The Pharmaceutical Industry at a Glance Recent Trends in the Approval and Listing of Pediatric Drugs in Japan

Printable PDF

Chie Yoshiura, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Kyumi Yoshino, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute
Takahiro Shiraishi, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

SUMMARY

  • Although there is a high need for pediatric drugs, challenges remain in terms of development difficulty and profitability.
  • Of the new drugs approved in Japan between January 2018 and December 2024, there were 237 approvals related to pediatric indications, 72 of which were new active ingredient drugs. Although the number of approvals related to pediatric indications was at most 30% of all approvals in each year, the number of approvals related to pediatric indications and its ratio to all approvals showed an increasing trend during the study period.
  • Of the pediatric approvals analyzed, 40% were for orphan drugs. Of the applications, 10% were based on public knowledge, and 4% were based on overseas clinical trial results alone. Other data were obtained in Japan, 41% from international clinical trials including Japan, and 45% from other sources.
  • The lag period between approval in adults and approval in pediatric patients for the same disease was investigated. 77% of the pediatric approvals were granted without any delay from the adult approval.
  • In terms of evaluation at the time of NHI drug price listing, in FY2024, the number of cases falling under the special exception (pediatric indication) for calculation of inter-standard adjustment only was significantly high. The number of cases of additions for children at the time of NHI price revision is also on the increase, but the number of cases falling under high addition rates increased significantly from FY2024 onward.

1. Introduction

Although pediatric drugs are in high demand for medical care, it is generally considered a problem that they are less developed than those for adults1, 2). The National Institute of Biomedical Innovation Policy (NIBIO) has also pointed out concerns about a drug lag between pediatric drugs and those available in Europe and the U.S. 3, 4). In recent years, changes have been issued in both the pharmaceutical affairs system and the drug pricing system to promote the development of pediatric drugs. For example, in the pharmaceutical affairs system, the NHI (Pharmaceuticals and Medical Devices Agency) has started to organize the concept of formulating development plans for pediatric drugs5, 6, 7) and to accept consultations on development plans at the PMDA (Pharmaceuticals and Medical Devices Agency) .8) In the drug pricing system, flexible decisions on the additional pediatric drug price and the addition of pediatric drugs to the product requirements for the additional drug price for new drug creation, etc., have been made. In the NHI drug price system, there have been changes in the environment for further development promotion, such as the addition of pediatric drugs to the additional pediatric drug category, an increase in the additional pediatric drug fee when a pediatric development plan is formulated and approved at the same time as adult development, and the addition of previously listed drugs that are being developed based on a pediatric development plan to the additional pediatric drug category in the re-calculation for market expansion9).

In this report, information on pediatric indications was extracted from the review reports, package inserts, interview forms, and other information published by the PMDA on its website and analyzed for changes over time, with the aim of visualizing the latest trends in new drug development for pediatric drugs. We also analyzed the trends in the evaluation of companies that have developed pediatric drugs based on data from the Central Social Insurance Medical Council and other sources.

Survey Methodology

The number of pediatric drug approvals in this report covers drugs listed in the "List of New Drug Approval Items " 10) on the PMDA website and covers approvals from January 2018 to December 2024, with one approval counted per review report. Approvals for pediatric indications were extracted from those that clearly stated pediatric use in the "Indications" or "Dosage and Administration" in the review report, package insert, or interview form, as well as those that were not restricted to adult use in the "Dosage and Administration" and whose use in pediatric patients was not restricted11). The analysis was conducted for the following items.

Approval of a new active ingredient was defined as a drug containing the new active ingredient listed in the "List of New Drugs Approved for Use " 10). Approval of new indications with pediatric indications were categorized as "new indications related to pediatric patients. In this report, the first addition of a pediatric dosage to an already approved indication for adults (a new dosage form) is also classified as a "new indication for pediatric use. Approval of an additional indication for the same indication in pediatric patients was classified as "Other. Vaccines were counted separately. Drugs that are clearly designated as orphan drugs in the "List of New Drugs Approved " 10) are counted as orphan drugs.

