Mamoru Narukawa

Oral 5-aminolevulinic acid mediated photodynamic diagnosis using fluorescence cystoscopy for non-muscle-invasive bladder cancer: A randomized, double-blind, multicentre phase II/III study.

BACKGROUND Photodynamic diagnosis (PDD) of non-muscle-invasive bladder cancer (NMIBC) following transurethral administration of a hexalated form of 5-aminolevulinic acid (5-ALA), 5-ALA hexyl ester, is widely performed in Western countries. In this study, effectiveness and safety of the oral administration of 5-ALA is assessed in a phase II/III study of PDD for NMIBC in comparison to those of conventional white-light endoscopic diagnosis. METHODS Patients with NMIBC were allocated to two groups that were orally administered 10 and 20 mg/kg of 5-ALA under the double-blind condition. Effectiveness was evaluated by setting the primary endpoint to sensitivity. Safety was also analyzed. Moreover, clinically recommended doses of 5-ALA was also investigated as an investigator-initiated multicenter cooperative clinical trial in which five medical institutions participated. RESULTS All 62 enrolled patients completed the clinical trial. The sensitivities of PDD were higher (84.4 and 75.8% in the 10 and 20 m g/kg-groups, respectively) than those of conventional endoscopic diagnosis (67.5 and 47.6%, respectively) (p = 0.014 and p < 0.001, respectively). Five episodes of serious adverse events developed in four patients; whereas a causal relationship with the investigational agent was ruled out in all episodes. CONCLUSION This investigator-initiated clinical trial confirmed the effectiveness and safety of PDD for NMIBC following oral administration of 5-ALA. Both doses of 5-ALA may be clinically applicable; however, the rate of detecting tumors only by PDD was higher in the 20 mg/kg-group suggesting that this dose would be more useful.

Approaches to Japanese Dose Evaluation in Global Drug Development: Factors That Generate Different Dosages Between Japan and the United States

Drug development in Japan is shifting from a bridging strategy to a global strategy, and the number of multiregional trials in which Japan is included is increasing every year. The Japanese drug regulatory authority requires that data be collected in Japanese populations, and therefore dose–response studies of various drugs are frequently conducted in Japan. However, the current standard for adequate dose–finding processes may sometimes hinder the timely participation of Japan in these multiregional trials. We studied the development approaches and review patterns of 99 new molecular entities (NMEs) approved in 2003–2008 and have identified some common factors that result in differences in approved dosages in Japan as compared with other countries, such as dose–response study design, pharmacokinetics, and the timing of development. The findings of our research will serve as an initial information base on which to build an efficient global drug development strategy in Japan.

Differences Between Japan and the United States in Dosages of Drugs Recently Approved in Japan

The internationalization of clinical and regulatory guidelines and disease treatment and the globalization of the pharmaceutical industry have led drug development strategies in Japan to shift from bridging studies to multinational trials. However, the current standard for adequate dose‐finding processes may sometimes complicate the timely participation of Japan in these multinational trials. The objective of this study is to investigate different factors that might influence dosage selection in Japan. Approved drug dosages in Japan and the United States during the period 2003–2008 were compared and assessed across different therapeutic areas and approval timings. Factors such as company type and daily dosage indication were demonstrated to have a statistically significant relationship with different dosages in Japan and the United States. Anticancer, antiviral, and enzyme drugs showed similar dosages in the 2 regions, whereas neurological drugs were observed to undergo more careful dosage‐finding processes, resulting in the approval of generally lower doses in Japan. A broader analysis is needed for detailed assessment. The findings in this study serve as an initial review to identify important factors that should be considered before planning global drug development.

The Current Situation of Oncology Drug Lag in Japan and Strategic Approaches for Pharmaceutical Companies

Drug lag, especially for oncology drugs, has recently been a big issue in Japan. Drug lag is considered to be the result of three separate types of delay or a combination of these: delay in the start of development, delay in the progress of development, and delay in review by regulatory authorities. Although various actions have been implemented, they are mainly for improving the latter two types of delay. As for delay in the start of development, there may be two major reasons: reactive or untimely decision making, and limited R&D resources at Japanese affiliates of multinational pharmaceutical companies. Concerning reactive or untimely decision making, authorities and study sites are also responsible to some extent. As it may not be practically feasible for Japanese affiliates to initiate development of all compounds at the same time as global headquarters, strategic approaches are needed to compensate for delay in the start of development. Global development and data sharing with other nations, especially in East Asia, could be workable options. By adopting these options, Japanese affiliates will be able to realize more productive drug development with less human and budgetary resources. By saving resources, Japanese affiliates may join global studies at earlier stages and lead development of drugs for tumor types prevalent in Asia.

