Searching for potential surrogate endpoints of overall survival in clinical trials for patients with prostate cancer.

BACKGROUND: The purpose of this study was to investigate the correlation between overall survival (OS) and other clinical outcomes in patients with prostate cancer. Further, we conducted subgroup analysis in the correlation of OS. AIM: This study intended to investigate potential surrogate endpoints of OS for prostate cancer by examining the correlation between OS and the other endpoints. METHODS: We performed a systematic review through a literature search by computer-based searches of the Medline database (January 1965 and May 2014). RESULTS: The contents of 115 studies with endpoint as OS were analyzed in our study. Our results showed that 47.8% (55/115) of the studies used progression-free survival as an endpoint besides OS, followed by time to progression (43.5% [50/115]) and PSA response (40.9% [47/115]). Also, the relationship between OS and each surrogate endpoint was examined using the hazard ratio (HR) by a Bayesian hybrid model for random effect multivariate meta-analysis. Our results showed that the endpoint that had the highest correlation with OS was progression-free survival (PFS) with an estimated marginal correlation of 0.939 (95%CI: 0.900, 0.967). Furthermore, our stratified analysis identified PFS in castration-resistant prostate cancer patients (0.937), in sensitive patients (0.932), in none of chemotherapy patients (0.929), in first line of the chemotherapy (0.948), in patients who received no Docetaxel previously (0.942), in both symptomatic and asymptomatic patients (0.950), in patients who received only chemotherapy (0.956), and in phase III (0.960), time to progression (TTP) in castration-resistant prostate cancer (CRPC) patients (0.942), in metastasis patients (0.948), in both symptomatic and asymptomatic patients (0.953), in patients who received only chemotherapy (0.938), and in Phase III (0.927) as endpoints, which showed a lower limit for 95% CI of estimated marginal correlation ≥0.850 with overall survival. CONCLUSIONS: Our study suggests that PFS is a potential surrogate endpoint of OS in clinical trials for patients with prostate cancer. It also suggests potential surrogate endpoints for CRPC and locally advanced prostate cancer.

ICH Culture: Its Maintenance and Development.

The founding industry members (European Federation of Pharmaceutical Industries and Associations [EFPIA], Japanese Pharmaceutical Manufacturers Association [JPMA], and Pharmaceutical Research and Manufacturers of America [PhRMA]) of the International Council for Harmonisation (ICH) have a 25-year track record of the contribution to ICH. Given that further globalization of ICH is expected, we should value this legacy and maintain the current ICH culture and its principles of "benefit to the patients first" and "science-based approach," through which industry members would ensure transparency and objectivity in their ICH activities. In order to maintain and develop the culture of the ICH and its current momentum, a 2-way approach is important: (1) sharing common views through dialogues among leaders of each industry association, such as through the Industry Executive Council, and (2) spreading the values through grassroots activities involving wider stakeholders in global forums such as DIA, as platforms for sharing the knowledge, views, and culture of ICH across the globe.

Historical and Hygienic Aspects on Roles of Quality Requirements for Antibiotic Products in Japan : Part 3-Introduction of Technology and Knowledge in the Production Process and Quality Control of Penicillin from the United States of America.

In order to investigate the roles of quality requirements for antibiotic products in Japan, from historical and hygienic aspects, we examined and analyzed how technology and knowledge in the production and quality control of penicillin were introduced from the United States of America, applied, and further developed. Owing to the strong support of Colonel Crawford Sams, the chief of the Public Health and Welfare Section of the Supreme Commander for Allied Power/General Headquarters, via the Ministry of Welfare in Japan, the technology and knowledge were acquired from an experienced leader, Dr. Jackson W. Foster, and as a result, domestic production of penicillin was successfully achieved in amounts required to meet national demands sufficiently within three years in a devastated post-war-torn Japan. Based on the consensus that penicillin should be dealt with as "biological products" similar to vaccines and antisera, the quality standards for penicillin were enacted as the "Minimum Requirements for Penicillin (MRP)" on the 1st of May 1947. Due to the development of penicillin production technology, the quality standards of penicillin provided by the MRP were revised often to higher levels ; content of the active element from no less than 60 units/mg (purity 3.8%) to no less than 1,430 units/mg (purity 89.7%). Regarding the penicillin preparations, the content of the active ingredient per vial was changed from 30,000 units at the beginning, to 100,000 units in January 1948, to 3,000,000 units in December 1950, and two preparations containing 200,000 units and 1,000,000 units per vial are currently available, according to clinical convenience.

