Shunsuke Ono

Exploring Differences in Drug Doses Between Japan and Western Countries

Japan is unique among Asian countries in that it requires inclusion of substantial domestic clinical trial data in new drug application data packages. Some question the need for this and call for globalization of approved doses. The current study examines international differences in maximum daily dose of drugs approved in Japan between 2001 and 2007, and for all cardiovascular system (CVS) and central nervous system (CNS) drugs marketed in Japan. For 32% of the drugs approved in Japan between 2001 and 2007, the maximum recommended dose in the United States was ≥2 times higher than the maximum dose approved in Japan. Dose differences were rare for antitumor and antiviral drugs and also for priority‐review and orphan drugs. Of all the price‐listed CVS drugs currently available in Japan, 65% had maximum doses that were ≥2 times higher in the Netherlands than in Japan; similarly, 57% of the drugs had maximum doses that were ≥2 times higher in the United States than in Japan. For CNS drugs, these figures were 32% (the Netherlands) and 29% (United States). These results underscore the necessity to carry out quantitative analyses to determine the causes of these differences.

Assessment of statin-associated muscle toxicity in Japan: a cohort study conducted using claims database and laboratory information

Objective To estimate the incidence of muscle toxicity in patients receiving statin therapy by examining study populations, drug exposure status and outcome definitions. Design A retrospective cohort study. Setting 16 medical facilities in Japan providing information on laboratory tests performed in and claims received by their facilities between 1 April 2004 and 31 December 2010. Participants A database representing a cohort of 35 903 adult statin (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin) users was studied. Use of interacting drugs (fibrates, triazoles, macrolides, amiodarone and ciclosporin) by these patients was determined. Main outcome measure Statin-associated muscle toxicity (the ‘event’) was identified based on a diagnosis of muscle-related disorders (myopathy or rhabdomyolysis) and/or abnormal elevation of creatine kinase (CK) concentrations. Events were excluded if the patients had CK elevation-related conditions other than muscle toxicity. Incidence rates for muscle toxicity were determined per 1000 person-years, with 95% CI determined by Poisson regression. Results A total of 18 036 patients accounted for 42 193 person-years of statin therapy, and 43 events were identified. The incidence of muscle toxicity in the patients treated with statins was 1.02 (95% CI 0.76 to 1.37)/1000 person-years. The estimates varied when outcome definitions were modified from 0.09/1000 person-years, which met both diagnosis and CK 10× greater than the upper limit of normal range (ULN) criteria, to 2.06/1000 person-years, which met diagnosis or CK 5× ULN criterion. The incidence of muscle toxicity was also influenced by the statin therapies selected, but no significant differences were observed. Among 2430 patients (13.5%) received interacting drugs with statins, only three muscle toxicity cases were observed (incidence: 1.69/1000 person-years). Conclusions This database study suggested that statin use is generally well tolerated and safe; however, the risk of muscle toxicity related to the use of interacting drugs requires further exploration.

Delays in New Drug Applications in Japan and Industrial R&D Strategies

The gap between Japan and both the United States (US) and the European Union (EU) with regard to access to new drugs is becoming a major issue in Japan. We analyzed the time lags involved in new drug application (NDA) and biological license application submissions in Japan, the US, and the EU in order to identify the causes of delayed access. The time lag related to submission of applications (“submission lag”) was longer for in‐licensed products and for non‐Japanese companies. Factors related to costs of clinical studies and potential volumes of sales were not associated with the submission lag. A bridging strategy (extrapolative use of foreign clinical data in the clinical data package based on International Conference on Harmonisation guideline E5) seemed to reduce submission lag, but the association between the two diminished when the cause‐and‐effect relationship was specifically investigated. These results suggest that multinational companies are likely to place more emphasis on the choice of development strategies that successfully lead to their goal rather than on direct costs and expected sales when deciding to introduce their pharmaceutical products in Japan. Our findings indicate that the clinical development guidances that helps pharmaceutical companies decide on investment and strategies are also the key to narrowing the gap in access to new drugs.

