The Pharmaceutical Industry at a Glance Orphan drug development trends Analysis of FDA-approved Orphan Drug Development in Japan

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Shinichiro Awamura, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Eriko Hashimoto, Senior Researcher
Tomoyuki Shibuguchi, Senior Researcher
Naoto Murakami, Senior Researcher

The National Institute of Biomedical Innovation (NIBIO) continuously collects and analyzes information on new drug approvals and review periods in Japan, the U.S., and Europe, based on information published by regulatory ^{authorities1)}. In the "Policy Research Institute News No. 58 ^"(2), we compared the approval status of new drugs in Japan, the U.S., and Europe up to 2018, and reported that the number of approved drugs with Orphan Drug designation in the U.S. (FDA) has been increasing in recent years, accounting for 57.6% of the New Molecular Entity (NME) drugs approved in 2018. The report showed that the number of approved NMEs accounted for 57.6% of the total number of NMEs approved in 2018. On the other hand, in Japan, the number of drug approvals for drugs with Orphan Drug Designation (Orphan Drug) accounted for only about 30% of NMEs, showing a difference in trend. Therefore, in order to predict whether the percentage of Orphan Drug approvals in Japan will increase to the same level as in the U.S., we surveyed the development status in Japan of Orphan Drugs that have been approved by the FDA in recent years.

Trends in Orphan Drug Approval Status in Japan and the U.S.

The number of approvals and the percentage of NMEs for items that received Orphan Drug designation in Japan and the U.S. during the most recent 10-year period (2010-2019) are shown (Figure 1).

Despite differences in the criteria for Orphan Drug designation, the percentage is higher in the U.S. The number of Orphan Drugs approved in Japan was 116 (29.3%) of 396 NMEs over the past 10 years, while in the U.S. 158 (41.8%) of 378 NMEs were Orphan Drugs. In addition, in Japan, the percentage has averaged around 30% (29.7-36.5%) in recent years, while in the U.S., the percentage of Orphan Drugs has been higher than in Japan, ranging from 39.1% to 57.6% since 2014.

First, let us look at the differences in the designation criteria and preferential treatment of Orphan Drugs between Japan and the United States.

Differences in Orphan Drug Designation System

Table 1 summarizes the designation criteria and preferential measures for orphan drugs in Japan and the United States.

In Japan, less than 50,000 patients (0.04% of the total population) are eligible for orphan drug designation, while in the U.S. less than 200,000 patients (0.06% of the total population) are eligible. In addition, among the criteria for designation, Japan includes medical necessity (severity of disease) and development potential, whereas the U.S. includes the item that development costs cannot be recovered in the U.S.

On the other hand, as for preferential measures, both Japan and the U.S. offer grants and preferential tax treatment, and both countries have the same priority in terms of consultation regarding drug development. The difference is that in Japan, priority review is applied along with orphan drug designation, while in the U.S., it is necessary to obtain a separate Priority Review designation. In addition, as a preferential measure after approval, Japan extends the reexamination period up to 10 years (8 years for drugs containing new active ingredients), preventing generic drugs from entering the market during the reexamination period, while the US has a 7-year data protection period, allowing market exclusivity.

In the U.S., the "Rare pediatric disease priority review voucher program" was established to issue priority review vouchers for drugs for diseases that mainly affect children up to the age of 18 and affect fewer than 200,000 patients in the U.S., thereby promoting the development of new drugs for the treatment of rare pediatric diseases. The program encourages the development of new drugs for the treatment of rare diseases in the pediatric field.

Status of Orphan Drug Approval and Development in Japan

158 Orphan Drugs approved by the FDA in the last 10 years (2010-2019) were surveyed for their approval and development status in Japan using the Evaluate Pharma, PharmaProject, and New Drugs for Tomorrow databases (Figure 2) As of December 31, 2019, 73 (46%) ³⁾ were approved, 29 (18%) were pending or in clinical trials, while 48 (30%) had no confirmed development status in Japan In 2018 and 2019, the number of Orphan Drugs was 34 and 21, respectively, but 12 and 11 were Although there is a possibility that development may start in the future, the percentage of Orphan Drugs not yet developed in Japan was high.