Trends in application data were counted based on the classification of studies submitted as evaluation data in the review report. Applications were classified as "applications based on off-label use notices," "applications based on prior evaluation notices/expedited review based on review notices for prior evaluation items," or equivalent, if the contents of the special notes in the "List of New Drugs Approved for Use " 10) were "applications based on off-label use notices," "applications based on prior evaluation notices/expedited review based on prior evaluation item review notices," or equivalent. For adult and pediatric lags, we investigated those that were judged to have the same indication based on the "Indications" in the review report, package insert, and interview form. The approval date was defined as the approval date listed in the "List of Approved New Drugs " 10). The drugs approved for pediatric indications only or those approved for pediatric indications prior to those approved for adult indications were included in the "no lag" category in this survey, as pediatric indications were not lagging behind adult indications.

Information such as additions at the time of listing of new drugs for pediatric use, which is the subject of this survey, was compiled from the "List of New Drugs" document provided by the Central Social Insurance Medical Council12). Information on additions at the time of NHI price revision (hereinafter referred to as "additions at the time of revision") was compiled from materials related to reimbursement information13). The same ingredient, the same dosage form, and the same indication were counted as one count, and if the addition rate for the addition at the time of revision differed by brand name, the higher rate was used. The period covered by the survey was defined as the period when drugs approved between January 2018 and December 2024 were in principle listed or evaluated at the time of revision, i.e., FY 2018 to FY 2024 for listing status, and FY 2020, 2022, 2024, 202514, 15, and 16 for revision status. This decision was made based on the fact that, in most cases, drugs are listed within 60 days of approval in principle, or 90 days at the latest17), and that additions at the time of revision are evaluated at the time of NHI price revision by summarizing two years or one year's worth of approval. However, the scope of coverage may not be completely consistent with the survey of approval status because of different information sources.

Results

(1) Number of new drugs approved in Japan for pediatric indications

Figure 1 shows the annual number of approvals related to pediatric indications for new drugs approved in Japan between 2018 and 2024, and Figure 2 shows the breakdown of the number of approvals. There were 237 approvals related to pediatric indications over the seven-year period, with 210 approvals excluding vaccines. As shown in Figure 1, the number of approvals for pediatric indications from 2018 to 2024 showed an increasing trend. The ratio of the number of approvals for pediatric indications to the total number of approvals (excluding vaccines) was calculated to be the highest in 2024 (35.2%), which is the highest in the study period, excluding 2022 when the number of pediatric indications was relatively low due to the large number of new drug approvals overall, as reported in previous surveys18), due to the prominent addition of new indications for infertility drugs. The number of new drug approvals generally showed an increasing trend, except in 2022, when the number of pediatric indications was relatively low due to the large number of new indications for infertility drugs (Figure 1).

Fig. 1 Number and ratio of new drugs approved in Japan for pediatric indications

The breakdown of the number of approvals was 72 (30%) for drugs with new active ingredients, 112 (47%) for new indications for pediatric use, and 26 (11%) for others (e.g., expansion of the age range for the same indication in pediatric patients, additional dosage and administration, etc.) (Figure 2).

Results (2) to (4) in this report analyze the 184 approvals for new active ingredients and new indications with pediatric indications shown in Fig. 2.

Fig. 2 Breakdown of new drug approvals for pediatric indications (number and ratio)

(2) Breakdown of new drugs approved in Japan for pediatric indications (Orphan drugs)

The presence or absence of orphan drug designation was investigated for drugs containing new active ingredients with pediatric indications approved in Japan between 2018 and 2024 (72 cases) and for new indications with pediatric indications approved in Japan (112 cases). As a result, as shown in Figure 3, 73 (40%) of the approvals related to pediatric indications were for orphan drugs.

