Yoshiaki Uyama

Moving Beyond the Hazard Ratio in Quantifying the Between-Group Difference in Survival Analysis

In a longitudinal clinical study to compare two groups, the primary end point is often the time to a specific event (eg, disease progression, death). The hazard ratio estimate is routinely used to empirically quantify the between-group difference under the assumption that the ratio of the two hazard functions is approximately constant over time. When this assumption is plausible, such a ratio estimate may capture the relative difference between two survival curves. However, the clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the underlying proportional hazards assumption is violated (ie, the hazard ratio is not constant over time). Although this issue has been studied extensively and various alternatives to the hazard ratio estimator have been discussed in the statistical literature, such crucial information does not seem to have reached the broader community of health science researchers. In this article, we summarize several critical concerns regarding this conventional practice and discuss various well-known alternatives for quantifying the underlying differences between groups with respect to a time-to-event end point. The data from three recent cancer clinical trials, which reflect a variety of scenarios, are used throughout to illustrate our discussions. When there is not sufficient information about the profile of the between-group difference at the design stage of the study, we encourage practitioners to consider a prespecified, clinically meaningful, model-free measure for quantifying the difference and to use robust estimation procedures to draw primary inferences.

Successful bridging strategy based on ICH E5 guideline for drugs approved in Japan

fi d g t b s n j C For a drug to be approved under the Pharmaceuical Affairs Law of Japan, clinical data in Japanese re, in principle, necessary for evaluating the effiacy and safety of the drug, even if foreign clinical ata are available. However, the International Conerence on Harmonization of Technical Requireents for Registration of Pharmaceuticals for Huan Use (ICH) has actively discussed how to lobally share information from clinical studies mong regulatory authorities in different regions to inimize duplicative work. The ICH E5 guideline ntitled “Ethnic Factors in the Acceptability of Forign Clinical Data,” issued in 1998, describes factors hat could lead to different responses in different thnic groups, including differences in pharmacokietic (PK), pharmacodynamic, and clinical properies. Acknowledging the potential importance of uch differences, the guideline recommends that satsfactory foreign clinical data (ie, foreign data that atisfy all of a new region’s requirements, except for eing foreign) can be used to support approval in a ew region if there is 1 additional bridging study that ill allow the new region to believe the drug will ehave similarly in both regions. The conduct and se of bridging studies have come to be known as a

Effective global drug development strategy for obtaining regulatory approval in Japan in the context of ethnicity-related drug response factors.

In recent years, drug development has become dramatically globalized, and global clinical trials (GCTs) are being conducted in both International Conference on Harmonisation (ICH) and non‐ICH regions. 1 To ensure the success of global drug development, ethnicity‐related factors must be taken into consideration. In this article, the experiences and initiatives of the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan are described, and the contours of an effective global drug development strategy are discussed.

Regulatory challenges in the review of data from global clinical trials: the PMDA perspective.

Regulatory agencies face challenges in reviewing data from global clinical trials (GCTs) in the era of globalization of drug development. One major challenge is consideration of ethnic factors in evaluating GCT data so as to extrapolate foreign population data to ones own national population. Here, we present the Pharmaceuticals and Medical Devices Agency (PMDA) perspective in reviewing GCT data in new drug applications (NDAs) and discuss future challenges for new drug approval.

Significant Differences in Drug Lag in Clinical Development Among Various Strategies Used for Regulatory Submissions in Japan

Although the number of global clinical trials (GCTs) conducted in multiple countries including Japan has increased recently, it is not clear how much these GCTs help in reducing the lag in drug development (LDD: difference between the submission dates for new drug applications (NDAs) in the United States and Japan). We examined the effects of various clinical development strategies on LDD because the development period depends on what types of clinical trials were conducted for the Japanese NDA. Although various drug development strategies are available, deciding early on an appropriate strategy is a key to minimizing the LDD in Japan. The inclusion of GCTs in the clinical development strategy is also important; simultaneously, the smaller sample size of the Japanese population should be taken into consideration. Furthermore, reinforcement of Japans capability to lead drug development may also be important in providing innovative drugs to Japanese patients without any significant LDD.

