and to identify issues and challenges of implementing HTA in Japan. Methods: A semi-structured 19-item questionnaire was designed, and a survey was conducted via face-to-face or phone interviews. Answers were transcribed in English after the interviews and confirmed by e-mail. The survey focuses on pharmaceutical companies that develop new innovative products to be associated with the planned HTA. Results: Differences between Japanese and global pharmaceutical companies were observed in terms of dedicated HTA teams in place, the use of quality of life data, and relationships with external vendors. Addressing a shortage of HTA professionals in Japan is critical to implement HTA. The survey found that list prices compared to those proposed by companies was an issue. Conclusions: Although the government decided to implement HTA for the pricing scheme in 2018, a shortage of experts and researchers remains a challenge. Findings suggest HTA should not be used solely to reduce pharmaceutical spending, as the impact by the HTA implementation will be temporary and discourage innovation.

Industry Perspective of Pediatric Drug Development in the United States: Involvement of the European Union Countries

Background: Efforts to promote the development of pediatric pharmacotherapy include regulatory frameworks and close collaboration between the US Food and Drug Administration and the European Medicines Agency. We characterized the current status of pediatric clinical trials conducted in the United States by the pharmaceutical industry, focusing on the involvement of the European Union member countries, to clarify the industry perspective. Methods: Data on US pediatric clinical trials were obtained from ClinicalTrials.gov. Binary regression analysis was performed to identify what factors influence the likelihood of involvement of European Union countries. Results: A total of 633 US pediatric clinical trials that met inclusion criteria were extracted and surveyed. Of these, 206 (32.5%) involved a European Union country site(s). The results of binary regression analysis indicated that attribution of industry, phase, disease area, and age of pediatric participants influenced the likelihood of the involvement of European Union countries in US pediatric clinical trials. Relatively complicated or large pediatric clinical trials, such as phase II and III trials and those that included a broad age range of participants, had a significantly greater likelihood of the involvement of European Union countries (P < .05). Conclusion: Our results suggest that (1) the pharmaceutical industry utilizes regulatory frameworks in making business decisions regarding pediatric clinical trials, (2) disease area affects the involvement of European Union countries, and (3) feasibility of clinical trials is mainly concerned by pharmaceutical industry for pediatric drug development. Additional incentives for high marketability may further motivate pharmaceutical industry to develop pediatric drugs.

Influence of Breakthrough Therapy Designation in the United States on Oncology Drug Development Timelines in Japan

BackgroundThe Breakthrough Therapy Designation (BTD) program was established in the USA in 2012 to expedite the development of new potential “breakthrough” drugs with promising early clinical evidence over available therapies. The majority of BTDs are oncology drugs, and previous research has reviewed the impact of this designation on drug development in the USA. Recent trends in the globalization of oncology drug development suggest that expedited programs in the USA may influence drug development timing in other countries.ObjectivesWe examined the influence of BTD in the USA on the development initiation date, development period, and approval of oncology drugs in Japan.MethodsWe analyzed oncology drugs approved in Japan between 2013 and 2017 that were also approved in the USA. The development period was calculated by subtracting the start date of the first clinical study or the investigational new drug application date from the drug approval date in the respective country. All data were obtained from publicly disclosed information.ResultsWe analyzed 72 approvals for oncology drugs. The development periods for BTD drugs, both in Japan and in the USA, were shorter than those for non-BTD drugs. Additionally, the difference both in the development start date and in the approved date between the USA and Japan was smaller for BTD drugs than that for non-BTD drugs.ConclusionsBTD designation itself and/or the characteristics and target diseases of drugs that are eligible for BTD in the USA may constitute factors that facilitate a shorter development period, earlier development initiation and earlier approval in Japan.

New quantitative method for evaluation of motor functions applicable to spinal muscular atrophy

OBJECTIVE The aim of this study was to develop and introduce new method to quantify motor functions of the upper extremity. METHODS The movement was recorded using a three-dimensional motion capture system, and the movement trajectory was analyzed using newly developed two indices, which measure precise repeatability and directional smoothness. Our target task was shoulder flexion repeated ten times. We applied our method to a healthy adult without and with a weight, simulating muscle impairment. We also applied our method to assess the efficacy of a drug therapy for amelioration of motor functions in a non-ambulatory patient with spinal muscular atrophy. Movement trajectories before and after thyrotropin-releasing hormone therapy were analyzed. RESULTS In the healthy adult, we found the values of both indices increased significantly when holding a weight so that the weight-induced deterioration in motor function was successfully detected. From the efficacy assessment of drug therapy in the patient, the directional smoothness index successfully detected improvements in motor function, which were also clinically observed by the patients doctors. CONCLUSION We have developed a new quantitative evaluation method of motor functions of the upper extremity. Clinical usability of this method is also greatly enhanced by reducing the required number of body-attached markers to only one. This simple but universal approach to quantify motor functions will provide additional insights into the clinical phenotypes of various neuromuscular diseases and developmental disorders.

TOWARD BETTER CONDUCT OF MULTINATIONAL CLINICAL TRIALS: COMPARISON OF CLINICAL ASSESSMENT SCALES BY REGIONS (NORTH AMERICA AND JAPAN)

data were obtained from the electronic medical record for all patients with a clinician’s diagnosis of Alzheimer’s disease (331.0) and Dementia with Lewy Bodies (331.82) at the UAB Memory Disorders Clinic from 4/30/2012 to 4/30/2015. ABCs and RCS data were available on 76 patients diagnosed with Alzheimer’s disease (mean age 75) and 34 patients diagnosed with Dementia with Lewy Bodies (mean age 72). The correlation between the scores on both tests was calculated. Additionally, mean ABCs scores were compared by Kruskal Wallis tests between the two groups. Results: ABCs and RCS scores showed a moderate strength correlation across all patients (Spearman Correlation Coefficient1⁄40.69). This correlation persists for each diagnosis individually, r1⁄40.68 for AD and r1⁄40.71 for DLB. Mean ABCs scores were 17.0 for subjects with AD and 20.3 for subjects with DLB (c21⁄46.1; P1⁄40.013). Mean RCS scores were 5.43 for AD and 5.76 for DLB; no statistical difference was observed between the 2 diagnoses. Conclusions: The predicted relationship between the performance on the ABCs and RCS was established. The RCS did not differentiate between groups. Mean ABCs scores were significantly higher among DLB patients suggesting the ABCs may be more sensitive to AD than DLB. Since the scoring distribution of the ABCs is similar to that of the MiniMental State Exam, our findings are consistent with prior observations that the Montreal Cognitive Assessment is better suited for identifying cognitive impairment associated with parkinsonism. These findings further support the utility of the ABCs for assessing cognitive impairment for common diagnoses among patients attending a Memory Disorders Clinic for dementia-related conditions.