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Restrictive regulations and cultural differences make regulatory approval in Japan elusive, but adopting new strategies may make that lucrative pharmaceutical market more accessible to non-Japanese companies.
Many of the new medications that come into the Japanese market originate in foreign countries, because the pharmaceutical industry in Japan is comparatively small. Despite this, foreign companies still have difficulty obtaining approval in Japan because of continued hesitancy about the exchange of foreign data. The most successful pharmaceutical products in Japan are still manufactured by Japanese companies1. For example, Japan stresses safety over efficacy, and daily doses are typically lower in Japan than in either the United States or the European Union2–3. It also appears that for a majority of drugs, dose differences are not due to pharmacokinetic differences, but rather differences in medical practice or culture.
Western companies have great interest in using foreign data to satisfy Japanese requirements for drug approval. And with the adoption of the Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data (available online at www.ich.org/pdfICH/e5.pdf), the Japanese became open to the use of foreign clinical data in applications for drug registration. ICH made it possible for the global pharmaceutical industry, in cooperation with Japanese regulators, to register medicines in Japan using data gathered abroad4. The willingness of other regions to use Japanese data is likely to emerge more slowly, primarily because the level of record-keeping detail and the Western ability to monitor and audit trials at the site level are relatively new concepts in the Japanese clinical trials environment.
Developing new medications is a painstaking, lengthy, and expensive process. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (generally referred to as ICH) focuses on technical requirements for medicines that contain new drugs. Most new drug products are developed in Western Europe, Japan, and the United States. Consequently, when ICH was established, the founding members agreed to concentrate on registration in those three regions. The founding members of ICH represent regulators and industry in the European Union, Japan, and the United States—the EU, EFPIA, MHLW, JPMA, FDA, and PhRMA.
In 1998, the ICH Steering Committee recommended adoption of the Harmonised Tripartite Guideline on Ethnic Factors in the Acceptability of Foreign Clinical Data, E5. The focus of the E5 guideline is on the use of data created in one region for regulatory filing purposes in another region.
Furthermore, that same year the FDA released a guidance with the International Conference on Harmonisation, “Guidance on Ethnic Factors in the Acceptability of Foreign Clinical Data,” recommending strategies that allow application of clinical data collected in one region to be used for the support of drug and biologic registrations in another region5. This document allows for the consideration and evaluation of such factors as the medication’s efficacy and safety at specified dosage and dose regimens. It was developed to facilitate the registration of study compounds among ICH regions. The guidance also suggests specific regulatory and development strategies to expedite the drug approval process, to allow adequate evaluation of the influence of ethnic and racial factors on drug intervention effects, and to minimize the duplication of clinical studies.
Clinical data generated in foreign regions can be either complete or incomplete, with the acceptability of the data depending on whether it can be accurately extrapolated to the new region. Extrapolation is the key concept behind accepting foreign clinical data and is highly contingent on the completeness of the package
.Complete packages should include data that adequately characterizes the pharmacodynamics, pharmacokinetics, and dose response in a relevant population and clinical trial data establishing dose response, efficacy, and safety. Successful extrapolation of data is more likely if the drug class has already been approved in the new region. If foreign data does not meet these stringent standards, the regulatory authority may require additional clinical trials. These clinical trials may focus on different subsets of the population (for example, including patients with renal or hepatic impairment), distinct comparator groups at clearly specified dosages or dose regimens, or drug–drug interactions.
If foreign clinical data can be accepted by extrapolation, it is not necessary to conduct bridging studies, because the data can be inferred based upon existing data only. However, if extrapolation is unsuccessful, then in order to be complete, the final data package must also contain “bridging” studies. Bridging studies are defined by the ICH E5 guideline as supplemental studies performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage, and dose regimen in the new region. Bridging studies will allow extrapolation of the foreign clinical data to the new region. Ethnic sensitivity to the study medication should guide the need and nature of the bridging study. Medications with the following characteristics are sensitive to ethnic factors and may be subjective to bridging studies:
Bridging studies considered by the regulatory agencies in Japan can be categorized into Phase 1 pharmacokinetic–pharmacodynamic (PK–PD) comparative studies and Phase 2/3 efficacy studies. As a practical note, while Western countries use the term bridging studies for both types of studies, Japan reserves the term “bridging” for only the Phase 2/3 efficacy studies.
The Phase 1 PK–PD studies comparing the two populations are almost always necessary and can be performed outside of Japan using a population representative of Japan. The need for Phase 2/3 efficacy studies is evaluated on a case-by-case basis and usually must be performed in Japan. Situations where additional efficacy trials are needed occur when medical practices in the new region are significantly different, the choice of dose in the new region is unclear, the new region has little or no experience with controlled trials, or when the class of medication is unfamiliar in the new region.