Pharmaceutical Pricing and Reimbursement in Japan For Faster, More Complete Access to New Drugs

Background: In Japan, National Health Insurance (NHI) has ensured that all Japanese citizens can use the health services they need for more than 50 years. This paper gives an overview of the Japanese NHI drug price listing scheme and practice, and it also discusses the issue of drug price setting and health insurance system from the viewpoint of better patient access to new drugs as well as the environment for innovative new drug development. Methods: For each New Molecular Entity (NME) approved between October 2004 and December 2014, we checked its presence in the list of NHI drug prices as of January 31, 2015, to calculate the NHI coverage rate and the average time between marketing approval and the date of NHI listing. Results: A total of 304 NMEs were listed in the NHI price list during the study period, and the NHI coverage rate (excepting preventive vaccines) was 97.4%. The average time between marketing authorization and the initiation of reimbursement was 66 days. There were 88 drugs that gained premiums for innovativeness/usefulness. Conclusions: From the view of NHI coverage scope and speed, the hurdle to access new drugs in Japan is shown to be lower than in other countries that also set public prices for reimbursement. Although the difficulty of controlling health expenditures increases, drug pricing that properly reflects the drug’s clinical value is important in that it also furthers the development of medical technology. Better price setting can also facilitate patient access to innovative drugs.

Factors Affecting Efficacy and Safety of Add-On Combination Chemotherapy for Non-Small-Cell Lung Cancer: A Literature-Based Pooled Analysis of Randomized Controlled Trials

BackgroundSeveral clinical trials of chemotherapy for non-small-cell lung cancer (NSCLC) have been conducted to date. However, these studies have not been effective at identifying category 1 recommended strategies for systemic chemotherapy according to the National Comprehensive Cancer Network clinical practice guidelines.Purpose and MethodTo investigate the factors that influence the efficacy and safety of add-on combination chemotherapy for NSCLC based on published reports, we searched the PubMed and EMBASE for reports of randomized, controlled trials that compared efficacy and safety between groups with and without the use of add-on drugs to base chemotherapy in patients with NSCLC. For all the selected articles, we systematically retrieved and assessed the full published report.ResultsOf the 753 citations yielded by the electronic search, 82 comparison pairs from 76 articles were selected. The logistic regression analysis showed the second- or third-line treatment for target patients (Line2_3), dose modification of the base drug(s) in the investigational arm, characteristics of the add-on drug, and the number of total combination drugs that had negative coefficients, and the percent of patients with performance status 2 who had positive coefficients for efficacy. For safety, Line2_3, and the percent of female patients had positive coefficient.ConclusionsThe present results indicate that the following points are important when investigating new regimen for add-on combination chemotherapy: (1) the number of total combination drugs should be reduced if at all possible; (2) an add-on drug should be noncytotoxic and should not necessitate dose modification (reduction) of the base drug(s).

Points to consider: efficacy and safety evaluations in the clinical development of ultra-orphan drugs

BackgroundThe unmet medical needs of individuals with very rare diseases are high. The clinical trial designs and evaluation methods used for ‘regular’ drugs are not applicable in the clinical development of ultra-orphan drugs (<1000 patients) in many cases. In order to improve the clinical development of ultra-orphan drugs, we examined several points regarding the efficient evaluations of drug efficacy and safety that could be conducted even with very small sample sizes, based on the review reports of orphan drugs approved in Japan.ResultsThe clinical data packages of 43 ultra-orphan drugs approved in Japan from January 2001 to December 2014 were investigated. Japanese clinical trial data were not included in the clinical data package for eight ultra-orphan drugs, and non-Japanese clinical trial data were included for six of these eight drug. Japanese supportive data that included retrospective studies, published literature, clinical research and Japanese survey results were clinical data package attachments in 22 of the 43 ultra-orphan drugs. Multinational trials were conducted for three ultra-orphan drugs. More than two randomized controlled trials (RCTs) were conducted for only 11 of the 43 ultra-orphan drugs. The smaller the number of patients, the greater the proportion of forced titration and optional titration trials were conducted. Extension trials were carried out for enzyme preparations and monoclonal antibodies with high ratio. Post-marketing surveillance of all patients was required in 36 of the 43 ultra-orphan drugs.For ultra-orphan drugs, clinical endpoints were used as the primary efficacy endpoint of the pivotal trial only for two drugs. The control groups in RCTs were classified as follows: placebo groups different dosage groups, and active controls groups. Sample sizes have been determined on the basis of feasibility for some ultra-orphan drugs.We provide “Draft Guidance on the Clinical Development of Ultra-Orphan Drugs” based on this research.ConclusionsThe development of ultra-orphan drugs requires various arrangements regarding evidence collection, data sources and the clinical trial design. We expect that this draft guidance is useful for ultra-orphan drugs developments in future.

