Topics Drug lag: Characteristics of unapproved drugs for pediatric indications in Japan
Drug Lag: Characteristics of unapproved drugs for pediatric use Part 1 - Rare Diseases

Printable PDF

Shinichiro Iida, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Hiroshi Azuma, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Masao Yoshida, Former Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

1. Introduction

In the late 2010s, the number of unapproved drugs in Japan increased and a new drug lag is ^emerging1-5). Many of these drugs were developed by emerging foreign biopharmaceutical companies and were characterized as being in rare disease areas or of high clinical ^{importance1-5)}.

In addition to these adult indications, it is assumed that the unapproved drugs include drugs indicated for pediatric use, and it is necessary to accurately understand the challenges of access to the latest medical care needed.

Drug lag, the so-called lag (delay) in the time required for a drug already approved overseas to receive regulatory approval in Japan, has become an issue. A survey by the Pharmaceutical and Industrial Policy Research Institute reported that the increase in the number of unapproved drugs in Japan includes many items for which no domestic development information has been confirmed. This is a serious problem, as unapproved drugs without development information in Japan are likely to become drug losses due to lack of opportunities to use them in Japan.

In this report, we focus on unapproved drugs with pediatric indications in the field of rare diseases in order to further understand the current status of unapproved drugs in Japan. The survey covered approved drugs with orphan drug designation in the U.S., and the characteristics of drugs with pediatric indications are analyzed by defining drugs that are unapproved in Japan and for which no development information is available (as of August 2022) as drug-loss items in this paper.

In the next paper ⁽⁶⁾, we will analyze the characteristics of drug-loss products that have pediatric indications for anticancer drugs in the U.S. (2000-2022) that are not approved in Japan and for which no development information is available (as of March 2023), as well as the drug-loss products that have obtained pediatric indications in Japan by 2020. The study also analyzes the drug lag of products that have obtained pediatric indications in Japan by 2020 and examines the causes of the drug lag.

Survey Methodology

New Molecular Entity (NME) approved by the Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration (FDA) from 2010 to 2021. For pediatric indications, the survey covered those NMEs that had received pediatric indications by the end of 2022. Since there is no database that comprehensively compiles pediatric indications, the presence or absence of pediatric indications was determined by checking the Indications and Usage and Pediatric Use sections of the Prescribing Information for each product listed by the U.S. FDA. The pediatric indications for which the FDA had approved the product were based on the Ministry of Health, Labour and Welfare's "List of Designated Intractable Diseases (November 1, 2021 edition)" and the "List of Diseases for Chronic Pediatric Diseases (November 1, 2021 edition)" published by the Japan Center for Information on Chronic Pediatric Diseases. List of Diseases Covered（ 20224 Year4 Month1 Date）」 and identified the name of the disease、 and identified the name of the disease.。 The Japan Pharmaceutical Manufacturers Association (JPMA) Industrial Policy Committee, Intractable and Rare Diseases Task Force assisted us in this check.

The companies that applied for FDA approval were classified as development leaders, and those that received FDA approval within 30 years of their establishment and had sales of less than US$500 million in the year prior to the approval were classified as startups. The other companies were defined as pharmaceutical companies.

Column: Changes in Unapproved Drugs in Japan, Drug Lag, and Drug Losses

The Pharmaceutical and Industrial Policy Research Institute (PIIPRI) tracks the number of unapproved drugs in Japan by checking whether drugs approved in the U.S. and Europe are approved or not in Japan. This number of unapproved drugs is a determination of whether a drug is approved or not at a given point in time, and is a figure that changes over time. For example, of the drugs approved in Europe and the U.S. during 2016-2020, 176 were unapproved in Japan as of the end of 2020 ^.1-5) When the Japanese approval status as of the end of 2022 is checked, the number of unapproved drugs decreased to 143, and 33 drugs were approved in 2021-2022, behind those in the U.S. and Europe. Of the said 176 products, 86 were unapproved as of the end of March 2023, and these are considered to be at high risk of drug loss, as there is no information on their development in Japan. Of these 86 drugs, 32 (37%) had pediatric indications in the U.S., and 24 (28%) had orphan drug designation. A total of 48 (56%) of the products had either pediatric or orphan designation, accounting for more than half of the total. Items not approved in Japan as of a given year include those that will be approved later than in the U.S. and Europe (so-called drug lag) and those that will not be approved in the long term (so-called drug loss). Since it is difficult to estimate the likelihood of long-term approval or non-approval in the future, unapproved drugs for which there is no domestic development information at the time of the survey are classified as drug losses in this report.

