Comparative analysis of GMO regulatory requirements for AAV vectors in the EU and Japan focusing on the shedding data and containment measures.

INTRODUCTION: Recombinant viral-based gene therapy products, such as those incorporating adeno-associated viruses (AAVs), fall under the category of genetically modified organisms (GMOs). The European Union (EU) countries and Japan must obtain environmental risk assessment (ERA) approval for the use of GMOs before starting any clinical trials. It has been reported that the development of GMO-containing products in these two regions encounters several regulatory obstacles due to the longer regulatory procedures and document preparation for ERA. AREAS COVERED: In this article, we comparatively analyzed the ERA document requirements in the EU and Japan for AAV-based recombinant medicinal products to highlight the differences in the context of potential future attempts of convergence. Additionally, we analyzed non-clinical and clinical shedding data requirements, which are key components of ERA reviews in the EU and Japan. Lastly, we compared the containment measures to minimize the spread of GMOs in the environment in the EU and Japan. EXPERT OPINION: Based on our comparative analysis, we present several policy recommendations of standardizing and simplifying the application materials and procedures for the ERA regulations on GMOs in the EU and Japan in the mid-, and long-term timeframe to achieve global regulatory convergence.

Application of estimand framework to the design and analysis of multi-regional clinical trials.

With the increasing globalization of drug development and the publication of the International Council for Harmonisation (ICH) E17 guideline (ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 2017), multi-regional clinical trials (MRCTs) have become a preferred option to accelerate the availability of new medical products by design, execution and simultaneous submission under one protocol. MRCTs, with the participation of all major regions including countries from both developed and emerging markets, surely make new drug development more efficient. Even though the proposed estimand framework (ICH E9 (R1) (2019), came later in 2019 and was not mentioned in ICH E17, the application of the estimand framework has the potential to enhance the design, execution, and analysis in MRCTs. Defining an estimand within the regional context in MRCTs is an important issue that requires careful consideration. Given that consistency evaluation of treatment effects across regions is critical in MRCTs, the utilization of the estimand framework for regional consistency evaluation is also worth discussion. This paper aims to address these two questions. The five attributes of the estimand definition are discussed within a multi-regional context. It is imperative to thoroughly consider regional intrinsic/extrinsic factors when planning the estimand and estimation of MRCTs. A holistic approach is summarized to conduct consistency evaluation. When a regional inconsistency is observed, the possible reasons need to be further explored under five attributes of the estimand framework. Two real case studies are discussed to illustrate the application of the estimand framework in the consistency evaluation.

A Bayesian approach based on discounting factor for consistency assessment in multi-regional clinical trial.

Multi-regional clinical trial (MRCT) has become an increasing trend for its supporting simultaneous global drug development. After MRCT, consistency assessment needs to be conducted to evaluate regional efficacy. The weighted Z-test approach is a common consistency assessment approach in which the weighting parameter W does not have a good practical significance; the discounting factor approach improved from the weighted Z-test approach by converting the estimation of W in original weighted Z-test approach to the estimation of discounting factor D. However, the discounting factor approach is an approach of frequency statistics, in which D was fixed as a certain value; the variation of D was not considered, which may lead to un-reasonable results. In this paper, we proposed a Bayesian approach based on D to evaluate the treatment effect for the target region in MRCT, in which the variation of D was considered. Specifically, we first took D random instead of fixed as a certain value and specified a beta distribution for it. According to the results of simulation, we further adjusted the Bayesian approach. The application of the proposed approach was illustrated by Markov Chain Monte Carlo simulation.

Regional efficacy evaluation in multi-regional clinical trials using a discounting factor weighted Z test.

Multi-regional clinical trial (MRCT) is an efficient design to accelerate drug approval globally. Once the global efficacy of test drug is demonstrated, each local regulatory agency is required to prove effectiveness of test drug in their own population. Meanwhile, the ICH E5/E17 guideline recommends using data from other regions to help evaluate regional drug efficacy. However, one of the most challenges is how to manage to bridge data among multiple regions in an MRCT since various intrinsic and extrinsic factors exist among the participating regions. Furthermore, it is critical for a local agency to determine the proportion of information borrowing from other regions given the ethnic differences between target region and non-target regions. To address these issues, we propose a discounting factor weighted Z statistic to adaptively borrow information from non-target regions. In this weighted Z statistic, the weight is derived from a discounting factor in which the discounting factor denotes the proportion of information borrowing from non-target regions. We consider three ways to construct discounting factors based on the degree of congruency between target and non-target regions either using control group data, or treatment group data, or all data. We use the calibrated power prior to construct discounting factor based on scaled Kolmogorov-Smirnov statistic. Comprehensive simulation studies show that our method has desirable operating characteristics. Two examples are used to illustrate the applications of our proposed approach.