PMDA's Challenge to Accelerate Clinical Development and Review of New Drugs in Japan

In recent years, Japans Pharmaceuticals and Medical Devices Agency (PMDA) has conducted several projects to shorten drug development and review times in Japan to resolve the “drug lag.” Key to achieving this goal is greater involvement by the PMDA in drug development through enhancement of scientific consultation and improvement of the review process by reinforcing the operational system, including hiring more reviewers. We discuss here the current projects of the PMDA as well as future challenges.

Regulatory science as a bridge between science and society.

Development of innovative drugs has recently become more difficult. The case of rosiglitazone shows the extreme difficulty of making the regulatory decision that will best balance the benefits and risks of a drug. There is a high expectation that regulatory science (RS) can improve the situation. However, without user understanding of its basic characteristics, RS will not deliver what is expected.

Multiregional Clinical Trials: Japanese Perspective on Drug Development Strategy and Sample Size for Japanese Subjects

Multiregional clinical trials including Japanese subjects are playing a key role in new drug development in Japan. In addition to the consideration of differences in intrinsic and extrinsic ethnic factors, deciding the sample size of Japanese subjects is an important issue when a multiregional clinical trial is intended to be used for Japanese submission. Accumulated experience suggests that there are several points to consider, such as the basic principles described in the guidance document, drug development strategy, trial phase, and disease background. The difficulty of interpreting the results of Japanese trials should also be considered.

Absence of ethnic differences in the pharmacokinetics of moxifloxacin, simvastatin, and meloxicam among three East Asian populations and Caucasians

Aim To examine whether strict control of clinical trial conditions could reduce apparent differences of pharmacokinetic (PK) parameters among ethnic groups. Methods Open‐label, single dose PK studies of moxifloxacin, simvastatin and meloxicam were conducted in healthy male subjects from three East Asian populations (Japanese, Chinese and Koreans) and one Caucasian population as a control. These three drugs were selected because differences in PK parameters have been reported, even though the backgrounds of these East Asian populations are similar. Moxifloxacin (400 mg) was administered orally to 20 subjects, and plasma and urine levels of moxifloxacin and its metabolite (M2) were measured. Simvastatin (20 mg) was given to 40 subjects, and plasma levels of simvastatin and simvastatin acid were measured. Meloxicam (7.5 mg) was given to 30 subjects and its plasma concentration was determined. Intrinsic factors (polymorphism of UGT1A1 for moxifloxacin, SLCO1B1 for simvastatin, and CYP2C9 for meloxicam) were also examined. Results AUCinf values for moxifloxacin, simvastatin and meloxicam showed no significant differences among the East Asian groups. Cmax values of moxifloxacin and simvastatin, but not meloxicam, showed significant differences. There were no significant differences of data for M2 or simvastatin acid. Genetic analysis identified significant differences in the frequencies of relevant polymorphisms, but these differences did not affect the PK parameters observed. Conclusions Although there were some differences in PK parameters among the three East Asian groups, the present study performed under strictly controlled conditions did not reproduce the major ethnic differences observed in previous studies.

Representation of older patients in clinical trials for drug approval in Japan

To examine how target patients seen in clinical practice are represented in clinical trials for approved drugs in Japan, we compared the age distribution of older patients enrolled in confirmatory clinical trials for regulatory approval with that of the estimated actual patient population. Drugs for 6 chronic conditions common among older patients (diabetes mellitus, hypertension, rheumatoid arthritis, non-small cell lung cancer, depression and Alzheimer’s disease) launched by 2012 in Japan were selected. The disparity in age distribution between patients in trials and patients seen in clinical practice varied depending on the disease, but older patients, especially those aged 75 or older, were generally underrepresented in clinical trials for regulatory approval in Japan. Under-representation of older patients in hypertension trials was particularly marked compared to other conditions, despite the similarity in age distribution of patients seen in clinical practice. One factor causing this disparity may be an upper age limit in clinical trial protocols. More effort is needed to properly characterize the benefits and risks of drugs for older patients. This should include the active enrollment of older patients in clinical trials, the establishment of better assessment tools such as pharmacometric approaches, and the appropriate planning and conducting of post-marketing surveys and studies.