In addition, items approved in Europe and the U.S. in 2016-2020 that are approved in Japan as of the end of 2020 are not classified as unapproved ^drugs1-5), but this may include some items that are in a drug lag. For example, an item approved in Europe and the U.S. in 2016 and in Japan in 2020 would have a drug lag of 4 years. Since the transition of unapproved drugs in Japan, which is surveyed and analyzed by the Pharmaceutical and Industrial Policy Research Institute (PIIPRI), is mainly for visualization of drug loss issues, this data characteristic should be kept in mind when analyzing drug lag and drug loss.

Results

3-1 Drug Losses of US orphan drugs with pediatric indications

Between 2010 and 2021, 215 new active ingredients were approved in the U.S. under orphan drug designation. Of these, 110 (51%) were unapproved in Japan as of the end of August 2022 (Figure 1).

Of the 105 items approved in Japan, pediatric indications in the U.S. and Japan have not yet been confirmed, leaving the possibility that some items may have pediatric indications in the U.S. but not in Japan. Such items are not covered in Japan and cannot be used in pediatric patients. Although this report does not provide comprehensive results of the survey, please refer to the next article for an analysis of the current status of pediatric anticancer agents.

Looking at the development status of the 110 drugs not approved in Japan, 40 (36%) were under development, while 61 (56%) had no information on development in Japan (Figure 2). In other words, of the 215 NMEs designated and approved as orphan drugs in the U.S., 61 (28%) were not confirmed to be under development in Japan according to public information and were considered drug losses (as of August 2022) in the context of this report.

Of the 40 drugs classified as under development in Japan, 12 had obtained pediatric indications in the U.S. (data omitted). The status of pediatric development in Japan is unknown because the distinction between adult and pediatric development is not disclosed, but as of the end of August 2022, the drug was not approved in Japan, which means that there is a drug lag in the initial indication.

In addition, the discontinuations shown in Figure 2 include items for which development has been discontinued or suspended and for which no further information is available. It should be noted that these items are based on scientific judgments such as the results of clinical trials and withdrawals overseas, but it cannot be denied that they may also include items based on business judgments, and thus drug lag/drug loss may be included.

In addition, a survey of the 61 drugs for which development information was not available in Japan to determine whether pediatric indications had been obtained in the U.S. confirmed that 29 of the 61 drugs (48%), or almost half, had pediatric indications (Fig. 3). The 32 products without pediatric indications included 12 infectious and tropical diseases, 8 oncology products, and 5 diagnostics products (data omitted).

In other words, 29 of the new active ingredients approved in the U.S. with orphan drug designation had pediatric indications in the U.S., but domestic development information was not confirmed, and they were found to be drug losses (as of the end of August 2022) as described in this paper.

3-2 Characteristics of Pediatric Drug Losses

Furthermore, of the 29 new active ingredients approved in the U.S. with orphan drug designation, for which development information was not confirmed in Japan, and for which pediatric indications were obtained in the U.S., we asked whether the indications were for diseases that fall within the scope of the Japanese designation of intractable ^diseases7) or chronic pediatric ^diseases8), We also checked whether the indications in the U.S. were for diseases designated as intractable diseases7) or chronic pediatric diseases8) in Japan (Fig. 4).

Of the 29 products, 16 (55%) were covered by designated intractable diseases and pediatric chronic specified diseases, and 9 (31%) were covered only by pediatric chronic specified diseases. A total of 25 items (86%) were covered by chronic pediatric diseases, indicating that there is a drug loss (as of the end of August 2022) in the items for diseases with high medical needs.

In order to understand the causes of drug loss (as of the end of August 2022), we surveyed the companies that had submitted FDA applications in the U.S. for these 29 products as development leaders.