Lag Time for New Innovative, First-in-Class, Drug Approval in Japan.

Early access to novel drugs, regardless of regional differences, is significant for patients worldwide. Although various efforts have been made to reduce the drug lag, it still exists in some regions, including Japan. In this study, we focused on the drug lag of first-in-class drugs in Japan and obtained fundamental information because we considered that first-in-class and me-too drugs are essentially different and should be treated separately. We analyzed 97 first-in-class and 176 me-too drugs in new molecular entity (NME)-approved drugs in Japan and the United States during the fiscal years between 2009 and 2019. Since government policy and the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs (the Committee) have a huge impact on drug lag, we distinguished NMEs developed at the Committee's request. First-in-class drugs were developed at the Committee's request significantly more than the me-too drugs (p = 0.0034). Although it was not statistically significant, the approval lags were 498.0 d for first-in-class drugs and 535.0 d for me-too drugs. Multiple regression analysis showed that multi-regional clinical trial (MRCT) development strategy (p = 0.0043) and foreign origin drugs (p = 0.0072) were a reducing factor and a prolonging factor of drug lag, respectively. In conclusion, the drug lag for first-in-class drug approval was one year. Global drug development using MRCT is one of the most effective development strategies for reducing drug lags.

Impact of expedited programs in the United States, as foreign regulatory factors, on clinical development time in Japan.

WHAT IS KNOWN AND OBJECTIVE: Regulatory authorities in several regions have introduced a number of expedited programs (EPs) to promote the development of innovative drugs for patients in their own countries. The EPs in the United States (US), alone or in combination, have been successful in shortening the clinical development time in the US. We examined whether US-EPs, as well as other related factors, have an impact on the clinical development time in Japan to obtain new insights for more efficient drug development. METHODS: In total, 168 drugs approved as new molecular entities (NMEs) in Japan and approved in the US between 2012 and 2019 were surveyed. We compared the clinical development time in Japan for those drugs with or without US-EPs. We also examined the impact of overlapping designations of US-EPs on clinical development time in Japan. Multiple regression analysis was performed to identify associated factors related to clinical development time in Japan, including US-EPs. RESULTS AND DISCUSSION: The clinical development time in Japan was significantly shorter at 37.4 [Interquartile range, IQR, 28.7-48.9] months for Accelerated Approval (AA), 42.2 [30.0-53.6] months for Breakthrough Therapy (BT), 42.3 [29.3-56.4] months for Fast Track (FT), 44.5 [30.7-60.0] months for US Priority Review, and 45.2 [31.3-61.8] months for US Orphan Designation. Multiple regression analysis revealed that AA (p = 0.008), FT (p = 0.013), Japan Priority Review, and the difference in development initiation dates between the US and Japan were significant factors related to a decrease in the clinical development time in Japan, whereas Japan Orphan Designation and the development of anticancer drugs were significant factors linked to an increase in the clinical development time. WHAT IS NEW AND CONCLUSION: US-EPs were associated with a decrease in the clinical development time in Japan for the drugs that were approved as NMEs in Japan and approved in the US. This association was not restricted to particular therapeutic areas or development strategies. Stakeholders involved in drug development, including the drug developers and regulatory authorities in Japan, should realize these effects for efficient drug development.

Bayes shrinkage estimator for consistency assessment of treatment effects in multi-regional clinical trials.

The primary objective of a multi-regional clinical trial is to investigate the overall efficacy of the drug across regions and evaluate the possibility of applying the overall trial result to some specific region. A challenge arises when there is not enough regional sample size. We focus on the problem of evaluating applicability of a drug to a specific region of interest under the criterion of preserving a certain proportion of the overall treatment effect in the region. We propose a variant of James-Stein shrinkage estimator in the empirical Bayes context for the region-specific treatment effect. The estimator has the features of accommodating the between-region variation and finiteness correction of bias. We also propose a truncated version of the proposed shrinkage estimator to further protect risk in the presence of extreme value of regional treatment effect. Based on the proposed estimator, we provide the consistency assessment criterion and sample size calculation for the region of interest. Simulations are conducted to demonstrate the performance of the proposed estimators in comparison with some existing methods. A hypothetical example is presented to illustrate the application of the proposed method.

Efficacy Comparison for a Schizophrenia and a Dysuria Drug Among East Asian Populations: A Retrospective Analysis Using Multi-regional Clinical Trial Data.

