Regulatory Strategy in Japan: How to Maximize your Chances of Success

It is ironic that Japan is the world's second largest pharmaceutical market, but still lags behind some much smaller markets in terms of regulatory efficiency and clinical research capabilities. In order to improve this situation, the Japanese Health Authorities have recently introduced a series of reforms to streamline the clinical development and regulatory approval process.

However ,it is still challenging for foreign pharma companies especially the new entrants to the Japanese market to navigate the murky waters of the regulatory environment and manage the intricacies of Japanese cultural barriers. In this article, I will try to introduce some of the unique aspects of Japanese regulatory requirements pertinent to CMC issues and will highlight some of the cultural aspects that have a deep impact on success of your business in Japan.

Whilst being an ICH member, there are still conceptual and technical aspects which keep Japan standing out compared with EU/US, particularly on the quality issues of pharmaceutical products. One of the most conspicuous differences between Japan and the rest of ICH countries is the Japanese concept of module 1. While it is viewed in EU/US as an administrative section of the CTD, in Japan it is regarded as the legally-binding document which summarizes the most important aspects of the application for approval. Module 1-which is commonly known in Japan as The Application Form- is the focus of regulatory review. There is a lack of a clear and transparent system for the evaluation of change controls in Japan. According to Japanese pharmaceutical law, it is necessary to identify in module 1 the critical and non-critical parameters in the manufacturing process. Changes to module 1 usually result in filing variations. It is also noteworthy to mention that information on product shelf-life should be also included in module 1.

In general terms, Japan has aligned its requirements with ICH standards, although in the past there used to be national guidelines which differ from Western practice. One example was the need of triplicate results for stability data though there are no guidelines, which explicitly stipulate such specific requirement.  In the present time, PMDA/MHLW often refers to ICHQ1A (R2) as a key document for stability requirements. However, special attention need to be taken to ensure that test methods used in generating stability data should follow Japanese Pharmacopeia. This is a critical point as it has brought about considerable delays in the approval of a number of NDAs.

For clinical trials in Japan, in contrast to the situation in Europe and US, the regulatory Agency does not require CMC data to perform clinical trials. However, the sponsor has to ensure quality of the investigational medicinal product based on the sponsor’s own judgment and responsibility. One of the other peculiar local practices in Japan regarding stability is the provision of stability data on unpacked tablets and capsules which is not a regulatory requirement per se, but a quality standard set by Japanese Society of Hospital Pharmacists.

It may be true that the Japanese industry's reputation of high quality has been shaken by the failures of Toyota’s hybrid cars, as covered by the media in the past few months. Yet Japan still boasts unparalleled quality standards. In the pharmaceutical industry, Japan has very strict requirements especially with regards to the appearance of the pharmaceutical product. Every year tens of products manufactured by pharmaceutical companies are recalled because of their failure to comply with the Japanese quality standards. Between April 2007 and May 2008, 42 products were recalled because of the detection of foreign particles such as glass particles, human hair, etc.  It is therefore crucial to take these aspects into account when devising a global quality strategy. In most of the cases, a well-thought Japan specific strategy is recommended. 

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In addition to these striking differences, foreign pharmaceutical firms face the daunting task of dealing with the linguistic and cultural challenges. These issues have a tremendous impact on the success in Japan as they affect greatly a key aspect of your business that is communication. In broad terms, Japanese are notorious for their limited English abilities as is demonstrated by their modest ranking in international English tests. In addition, the Japanese business culture is very different from the western style and concept. It takes time and a great deal of effort to understand the complex psycho-sociological aspects that underline the Japanese concepts of company (in Japanese language Kaisha or Uchi which also means house), communication (including decision making), hierarchy, compensation and pride. It is not the scope of this article to develop further these concepts, but a cultural training -preferably tailored to pharmaceutical industry- is highly advisable for new entrants to the Japanese market.

Your success in Japan hinges on two key elements: The first is to develop a communication strategy with your local representative in Japan. This is crucial as you would rely on your Japanese partner to liaise with the Japanese regulatory authorities.  Therefore , gaps in communication between the company’s headquarters and the local representative will cause confusion of the Japanese regulatory Agency, thus compromising the long term relationship with PMDA. 

The second key element which is extremely important is to seek the expertise of an independent third party to validate some of the advice you would receive from your local representative in Japan. This advice can be influenced by cultural considerations and also by the lack of the global perspective and experience. In many instances, foreign companies face some resistance from their Japanese counterpart to challenge the regulatory authorities on a specific issue. Third party advice can be also particularly useful in making the distinction between the regulatory requirement and the local practice. Such insight will broaden your options and gives you more flexibility in dealing with specific situations.

In conclusion, Japan is an attractive market, but new comers should heed the regulatory and cultural challenges in order to avoid as much as possible a bumpy ride in the country of the rising sun.