The quality of conduct in Japanese clinical trials: deficiencies found in GCP inspections

The quality of commercially sponsored clinical studies in Japan was examined with reference to deficiencies in the audit reports issued by the Organization for Pharmaceutical Safety and Research (OPSR). The OPSR is responsible for domestic good clinical practice auditing in Japan. Routine audits from 1997 to 2000 for 331 hospitals revealed various types of deficiencies such as errors in case report form (CRF) entries, institutional review board problems, and protocol deviations. The high prevalence of CRF-related deficiencies seemed to stem from peculiarities of the Japanese study environment such as the historical lack of on-site monitoring by the sponsor and the absence of research nurses. Characteristics in usual medical practices such as multiple drug use and loose informed consent also seemed to be associated with prevalence of similar deficiencies in clinical trials.

Analysis of the success rates of new drug development in Japan and the lag behind the US

OBJECTIVES The launch delay of new drugs has been a major public concern in Japan. Although it is recognized that the delay results from industrial R&D behaviors and regulatory conditions in the global market, the specific mechanisms underlying the significant delay have been unexplained. This study analyzed the association between the success rates of clinical development programs of new molecular entities in Japan and the development lag behind the US and provides clues for policy planning. METHODS The association between the success rates of clinical development and the development time lag between Japan and the US was estimated using the Cox proportional hazard model. RESULTS The phase II transition success rates in Japan were positively associated with the lags behind US development. Cox regression analysis results of phase III success rates were similar to phase II success rate results but were not statistically significant. CONCLUSIONS The advantageous effect of lags on development success in the latter country (i.e., Japan) appears to explain the persistent delays in development and launch. The governments countermeasures to reduce the access gap of new drugs must consider this mechanism and the influence on both the industry and the target population.

Differences in drug approval processes of 3 regulatory agencies: a case study of gemtuzumab ozogamicin

SummaryMajor discrepancies concerning risk-benefit assessments and regulatory actions are frequent among regulatory agencies. We explored the differences by scrutinizing a case of gemtuzumab ozogamicin (GO) in patients with acute myeloid leukaemia (AML). Assessment reports of GO were retrieved form the websites of the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and Japanese regulatory agency, and we also reviewed published clinical trials. While GO was approved by the US FDA under the accelerated approval program in 2000, it was withdrawn from the market in 2010, based on the required post-marketing commitment failure. The EMA refused granting marketing authorization for GO in 2008 on the grounds that there were no randomised controlled trials (RCTs). GO was approved as an orphan drug in Japan in 2005, and the Japanese regulatory authority decided to continue with the approval in 2010 on the condition that post-marketing surveillance is strengthened. Under these situations, promising new results of RCTs appeared in 2011, and the role of GO in AML treatment was refocused worldwide. The stringent regulation may not be suitable in case of an orphan drug of targeted therapy, and more room should be kept to facilitate effective developments of new anti-neoplastic agents.

Analysis of Pharmaceutical Safety-Related Regulatory Actions in Japan: Do Tradeoffs Exist Between Safer Drugs and Launch Delay?

Background: Prediction and management of drug safety is a global regulatory issue. Safety-related regulatory actions (SRRAs) are taken mostly when unexpected adverse drug reactions occur. Currently, Japan is reconciled to delayed access to new drugs (ie, launch delay compared to Western countries), but may have been benefiting by free-riding on safety data accumulated in other countries prior to Japanese launch. Objective: To identify factors that are significantly associated with SRRAs, and to discuss the challenges that Japan might have to face with increasing access to new drugs. Methods: The SRRAs of 135 new drugs approved from January 2000 to December 2005 were analyzed to investigate association with launch lag, company and drug characteristics, market size, submission data, and regulatory status. SRRAs were measured in terms of the number of emergency safety information notifications and official safety instructions issued by the Japanese regulatory agency within 3 years after approval. A negative binomial distribution model was used for regression analysis. Results: Longer launch lags and presence of drugs with similar modes of action were associated with fewer SRRAs. Bridging strategy showed increased SRRAs. No significant association was observed between SRRAs and the subject number in clinical data packages. Occurrence of SRRAs was varied among development strategy, preceding products, and regional regulations. Conclusions: The occurrence of SRRAs was associated with the accumulation of both foreign and domestic postmarketing evidence rather than with clinical trial data upon launch. Considering the paradigm shift to simultaneous global drug development and filing for regulatory approval, this study indicates the importance of intensive data collection in the early postmarketing phase and use of safety information in early markets. However, even if we would be sufficiently cautious about safety risks of new drugs, a population that enjoys first-in-class drugs probably has to bear the risks.