Fig. 3 Breakdown of new drug approvals for pediatric indications (orphan drugs) (number and ratio)

(3) Breakdown of the number of new drugs approved in Japan for pediatric indications (trends in application data)

Trends in application data for drugs containing new active ingredients with pediatric indications approved in Japan between 2018 and 2024 (72 applications) and for new indications with pediatric indications approved in Japan (112 applications) were investigated. As a result, as shown in Figure 4, 19 applications (10%) were based on public knowledge. Of those for which clinical trial results were submitted as evaluation data, 8 (4%) were approved based solely on overseas clinical trial results. Of those for which clinical trials in Japan were submitted as evaluation data, 82 (45%) included clinical trials in Japan, and 75 (41%) included international clinical trials including Japan ("international clinical trials") as evaluation data.

Fig. 4 Breakdown of new drug approvals for pediatric indications (trends in application data) (number and ratio)

(4) Lag from adult to pediatric indication

For drugs containing new active ingredients with pediatric indications approved in Japan between 2018 and 2024 (72 cases) and for new indications approved for pediatric indications (112 cases), we examined the lag (elapsed time) and its annual change since the first approval of an adult dosage and administration for the same indication. As shown in Figure 5, 142 (77%) of the 184 cases analyzed had no adult pediatric lag. Of these, 72 (39%) were drugs with new active ingredients. Of these, 6 (3%) had a lag of 3 years or less. Together, 80% of these drugs were also approved for pediatric indications within 3 years of their approval for adults. The annual trends of these breakdowns are also shown in Figure 6.

Fig. 5 Breakdown of new drug approvals for pediatric indications (Adult pediatric lag) (number and ratio)
Fig. 6 Breakdown of new drug approvals for pediatric indications (adult-pediatric lag) (annual trends)

(5) Evaluation in NHI drug prices (trends in additions)

For the purpose of confirming the NHI price evaluation of new drugs related to pediatric indications approved in Japan between 2018 and 2024, we investigated the status of additions at the time of accession and at the time of revision. Figure 7 shows the number of applicable pediatric additions to the NHI drug price. Since pediatric additions cannot be calculated concurrently with marketable additions I, it is difficult to consider only the number of pediatric additions, but the total number of pediatric additions increased in FY2024, while the number of marketable additions I did not decrease (13 in FY2022, 9 in FY2023, and 17 in FY2024). The number of cases of pediatric additions increased in FY2024. In addition, among the pediatric additions, the number of cases of "special exceptions (pediatric additions) in the calculation of interstandard adjustments only" was outstandingly high (FY 2018-2023: 0-1 cases/year, FY 2024: 7 cases/year). However, the number of cases of "special exception (pediatric addition) for calculation of inter-standardization only (pediatric addition)" was significantly higher than that of "special exception (pediatric addition) for calculation of inter-standardization only (pediatric addition)" (FY 2018-2023: 0-1 case/fiscal year 2024: 7 cases/fiscal year 2024). However, the special exception (pediatric addition) for the calculation of interspecification adjustment only is considered to be an evaluation of the addition of pediatric indications for drugs with prior adult indications.

Fig. 7 Changes in the number of applicable pediatric indications at the time of marketing approval

Figure 8 shows the changes in the number of cases of additions to pediatric indications and additions to indications for specific uses (pediatric-related) 19). Although the number of cases in FY2025 was the same as that in FY2024, it can be said that the number of cases including those in FY2025 continues to increase, given that approvals for the past two years until FY2024 were evaluated together at the time of revision, while those for the past one year were evaluated in FY2025. The trend of increase in the number of applicable cases is continuing, including FY2025. On the other hand, with regard to the addition ratio, the number of cases with an addition ratio of 10% or more (A=10 to 20) ) increased markedly after FY2024.