Historical and hygienic aspects on roles of quality requirements for antibiotic products in Japan: Part 4 - Enactment of requirements for individual antibiotic products.

Supplies of high quality antibiotic products to clinics contributed greatly to the health maintenance of the citizens of Japan. In this report, we describe the results of our investigation and analyses on the establishment and amendments of 'he quality standards for individual antibiotic products, which were regarded as the guidelines for quality control in the production processes. "The minimum requirements of penicillin" enacted in May of 1947 was at a relatively moderate standard level, due to considerations for domestic technical levels. However, after several amendments, in response to the rapid development of manufacturing technologies and new penicillin preparations, standards became increasingly stricter. "The minimum requirements of streptomycin" enacted in December of 1949 was prepared by the use of streptomycin preparations imported from the USA. The 3rd and 4th standards, "the minimum requirements of dihydrostreptomycin" and "the minimum requirements of chloramphenicol", were prepared by applying provisions described in the rules for certification of the U.S. Food and Drug Administration. In accordance with an increase in the varieties of antibiotic products, "the minimum requirements of antibacterial products" was enacted by the integration of previously existing standards and newly enacted ones. Thereafter, in response to the innovation of scientific technologies and the globalization of antibiotic products, "the minimum requirements for antibiotic products in Japan" was further developed and became the basis for supplying high quality antibiotic preparations.

Historical and hygienic aspects on roles of quality requirements for antibiotic products in Japan: Part 5 - Introduction of technology and knowledge on streptomycin production from the United States of Americat.

In order to investigate the roles of quality requirements for antibiotics products in Japan, from historical and hygienic aspects, we examined how technology and knowledge in the production and quality control of streptomycin were introduced from the United States of America. In this study, through detailed investigations and analyses, it was confirmed that the introduction of technology and knowledge on streptomycin was strongly supported by Brigadier General CRAWFORD SAms, the chief of the Public Health and Welfare Section (PHW) of the Supreme Commander for Allied Powers/General Headquarters, via the Ministry of Welfare in Japan. Dr. SELMAN WAKSMAN, the discoverer of streptomycin, along with scientists of Merck & Co., also helped Japanese industries extensively, via PHW, by providing the original streptomycin-producing strains and transferring expertise in streptomycin production. With the technology and knowledge being introduced from the USA, domestic production of streptomycin preparations increased very rapidly. As noted in our previous report, domestic production reached amounts enough to satisfy national demand within three years. Japanese people have a racial tendency to be highly susceptible to tuberculosis known as an incurable national disease. Thanks to streptomycin therapy, the tuberculosis mortality rate (per 100,000 population) had fallen dramatically within only five years from 187.2 in 1947 to 82.2 in 1952.

Cost-effectiveness analysis of EGFR mutation testing and gefitinib as first-line therapy for non-small cell lung cancer.

OBJECTIVES: The combination use of gefitinib and epidermal growth factor receptor (EGFR) testing is a standard first-line therapy for patients with non-small cell lung cancer (NSCLC). Here, we examined the cost-effectiveness of this approach in Japan. MATERIALS AND METHODS: Our analysis compared the 'EGFR testing strategy', in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the 'no-testing strategy,' in which genetic testing was not conducted and all patients were treated with standard chemotherapy. A three-state Markov model was constructed to predict expected costs and outcomes for each strategy. We included only direct medical costs from the healthcare payer's perspective. Outcomes in the model were based on those reported in the Iressa Pan-Asia Study (IPASS). The incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life-years (QALYs) gained. Sensitivity and scenario analyses were conducted. RESULTS: The incremental cost and effectiveness per patient of the 'EGFR testing strategy' compared to the 'no-testing strategy' was estimated to be approximately JP¥122,000 (US$1180; US$1=JP¥104 as of February 2014) and 0.036 QALYs. The ICER was then calculated to be around JP¥3.38 million (US$32,500) per QALY gained. These results suggest that the 'EGFR testing strategy' is cost-effective compared with the 'no-testing strategy' when JP¥5.0 million to 6.0 million per QALY gained is considered an acceptable threshold. These results were supported by the sensitivity and scenario analyses. CONCLUSION: The combination use of gefitinib and EGFR testing can be considered a cost-effective first-line therapy compared to chemotherapy such as carboplatin-paclitaxel for the treatment for NSCLC in Japan.

Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan?