BACKGROUND AND OBJECTIVES: Multi-regional clinical trials (MRCTs) are an efficient drug development strategy for eliminating drug lag in East Asian countries. In planning MRCTs according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E17 guideline, it is expected that East Asian populations with relatively similar ethnicity can be pooled as one population. However, evidence supporting this assumption is limited. This study aimed to investigate population/regional differences considering influencing factors among East Asian regions using MRCT data as a research model. METHODS: A retrospective analysis was conducted to determine the efficacy of two drugs, asenapine, a schizophrenia drug, and tadalafil, a dysuria drug for benign prostatic hyperplasia, using MRCT data from Japan, Korea, and Taiwan. First, predictive factors and effect modifiers were evaluated. Then, population/regional differences were evaluated using multivariate regression models, with the interaction term Region-by-Treatment group and adjustment for influencing intrinsic/extrinsic factors. RESULTS: Among the 4 outcomes for the two drugs, no significant population/regional differences were detected (P > 0.05) by the adjusted regression models. The effect modifiers, such as pretreatment drug status or concurrent diseases, were common among countries. CONCLUSIONS: No significant population/regional efficacy differences were found for the two drugs among the three regions. This finding supported the possible applicability of the region pooling strategy for MRCTs in East Asia, emphasizing the benefits of exploring ethnic difference/influencing factors at an early stage to design further confirmatory studies. However, further evidence for various drugs should be accumulated.

Identification of Drug Characteristics for Implementing Multiregional Clinical Trials Including Japan.

PURPOSE: Multiregional clinical trials (MRCT) are a standard strategy used to improve global drug approval efficiency and the feasibility of clinical trials. Japan is the world's third largest drug market with a unique health care system, making it a key inclusion as an operational region for MRCT (MRCT-JP) for global drug development. We aimed to identify the factors required for efficient drug development by comprehensively reviewing the clinical trials of drugs approved in Japan to identify the factors associated with whether or not MRCT-JP is implemented. METHODS: We surveyed the review reports and summaries of application data published by the Pharmaceuticals and Medical Devices Agency. We identified drugs for which the clinical trial data package included MRCT-JP and selected the same number of drugs for which the clinical trial data package did not include MRCT-JP from the most recent survey period for comparison. We also examined other publication information, in addition to the review reports, as necessary. The influence of each explanatory variable was analyzed by logistic regression analysis, with whether or not MRCT-JP was implemented as the explanatory variable. Statistical significance was set at 5%. FINDINGS: In the survey period up to September 2017, 165 drugs developed with MRCT-JP were approved for manufacture and sale in Japan. "Respiratory system," "inhalation," "biological drug," and "under review" evaluation status for the United States, European Union, and other areas, "approved" evaluation status for the United States, "new ingredients," "priority review," "non-Japanese firm," and "Top 1-10" and "Top 11-20" drug sales rankings for pharmaceutical companies were identified as potential factors leading to the implementation of MRCT-JP. In contrast, "general anti-infectives for systemic use," "various," "external," "chemical compound," "unsubmitted" evaluation status for both the United States and European Union, and "Top 51+" drug sales rankings were potential factors for not implementing MRCT-JP. IMPLICATIONS: Therapeutic classification and agent type, in addition to capital type and United States and European Union evaluation status suggested by a previous study, were associated with implementing MRCT-JP. It is important to determine the best way to utilize MRCT-JP to maximize the value of products. Our findings were based on successful cases and may therefore be helpful for designing clinical development plans. Appropriate use of MRCT-JP will improve productivity in the pharmaceutical industry.

Evaluation of local treatment effect by borrowing information from similar countries in multi-regional clinical trials.

One key objective of a multi-regional clinical trial (MRCT) is to quantify country-specific treatment effects to support local registration. Naïve estimate of the treatment effects based on country-specific subsets of data are inefficient because of relatively sparse country-specific sample sizes, even in large MRCTs, and subject to many limitations. The recently developed shrinkage estimate approach improves efficiency by incorporating data from other countries but treating all other countries equally, thus ignoring similarity to the country of interest. Ideally, for the estimation of treatment effect in a country of interest, it is more efficient to use all relevant data such as that from countries that are similar to the one of interest. We propose a tree-based approach to incorporate similarity, with branches or forks used to represent the relationship of treatment effects between countries. Similarity in certain characteristics among countries in either continuous scale or categorical scale is used to build the tree. By allowing local treatment effects for countries to be random effects and follow a Gaussian process along the tree, we demonstrate that countries sharing the same internal parent nodes are more correlated and a country borrows more information from the neighbors sharing the same parent node. We illustrated this statistical framework using a MRCT with a continuous endpoint.