Assessment of the Risk of Hospitalization for Heart Failure With Dipeptidyl Peptidase-4 Inhibitors, Saxagliptin, Alogliptin, and Sitagliptin in Patients With Type 2 Diabetes, Using an Alternative Measure to the Hazard Ratio

Background: Saxagliptin statistically significantly increased the risk of hospitalization for heart failure compared with placebo in the clinical trial of SAVOR-TIMI 53. Neither the reason why only saxagliptin among several dipeptidyl peptidase-4 (DPP-4) inhibitors increased the risk, nor the clinical implication of the result has been explained. Objective: To evaluate the risk of hospitalization for heart failure associated with DPP-4 inhibitors by using an alternative measure to the hazard ratio. Methods: We used the difference in restricted mean survival time (RMST) between DPP-4 inhibitors and placebo to evaluate the risk of cardiovascular events, including hospitalization for heart failure associated with DPP-4 inhibitors. Three randomized clinical trials with cardiovascular events as a primary end point—EXAMINE (alogliptin), SAVOR-TIMI 53 (saxagliptin), and TECOS (sitagliptin)—were reevaluated by estimating the RMSTs for the DPP-4 inhibitors and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. Results: The differences of RMSTs (DPP-4 inhibitors minus placebo) for hospitalization for heart failure were −4 days [−6, −2] in the SAVOR-TIMI 53 (720 days follow-up), −3 days [−9, 3] in the EXAMINE (900 days follow-up), and 1 day [−5, 7] in the TECOS (1440 days follow-up). There were no substantial differences in the risk of other cardiovascular outcomes between DPP-4 inhibitors and placebo. Conclusions: There are no substantial clinically relevant differences in the risk of cardiovascular events, including hospitalization for heart failure, between 3 of the DPP-4 inhibitors and placebo.

Meta-analysis of dipeptidyl peptidase-4 inhibitors use and cardiovascular risk in patients with type 2 diabetes mellitus

AIMS Some meta-analyses have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors decrease the risk of major adverse cardiovascular events (MACE) compared to placebo. However, this association has not been confirmed in large placebo-controlled clinical trials with cardiovascular events as a primary endpoint. The aim of the present meta-analysis is to assess the association between DPP-4 inhibitors use and cardiovascular risk using uniform definition of MACE. METHODS Relevant studies through 31 December 2014 were searched in the electronic databases, and we identified all eligible trials comparing DPP-4 inhibitors with active drugs or placebo. Summary odds ratio (OR) with 95% confidence interval (CI) for MACE was calculated using random-effects model. RESULTS In 69 trials included in our study, 36,488 patients were treated with DPP-4 inhibitors and 31,290 with other comparators. Treatment with DPP-4 inhibitors was associated with a lower risk of MACE (OR [95% CI]=0.52 [0.36,0.76]) compared to sulfonylureas, while showed a trend toward increased risk (OR [95% CI]=1.89 [0.60,5.93]) compared to sodium-glucose cotransporter 2 (SGLT2) inhibitors. The difference was not statistically significant when compared to placebo (OR [95% CI]=1.04 [0.92,1.18]), and this tendency was similar in both subgroup analyses conducted with a general type 2 diabetes population as well as the population at high cardiovascular risk. CONCLUSIONS There is no significant difference in the risk of MACE between DPP-4 inhibitors and placebo groups. DPP-4 inhibitors show significantly lower risk of MACE when compared to sulfonylureas, while SGLT2 inhibitors might have lower risk compared to DPP-4 inhibitors.

Assessment of Cardiovascular Risk With Glucagon-Like Peptide 1 Receptor Agonists in Patients With Type 2 Diabetes Using an Alternative Measure to the Hazard Ratio:

Background: Randomized clinical trials with the aim of evaluating the cardiovascular risks associated with glucagon-like peptide 1 (GLP-1) receptor agonists, lixisenatide, liraglutide, semaglutide, and exenatide, have been conducted. They showed different results among the agents, but the reason has not been explained. Objective: To evaluate the cardiovascular risks associated with GLP-1 receptor agonists by using an alternative measure to the hazard ratio. Methods: We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Four randomized clinical trials with cardiovascular events as a primary endpoint, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide), were reevaluated by estimating the RMSTs for each of the agents and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. Results: The differences of RMSTs (GLP-1 receptor agonist minus placebo: point estimate and 95% CI) for primary composite endpoint of cardiovascular events were 0 days [−14, 14] in ELIXA (1080 days follow-up), 20 days [6, 34] in LEADER (1620 days follow-up), 8 days [1, 15] in SUSTAIN-6 (672 days follow-up), and 11 days [−3, 26] in EXSCEL (1825 days follow-up). As for the risk of other cardiovascular outcomes, there were no substantial differences between GLP-1 receptor agonists and placebo. Conclusions: Liraglutide and semaglutide decrease the risk of major adverse cardiovascular events compared with placebo when using the difference in RMST. The previously reported result that GLP-1 receptor agonists do not increase the risk of cardiovascular outcomes compared with placebo is also confirmed.