BACKGROUND: This study exhaustively and historically investigated the status of drug lag for oncology drugs approved in Japan. METHODS: We comprehensively investigated oncology drugs approved in Japan between April 2001 and July 2014, using publicly available information. We also examined changes in the status of drug lag between Japan and the United States, as well as factors influencing drug lag. RESULTS: This study included 120 applications for approval of oncology drugs in Japan. The median difference over a 13-year period in the approval date between the United States and Japan was 875 days (29.2 months). This figure peaked in 2002, and showed a tendency to decline gradually each year thereafter. In 2014, the median approval lag was 281 days (9.4 months). Multiple regression analysis identified the following potential factors that reduce drug lag: "Japan's participation in global clinical trials"; "bridging strategies"; "designation of priority review in Japan"; and "molecularly targeted drugs". CONCLUSIONS: From 2001 to 2014, molecularly targeted drugs emerged as the predominant oncology drug, and the method of development has changed from full development in Japan or bridging strategy to global simultaneous development by Japan's taking part in global clinical trials. In line with these changes, the drug lag between the United States and Japan has significantly reduced to less than 1 year.

Regulatory review time for approval of oncology drugs in Japan between 2001 and 2014. Considerations of changes, factors that affect review time, and difference with the United States.

In this study, we comprehensively and historically studied the review time of oncology drugs approved by the regulatory authorities in Japan with publicly available information. A total of 120 applications of oncology drugs were approved in Japan between April 2001 and July 2014. The review time peaked with 732.0 days (24.4 months) in 2005, and showed a tendency to decline gradually each year thereafter. After 2012, a significant reduction of the review time was seen in comparison to the median of 13-year median time. In addition, we compared the review time with that in the United States. The median review time lag with the United States was significantly peaked in 2005. After 2005, the review time lag with the FDA has decreased, but lag did not significantly reduce by 2014. We also examined factors influencing the review time in Japan with multiple regression analysis. It was found that the factors related to a use of overseas data and expedited program for accelerating the reviews influenced the direction of shortening the review time. We consider that regulatory authorities in Japan need to keep making efforts to reduce the review time further and eliminate the review time lag with the United States.

[Historical and Hygienic Aspects on Roles of Quality Requirements for Antibiotic Products in Japan: Part 1--Development of Antibiotic Products].

Antibiotic products have contributed greatly to keep Japanese people healthy by controlling lethal infections. In the early days, antibiotics such as penicillin and streptomycin were produced using microbial fermentation processes. Therefore, the component ratio of the active element and related substances varied lot by lot. For the purpose of efficacy and assuring safety, minimum requirements for penicillin and streptomycin products were enacted. Both variations and the number of clinically available antibiotic products have increased due to the pharmaceutical development of novel natural antibiotics. In addition, semi-synthetic derivatives of various antibiotics have been developed for the purpose of enhancing antimicrobial activity or improving pharmacological properties. As a result, 202 entities of antibiotic products have been approved and used clinically as of 2012. We conducted a detailed investigation of the progress made in the field of antibiotic products, and analyzed the characteristics of those belonging to each class of antibiotics by means of setting up a system of classification that reflects clinical applications. This report is intended to serve as an introduction to our series of investigations into the role and influence of quality requirements on development of antibacterial antibiotic products in Japan. As described here, the general view of antibacterial antibiotic products spanning a time frame of 67 years in Japan might serve as an ideal reference for future reports.

[Historical and Hygienic Aspects on Roles of Quality Requirements for Antibiotic Products in Japan: Part 2--Achievements of Domestic Production of Penicillin and Streptomycin].

Domestic production of penicillin was initiated in 1946 and that of streptomycin in 1950. In the early days, however, the quality of products was considerably lower and the capacity of production small. Surprisingly, there was a sufficient amount of penicillin preparations, with a purity of 85% or more, satisfying domestic demand within three years (1949). In the case of streptomycin, within three years (1953), preparations with a purity two-fold higher than initially available were produced in amounts sufficient to meet both domestic demand and create a surplus availability for exporting purposes. Such increases in quality and production were considered to be made possible by strict quality control of penicillin and streptomycin preparations, based on "Minimum Requirements for Penicillin" established in May 1947 and "Minimum Requirements for Streptomycin" established in December 1949. These requirements were also amended over time in order to provide even higher quality standards in response to the evolving improvements in production processes. Life-threatening diseases such as septicemia and pneumonia were controlled by the sufficient supply of high-quality penicillin preparations and the mortality rate of tuberculosis, regarded as a national disease at the time, markedly decreased by that of streptomycin preparations. Achievements of domestic production of penicillin and streptomycin were considered important factors that contributed greatly to the maintenance of public health in Japan.