Clinical development and review times for new drugs in Japan: associated factors.

The length of clinical development and review procedures related to new drugs approved in Japan in 2000–2009 were analyzed. The length of time taken for clinical development varied depending on diversification of strategies, and the review times showed a decline during this period. Regression analyses suggested that clinical development times were significantly shorter for non–new molecular entities (non‐NMEs), priority reviews, conditional approvals, and drugs utilizing foreign clinical data. The review times were shorter for new drug applications (NDAs) submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) and for priority reviews. The effects of pre‐NDA consultations were mixed; the review time was shorter, but the clinical development period was prolonged.

Assessment of Factors Associated With Dose Differences Between Japan and the United States

Although it is well known that there are differences in approved doses between Japan and the United States, there has been no comprehensive research into the causes thereof. This study furthers the discussion of our previous investigation in 2010, with particular focus on pharmaceutical industry strategy and regulatory policy, among drugs approved in Japan between 2001 and 2009. Dose differences were observed in 73 of 190 drugs. Non‐Japanese firms were more likely to have a similar dose approved between Japan and the United States, the association being more pronounced when limiting the analysis to drugs for which a Japanese dose‐finding study was not conducted. Furthermore, dose differences were less frequent when non‐Japanese efficacy data were included in the application data package. No relation between potential intrinsic ethnic difference and dose difference could be identified. The results suggest that the pathway of drug development is more strongly associated with dose difference than are drug characteristics.

Ethnic Differences in Pharmacokinetics in New Drug Applications and Approved Doses in Japan

1237 2011 51 1237-1240 E difference has been gaining attention in recent drug development. Typically, global companies start clinical development in Japan after the United States and Europe, and clinical data packages filed in Japan often include foreign clinical data. To correctly interpret and apply the results of clinical trials in different populations, the differences in pharmacokinetic (PK) parameters play an important role. The International Conference on Harmonization (ICH) E5 guideline (E5 GL), which states the basic concepts in extrapolating clinical data of one region to another, requires consideration of pharmacokinetic differences between the regions as one of the ethnic influences. Furthermore, the Notification of Basic Principles on Global Clinical Trials recently issued by the Pharmaceutical and Medical Devices Agency (PMDA), the Japanese regulatory agency, strongly recommends the conduct of clinical pharmacology studies in Japanese subjects before or in parallel with simultaneous global studies. This applies even in cases in which domestic phase I trials have been omitted, in order to justify the dose applied in Japan. It is often argued how ethnic difference found in early clinical phases, often measured by PK parameters, affects the later phases and especially dose setting. Intrinsic factors such as body size and genetic polymorphisms of metabolic enzymes and transporters may account for differences in PK and are associated with clinical efficacy and safety in target populations. Not only intrinsic factors but also extrinsic factors such as medical practice exert significant impact, according to E5 GL. It is unclear, however, to what extent these intrinsic and extrinsic factors contribute to the evaluation of efficacy and safety of drugs. In the context of dose setting, there are some reports on regional discrepancy of approved dosage, but to date there is no rigorous research on the association between PK differences and dose determination in multiregional drug development. We conducted a comprehensive search of PK differences of Japanese and white patients and the association with approved doses in Japan and the United States.