Timing of Japanese approval of Orphan Drugs approved by the FDA in the past 10 years and the lag

Of the 158 Orphan Drugs approved by the FDA in the past 10 years (2010-2019), 72 were also approved in Japan (Figure 3), showing the respective approval dates and item-by-item lags for Japan and the U.S. Of the 72 drugs, 15 (21%) ⁴ were approved in Japan first, The remaining 58 items (79%) were approved in the U.S. first. The median difference in approval timing between the U.S. and Japan was 0.83 ^years5), and 19 products were approved more than 3 years later in Japan than in the U.S. Considering the lag in approval timing of Orphan Drugs, it is expected that applications for approval will be filed in Japan within a few years for products that are currently in the development stage in Japan. Figure 2: FDA's approval of Orphan Drugs in the past 10 years.

Breakdown of Orphan Drugs not yet developed in Japan

Of the 158 Orphan Drugs approved by the FDA in the last 10 years (2010-2019), we surveyed 48 drugs for which development information was not confirmed in Japan, based on the efficacy indications disclosed by the FDA (Table 2). As a result, of the 48 drugs not yet developed in Japan, 15 were genetic diseases (e.g., the number of Japanese patients is significantly smaller than in Europe and the U.S., making it impossible to conduct clinical trials) and 11 were infectious/tropical diseases (e.g., malaria, an infectious disease that rarely occurs in Japan), in that order.

Among the drugs not yet developed in Japan, some diseases were difficult to develop because there were no cases occurring in Japan or the number of patients was significantly small, and it was considered difficult to develop all of these items in the same way as in the U.S. Therefore, the increase in the number of FDA approvals in recent years did not necessarily lead to an increase in the number of orphan drug approvals in Japan.

Summary

In the past, despite the high medical need for drugs for intractable diseases and AIDS, research and development of such drugs had not progressed sufficiently due to the small number of patients, etc. In 1983 in the U.S. and 1993, 10 years later in Japan, a system to promote the development of orphan drugs was enacted into law, Since then, pharmaceutical companies and regulatory authorities have been working together to develop these drugs. In addition, Japan has been promoting the development of unapproved drugs of high medical necessity, including those for rare diseases (public knowledge approval), and has made progress in eliminating the drug lag for these drugs through the organization of the Study Group on Unapproved and Off-label Drugs of High Medical Need since 2010.

Noting that more orphan drugs have been approved in the U.S. than in Japan in recent years, we investigated the breakdown of orphan drugs approved in the U.S. in recent years and the development status of these drugs in Japan. The results showed that approximately two-thirds of the orphan drugs approved in the U.S. in the past 10 years have been approved or are in the development stage. In addition, some of the items that had not yet been developed in Japan (for which no development information could be confirmed) included diseases for which no cases had been reported in Japan, or for which the number of patients was extremely small and development would be difficult. Although it is difficult to assert a conclusion based solely on the results of this study due to differences in designation criteria, given the types of Orphan Drugs not yet developed in Japan, it is believed that Orphan Drugs will not necessarily be developed in Japan in the same way as in the United States.

On the other hand, treatment satisfaction for many diseases, especially lifestyle-related diseases, has increased dramatically, partly as a result of the contributions that have been made over the years to create new drugs. In addition to this, technological innovations such as gene technology are advancing, and highly advanced and highly useful personalized medicine is being realized. In light of the above, it is expected that the creation of innovative drugs for rare and intractable diseases with high unmet medical needs will become possible, and that the development of such drugs will become a major trend not only in the United States but also in the entire world, including Japan.

Although there are issues of market size and feasibility of clinical trials due to the rarity of the disease, it is a fact that patients suffering from rare and intractable diseases are eagerly awaiting the creation of drugs that will improve these diseases. As a pharmaceutical company, our mission is to always put patients first and strive to create innovative drugs that contribute to the health of people around the world, including those suffering from these diseases.

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