The Relationship Between Development Start Lag and Approval Lag in Oncology Drug Development in Japan.

BACKGROUND: The delay of initiation of clinical development is considered a causes of delay of approval of drugs (drug lag) in Japan. METHODS: For oncology drugs newly approved between 2000 and 2012 in Japan, a possible impact of delay of initiation of clinical development (development start lag [DSL]) on delay of approval (approval lag [AL]) was investigated, focusing on the delay from the US timelines. The equation defining the relationship between the DSL and AL of 33 oncology drugs was calculated by using simulation models, then the Pearson coefficient of correlation between parameters was calculated. RESULTS: From the analysis of all drugs investigated, a positive relationship between the DSL and AL was suggested. However, the relationship seemed to have 2 phases, including a flat phase, followed by a linearly increased phase with a breakpoint at 2340 DSL days (approximately 6.4 DSL years). CONCLUSIONS: Shortening the DSL is important for reducing large AL, but it is not necessary to eliminate the DSL completely for the purpose of minimizing the AL.

Differences in maximum tolerated doses and approval doses of molecularly targeted oncology drug between Japan and Western countries.

Approved doses of a number of drugs in Japan are known to be different from those in the United States (US) and the European Union (EU), and doses are often set lower for the Japanese than for the western people. Similarly, some oncology drugs also have lower dose approved for the Japanese than for the western people. A total of 40 oncology drugs were approved as new molecular entities in Japan between 2001 and 2013. Of the 40 drugs, 21 were molecularly targeted drugs and 13 were cytotoxic drugs. Five (12.5 %) of the 40 drugs had different approved dose from that in the US and the EU. Of the 13 cytotoxic drugs, four drugs (30.8 %) differed in approved dose, while all the molecularly targeted drugs (21 of 21 drugs) had the same approved dose. We compared the maximum tolerated dose (MTD) of the 21 molecularly targeted drugs in the Japanese with that in the western people and found that the MTD was determined lower in the Japanese than that in the western people (two drugs), was not different (10 drugs), and MTD was not determined in the Japanese and incommensurable because of the different dose range tested in Japan (nine drugs). All the molecularly targeted drugs are the same in approved doses and few molecularly targeted drugs differ in MTD between Japan and the Western countries.

Drug discovery in renal disease--towards a more efficient framework.

The time and cost involved in bringing new drugs to the market hamper their approval. This problem is especially apparent in the case of renal diseases. Efficient drug research requires an a priori understanding of disease pathophysiology, target validation, rational and efficient drug discovery strategies and early testing of the physiological and pharmacological effects of the new agent in humans. Drug development initiated by academia benefits from international research networks and relies on internationally acceptable high-quality nonclinical data packages and bulk investigational drugs. Academics should, therefore, better understand pharmaceutical practice regulations and novel, efficient drug-development strategies. Many researchers remain unfamiliar with these areas and should collaborate with regulatory authorities to discover and validate surrogate markers for use in drug development, and to efficiently and effectively maximize the benefits and minimize the adverse effects of new drugs. The Japanese government and regulatory authorities have implemented a framework to encourage such collaborations; extension of this framework beyond its current reach is envisaged.

Comparison of global versus Asian clinical trial strategies supportive of registration of drugs in Japan.

The number of worldwide and Asian multiregional clinical trials (MRCTs) submitted for Japanese New Drug Applications increased markedly between 2009 and 2013, with an increasing number performed for simultaneously submission in the USA, EU, and Japan. Asian studies accounted for 32% of MRCTs (14/44 studies) and had comparatively small sample sizes (<500 subjects). Moreover, the number of Japanese subjects in Asian studies was 2.1- to 13.4-fold larger than the sample size estimated using the method described in Japanese MRCT guidelines, whereas the ratio for worldwide studies was 0.05- to 4.9-fold. Before the introduction of this guidelines, bridging or domestic clinical development strategies were used as the regional development strategy in accordance with ICH E5 guidelines. The results presented herein suggest that Asian studies were conducted when the drug had already been approved in the US/EU, when phase 3 clinical trials were not be planned in the USA/EU, when there was insufficient knowledge of ethnic differences in drug efficacy and safety, or when Caucasian data could not be extrapolated to the Japanese population. New strategies with Asian studies including the Japanese population could be conducted instead of Japanese domestic development strategy.

