Focus on Medicinal Products for Rare Diseases; Comparison of System in Japan with US and EU

October 2011

In our August 2011 publication on the Japanese Orphan Medicinal Product Rules, we presented the system in Japan for medicinal products to treat rare diseases, and some government supported opportunities for the development of Orphan products. An Orphan product in Japan is a drug or device that is intended to treat a disease affecting less than 50,000 persons in the country. This article focuses on the comparison of the system to support the development of Orphan drugs in Japan with that in the United States and Europe. We will also discuss areas where the system in Japan may improve in the coming years.

Since the April 1993 revisions to the Pharmaceutical Affairs Law (PAL) in Japan, the Ministry of Health Labor and Welfare (MHLW) introduced various measures to support the development of Orphan products. This system was to some degree modeled after the Orphan Drug Act in the United States that was introduced in 1983 and have been revised several times since. In Europe, the European Commission introduced legislation for a centralized system to support the development of Orphan products through the EMA in 1999. While each of these systems are similar in some aspects, there are distinct and meaningful differences and perhaps areas for improvement in each region.

There are approximately 30,000 recognized diseases in medical textbooks, of which fewer than 6,000 to 8,000 can be regarded as rare diseases. Approximately 70% of all rare diseases are of genetic origin. The definition of what constitutes a 'rare' disease varies from one region to another. The prevalence figure accepted in the EU is no more than five individuals per 10,000 of the population. In the USA, the proposed prevalence is less than 200,000 individuals out of the entire population, which currently equates to fewer than 7.5 per 10,000 of the population. Similarly, the prevalence thresholds stipulated in Japan is no more than 50,000 patients, which equates to no more than 4 individuals per 10,000 of the corresponding populations. Thus, while Japan has been diligent in supporting Orphan products and provides various benefits for companies developing drugs and devices for rare indications, the lower criteria for prevalence in Japan as compared to the US and EU, means that some diseases designated in the US as Orphan, may not receive that designation in Japan. As in the US, part of the reason for this difference is the fixed number of patients (50,000) with a disease that is designated in the PAL. In contrast, the system in the EU is based on individuals (5) per 10,000 of the population and thus changes in population do not affect the prevalence calculation.

Currently in Japan, Orphan designation is awarded through the MHLW, with research support and grants coming from National Institute of Biochemical Innovation (NIBIO: www.nibio.go.jp), and review of the applications for clinical investigations and market authorization is through the Pharmaceuticals and Medical Device Agency (PMDA: www.pmda.go.jp). There are several other government agencies involved in the Orphan product designation process including the Pharmaceutical and Food Safety Bureau's Evaluation and Licensing Division (PFSBE) and the Pharmaceutical Affairs and Food Sanitation Council (PAFSC). Thus the current system is shared between several organizations in the Japanese government. In the United States, the primary responsibility for Orphan designation, grants and approval all reside with the US FDA. In the EU, the Orphan product process is also primarily managed through the EMA. Given the PMDA as an organization is relatively new in Japan, the effort towards consolidation and streamlining the process for Orphan products is expected to continue in the coming years. Nonetheless, the system for designation, research support and application review is executed well in Japan with good communication across the various government agencies involved in the process.

More often, in all regions, Orphan products are developed by smaller companies due to the market size and, at times, due to novel (risky) nature of the therapies. As such the need for consultation for Orphan products is more important. In the US, as with all meetings for Investigational Products, there is no fee for obtaining FDA advice. While FDA tries to limit the meeting opportunities for development products given the workload, for Orphan products there is more flexibility to obtain advice. In the EU, a system was also created for consultation meetings for Orphan products that is free of charge. Given that Scientific Advice for other products in the EU is a significant fee, the ability for companies developing Orphan products to get 'Protocol Assistance' at no cost is an important benefit of the Orphan designation. In Japan, products with Orphan designation can receive some advice from NIBIO at no cost, but for consultation with PMDA a fee is still charged or consultation with only a small discount for Orphan products. In some cases, these fees are a deterrent to small companies asking for consultation advice from PMDA, but with careful planning may be strategically managed.

Orphan products also received special treatment in all three regions during the approval process. In most cases these products receive fast track or priority review and are approved in a shorter time frame. If for a life-threatening disease, the US FDA will often award 'priority' review in which a product can be approved within 6 months. In Japan, 'fast-track' approval for Orphan products is typically 10 months. The data requirements for an Orphan product are also more flexible and, depending on the prevalence of the disease and condition, regulatory agencies often accept less data than for standard applications. In Japan, PMDA has been flexible with regards to the amount of data and some requirements including approving some Orphan products with no or very little data in Japanese.

Application fee reductions are also possible in all regions. While in the US, FDA does not charge a fee for the submission or marketing of an Orphan product, in Japan and the EU an application feel still applies, but is reduced. Japan has a number of other benefits for developers of Orphan products, including grants that can be up to 50% of the direct costs for developing an Orphan product for Japan. There are also tax advantages and other post-marketing benefits available.

However, it is recognized that Japan's current approach to management of Orphan products may have room for improvement. In particular, the lower prevalence that is a result of the fixed 50,000 patient requirement for an Orphan product may more appropriately be adjusted to a prevalence per 10,000 persons such as in other regions. The US prevalence of fewer than 7.5 per 10,000 persons results in some Orphan products in the US not receiving Orphan designation in Japan.

In September 2011, The Federation of Pharmaceutical Manufacturers' Associations of Japan (FPMAJ) filed a request concerning revisions of the pharmaceutical regulatory system currently under discussion by a study committee of the MHLW (Korosho). The FPMAJ's request was focused on research and development promotion system of orphan drugs, and primarily the need to revise the number of patients that would allow for designation as an Orphan product in Japan and that the MHLW consider creating a system that matches the US on prevalence. The concerns raised are that the discrepancy between requirements makes it difficult not only to manage the simultaneous global development of orphan drugs, but also the development of drugs in Japan. The FPMAJ also has requested special measures for Orphan products, such as allowing applications based on data from the public domain, to support the development of "ultra orphan" drugs with very few patients, that in some cases make clinical trials impractical.

The request also points out the inefficiency of consultation and review systems for orphan drug designation. These concerns include the fees charged for Orphan products that may inhibit some small companies from seeking consultation in Japan. The FPMAJ was also concerned that there are several organizations are currently involved including the PFSBE, the PMDA, NIBIO, and the PAFSC in addition to the MHLW. Citing organizations specializing in orphan drug regulatory that are established in the US and Europe, the FPMAJ calls for the restructuring of these organizations and responsibilities in Japan.

Thus, internal advocates for Orphan products within Japan are supporting changes to request MHLW to revise certain aspects of the current Orphan product designation process. It is expected that in the coming years, many of these changes will be implemented to further support development or products for rare diseases in Japan and facilitate global development that reduces the drug lag in Japan for these critical Orphan products.

Richard E. Lowenthal, MSc MBA
Pacific-Link Consulting LLC (San Diego and Tokyo)
JETRO North America Health Care Advisor