Data generated from bridging studies may yield several possible results:
The concept of extrapolation and bridging discussed in the guideline is difficult to understand because the performance of the bridging study is not clearly described. Therefore, discussion of bridging study designs between the regional regulatory authority and the sponsor is encouraged prior to completion of the clinical data package. Designing the bridging study is crucial to the success of the program. In order to be valid, the bridging study must have the same design as the study conducted in the foreign region. More often than not, however, it is difficult to conduct an identical study because medical practices and therapeutic strategies may vary. Other issues that arise include differences in definitions and diagnosis of the target disease between regions. This can be overcome by choosing the definition and diagnosis used in either the foreign region or globally.
Another example includes the choice of appropriate endpoints, which can differ from region to region. Endpoints that are commonly accepted in one region may not be widely recognized as the best endpoint in another region. Therefore, it is most appropriate to choose endpoints that have been globally used and validated. In addition, common medical practices and customs in distinct regions may greatly influence the appropriateness of endpoints. Therefore depending on choice of endpoint, data gathered from randomized, controlled clinical trials in one region may not be applicable in a new region, especially across ethnic differences.
As discussed before, whereas the Phase 2/3 efficacy trials must always be performed in Japan, the Phase 1 PK–PD comparative trials may be performed outside of Japan. Sponsors may have a number of reasons for wishing to conduct such studies outside of Japan. For example,
Investigators involved in these trials must pay particular attention to subject selection and ethical conduct. Although many Japanese reside outside of Japan, we must further define these individuals in order to ensure that they indeed are representative samples of Japanese in order to satisfy both scientific and regulatory concerns. Ostensibly, they must be first-generation Japanese living abroad, meaning that they must have been born in Japan to parents of Japanese descent. One may also consider documentation of other Japanese descendants such as grandparents. Neither second-generation nisei nor third-generation sansei Japanese-Americans should be considered for these types of studies. Furthermore, the length of stay outside of Japan should be limited for volunteers in order to minimize extrinsic influences such as diet or lifestyle choices (for example, smoking and alcohol consumption).
Although it is difficult to identify a time limit, investigators and regulatory agencies have said that individuals may assimilate to a new country of residence in a time period of approximately five years. Indeed, many countries, including the United States, allow immigrants to apply for citizenship after five years of legal residence.
The most important message is that the individuals participating in these studies must be representative of the Japanese living in Japan and their lifestyles must not have changed significantly since relocating from Japan. In order to satisfy this requirement, these Japanese individuals must be living in cities with large and well-established Japanese communities (for example, Los Angeles) where they continue to interact with other Japanese, frequent Japanese restaurants and markets, and have complete access to the Japanese lifestyle and culture. Only by abiding by these rigorous requirements can sponsors confidently use data from non-Japanese investigative sites to satisfy the Japanese regulatory bodies. Additional investigative site infrastructure requirements for the ethical conduct of these studies include, but are not limited to, bilingual Japanese staff and availability of Japanese informed consent forms.
The Japanese pharmaceutical market is the second largest in terms of total annual expenditure ($62 billion), outranked only by the United States market ($86 billion). Opportunities abound for new product development in the Japanese market
. Currently, foreign companies are poorly represented in Japan. Until very recently, foreign enterprises were not allowed to control a majority share in a Japanese company, and joint ventures were the most direct way to enter the market. In addition, drugs approved in other regions had to pursue a costly and lengthy approval process that repeated the original trial process
. Recent changes in the applicability of foreign data and economic restructuring have alleviated some of these burdens. Yet the number of new products introduced by foreign companies into Japan is consistently below the number introduced worldwide.
Although the Japanese market appears full of promise, several complications are associated with it. The approval time for new chemical entities in Japan has increased significantly in the past decade, rising from approximately 1.7 years in 1992 to over 3 years in 19989. And most of the new drugs approved in the United States have not been approved in Japan. In fact, since 1992, less than 40% of the drugs approved in the United States have been approved in Japan10.
Further complications arise from the adoption of the ICH Guideline for Good Clinical Practice (www.ich.org/pdfICH/ e6.pdf) in Japan and, as a result, the introduction of GCP regulations into the region. Unquestionably, adoption and implementation of the guideline increase the difficulty of conducting clinical trials.
One of the greatest concerns pertains to the procedure for written informed consent. Japanese patients tend not to request details about diagnosis and treatment, and physicians fear that sharing this information as stipulated by the GCP guideline may undermine the physician–patient relationship11. Japanese patients also tend to be reticent about participating in clinical trials and are reluctant to be randomized and take placebos. These factors may adversely affect subject recruitment, limiting the number of subjects recruited and extending recruitment times. This will likely translate into increased trial length as well as increased cost12. Because changes to GCP in Japan are changing the way trials are conducted there, it is likely that study length will parallel the increase that resulted in Europe when obtaining written informed consent became standard practice.
The drug development process in the pharmaceutical industry evolved tremendously in the past decade following the successful implementation of ICH guidelines. Needless to say, some very real challenges to entering the Japanese pharmaceutical market remain. And to be successful in capturing the Japanese market, global pharmaceutical firms will have to be patient and sensitive to regulatory and cultural issues. It behooves pharmaceutical companies to compile a strong bridging data package to ensure success in this market. However, attention to cultural details and courtesies will aid significantly in a successful enterprise.
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