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.

[The history of developing anticancer Drugs and their evaluation guidelines in Japan].

The cancer therapies currently available do not yet offer fully satisfactory treatments, even in 21st century, and efforts and progress are being made daily in the area of drug development. Anticancer drugs, which play the leading role in cancer therapy, are being developed dynamically around the world, and Japan is not an exception. Looking back on the history of developing anticancer drugs, cytotoxic drugs were the mainstream of drug development until the end of the 20th century. In the 21st century, they have been replaced by molecularly targeted drugs, and thus the development of cytotoxic drugs has been declining rapidly. There were various approaches to the development of anticancer drugs and clinical trial endpoints until the 1980s. In 1991, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was issued. From 2000 onwards, there was vigorous discussion on the clinical trial endpoints of anticancer drugs in the United States. In conjunction with this discussion, the "Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan" was revised in 2005. The revised guidelines required survival data at the time of filing a new drug application (NDA) as a general rule. Around 2005, a bridging strategy was promoted as the "International Conference on Harmonization E5" was promulgated among Japan, the U.S. and EU, resulting in an outflow of clinical trials to overseas, with more non-Japanese survival data generated outside of Japan used for NDAs than Japanese data. Subsequently, the "Guideline for Basic Principles on Global Clinical Trials" was issued in 2007, which promoted the change in the mainstream approach from a bridging strategy to a pivotal, global study involving Japan. Thus, an era of full-fledged globalization in clinical trials began. We believe Japan will need systems to enhance the motivation for anticancer drug development, such as an expedited program or pediatric program, from now on. We hope that the enhancement of these systems will contribute to shortening the period required for approving an anticancer drug and reducing developmental costs. Furthermore, we expect Japan to be creating breakthrough anticancer drugs in the near future.

Involvement of anticancer drugs in the relief system for adverse drug reactions in Japan.

OBJECTIVE: The compensation scheme for adverse drug reactions in Japan was implemented more than three decades ago as relief system by regulatory agencies. Because of the high frequency of adverse drug reactions, anticancer drugs have been excluded from coverage by the relief system since its implementation. Requests have recently been made by some patient advocates for the expansion of relief coverage to include anticancer drugs. In response to these requests, the Ministry of Health, Labor and Welfare of Japan established a committee to discuss relief from anticancer drug-induced health damages in June 2011. METHODS: We conducted comprehensive research into the compensation scheme for adverse drug reactions in the world. We also investigated the situation of compensation and the committee for discussing inclusion of anticancer drugs into the relief system in Japan. RESULTS: Many countries including the United States and UK do not have relief or compensation schemes for no-fault compensation. We investigated whether a no-fault compensation system exists in Nordic countries (Sweden, Denmark, Norway and Finland), France, Germany, New Zealand and Taiwan in the world, although they offer different services from Japan. We also reviewed current situation and the fundamental difficulties associated with including anticancer drugs in the systems in Japan. CONCLUSIONS: The present study investigated the current situation and the fundamental difficulties associated with including anticancer drugs in the systems in Japan and pointed out part of the reason why the committee could not conclude involvement of anticancer drugs in the relief system.

KRAS mutational status in Japanese patients with colorectal cancer: results from a nationwide, multicenter, cross-sectional study.

OBJECTIVE: KRAS gene mutations are a useful predictive factor for the efficacy of anti-epidermal growth factor receptor therapeutics. Since there were no large-scale studies among Asian populations, we designed an observational nationwide study in Japan. METHODS: Formalin-fixed paraffin-embedded tissue blocks or sections from primary or metastatic lesions were obtained from patients registered between 2009 and 2010 for genomic DNA extraction. KRAS gene was analyzed by direct sequencing or Luminex assay. The primary endpoint was the frequency of KRAS gene mutations and the secondary endpoints were differences in KRAS mutation rates by various stratification factors. Univariate and multivariate analyses were performed to investigate relationships between KRAS mutation rates and patient background factors. RESULTS: We analyzed 5790 eligible samples out of 5887 registered. The overall KRAS mutation rate was 37.6%, with 29.9% in codon 12 and 7.7% in codon 13, and wild type was 62.4%. A significant relationship with the KRAS mutation rate was found for gender, age, the year that the sample was prepared and the site of the primary lesion. CONCLUSION: The KRAS mutation rate of Japanese colorectal cancer patients was 37.6%. Gender, age, the site of the primary lesion and the year that the sample was prepared were independent risk factors for KRAS mutations.