Of the 29 drugs, 15 (52%) were developed by startups and 14 (48%) by pharmaceutical companies (Figure 5). When we narrowed down the category of companies to the 25 products for pediatric chronic diseases, 13 were startups and 12 were pharmaceutical companies, similarly split evenly between the two groups (data omitted).

We have already reported that many of the drugs approved in the U.S. and Europe are being developed by startup companies as a reason for the increase in the number of drugs not yet approved in ^Japan1-5). On the other hand, half of the drug-loss items were from pharmaceutical companies, suggesting that there are issues unique to pediatric drug-loss in Japan.

Table 1 summarizes the indications for the 29 products. The main disease categories of the items designated as pediatric specific chronic diseases were genetic diseases, which accounted for 14 diseases and 21 items. This was followed by rare cancers with 3 items.

Among the products not designated as pediatric specific chronic diseases, 2 and 3 products were indicated for infectious and tropical diseases, and 1 product was indicated for other diseases.

4. summary and discussion

Of the 215 products approved with orphan drug designation in the U.S. from 2010 to 2021, there were 29 products with pediatric indications for which no development information was available in Japan (as of August 2022), which are referred to as drug losses in this report. When we checked whether these drugs are applicable to designated intractable diseases or chronic pediatric diseases in Japan, we found that 25 of the 29 drugs are applicable to such diseases, indicating that drug loss (as of August 2022) is occurring for drugs that are expected to be indicated for pediatric use in the disease areas in need of such drugs in Japan.

Genetic diseases accounted for the majority of the 29 diseases. It is assumed that the number of drugs in genetic diseases has increased due to progress in the development of new drugs in the U.S. as the causative genes of congenital diseases are elucidated and therapeutic modalities are ^expanded9). Further investigation and research will be needed to determine the factors that led to the rapid development of these drugs in the United States.

In rare diseases and pediatric indications, the market size is generally very small, but additional R&D investment is required, so this is a business area where economic rationale is not viable. However, in the case of genetic diseases, there are likely to be ethnic differences in the frequency of genetic mutations, and it is not difficult to imagine that the number of target patients in Japan is smaller than in other countries, making it more difficult to ensure profitability in Japan. In addition, half of the pediatric drug-loss products for rare diseases (as of August 2022) are from start-ups, which is similar to the trend in the increase of unapproved drugs in recent years ^(1-5), suggesting that Japan's marketability and R&D environment are likely to be an issue. In addition, half of the pediatric drug-loss items (as of August 2022) were also from pharmaceutical companies, suggesting issues specific to pediatric indications. In light of the importance of drug development for intractable and rare diseases and pediatric indications, Japanese policy also encourages the development of drugs for rare diseases and pediatric indications through the "Orphan Drug Designation System" and the "Drug Designation System for Specific Uses " ^{7, 8)}. However, the number of orphan drug designations has increased less than in Europe and the U.S. ¹⁰⁾, and it is possible that these support measures do not respond to the rapid scientific progress and changes in the drug development environment in recent years. Even in the case of rare diseases, investment in R&D in Japan is considered necessary to ensure access to the latest medicines in Japan. In such rare disease areas, simultaneous development on a global basis will become even more important for investment efficiency, and in the case of rare diseases where profitability cannot be ensured, it will be necessary to develop policies that take into account pediatric drug development as a national healthcare policy, rather than as a business for individual companies.

The factors that contribute to this issue are discussed in "Drug lag: Characteristics of unapproved drugs for pediatric use in Japan, Part 2: Anticancer drugs," ⁶⁾ by Azuma et al. in the next issue.

Drug lag and drug loss in Japan is an issue that is expected to be resolved by all parties involved, including patients, their families, and medical professionals who are waiting for the latest drugs. The factors that contribute to this problem are expected to be complex and diverse, so solving it will require not only the improvement of individual systems, but also a change in business models for the pharmaceutical industry and medical institutions, and a major step forward in reform, including new laws, support systems, and support measures for pharmaceutical regulators and policy makers. For the pharmaceutical industry and medical institutions, it will be necessary to reform their business models.

Return to News List

TOP