Fig. 8 Trends in the number and ratio of additions to the pediatric indication or additional indications for specific uses at the time of revision

Summary and Discussion

While pediatric drugs are in high demand, the hurdles to new drug development are high, and various discussions are underway to promote their development. In this report, we extracted information on pediatric indications from the PMDA's publicly available data and analyzed changes over time, with the aim of visualizing the latest trends in pediatric drug development. In addition, trends in the NHI price listing of new drugs and the additions to the NHI price at the time of drug price revision were also analyzed from publicly available data from the Ministry of Health, Labour and Welfare. The results are discussed below.

As shown in Figure 1, the number of approvals related to pediatric indications and the ratio to the total number of approvals from 2018 to 2024 showed an increasing trend, although approvals related to pediatric indications account for at most about 30% of the total. In 2020, a notice was issued to encourage research and development of drugs for pediatric indications, including the extension of the reexamination period22) and the establishment of a system for designating drugs for specific indications23). Considering the time required from the start of drug development to obtaining approval, it is possible that the recent upward trend reflects the effects of these measures taken several years ago. In the future, it is expected that the effects of more recent measures may also be seen as an increase in the number of drug approvals.

As shown in Figure 3, 40% of the total number of approvals of new active ingredients and new indications for pediatric indications were for orphan drugs. Since the number of patients for both pediatric drugs and orphan drugs is small, it was thought that the number of approvals would be small if they overlapped, making the development of such drugs more difficult. The percentage of orphan drugs was higher in the approvals of drugs for pediatric indications. Among the pediatric and orphan drug approvals surveyed in this report, 0 applications were publicly available and 6 were based solely on overseas clinical trial results, while the other 67 approvals were based on international clinical trials or domestic clinical trial results. Although the level of difficulty and the issues involved in the development of pediatric drugs and drugs for rare diseases have been discussed, it is believed that companies are steadily advancing the development of pediatric drugs in spite of the difficulty of the task.

Figures 5 and 6 show the lag (elapsed time) between the approval of new drugs for pediatric indications and the first approval of adult dosage and administration for the same indication. Of these, 39% were new active ingredient-containing drugs and 38% were new indications, meaning that 77% had no lag, i.e., were approved in pediatric patients without any delay from adults. In addition, the percentage of drugs with pediatric indications in the total number of drugs containing new active ingredients has been increasing and will be at a level of 25% or higher after 2021 (results of a survey conducted by the Pharmaceutical and Industrial Policy Research Institute). This suggests that pediatric indications were taken into account in the development of these products from the adult development stage. In addition, many of the drugs surveyed in this report for pediatric indications have been approved overseas. In Europe and the U.S., pediatric development plan review at the time of new drug development is mandatory24, 25), and in the U.S., a voucher program for priority review related to rare pediatric diseases has been introduced26), etc. There are also measures to promote pediatric drug development in other countries. It is possible that these overseas conditions have affected Japan due to the large proportion of global products, resulting in the large number of products without adult pediatric lag. In fact, for the 12 cases with long lags in which pediatric indications were added 10 years after approval for adult indications, the proportion of global studies was significantly lower than those with lags of 10 years or less (Table 1, lag >10 years: 17%). On the other hand, for those with a lag of more than 10 years, 8 of the 12 cases (including 2 international clinical trials) had obtained approval based on the results of clinical trials in Japan, which was more than the 4 public knowledge applications. This was the result of companies' active efforts to expand the indications of existing drugs for pediatric use. In addition, looking at the percentage of lag periods by orphan drug category, the percentage of orphan drugs was small in the number of approvals with long lags (Table 1, for drugs with a lag of more than 10 years: 12%). In other words, it tends to take longer to develop pediatric indications for non-rare disease drugs than for rare disease drugs. Although we were not able to investigate the factors, it is possible that the difficulty of recruiting pediatric subjects is higher in areas where there are drugs with similar indications than in the case of rare diseases.

Table 1 Characteristics of pediatric drug approvals by lag period

While we have discussed trends related to the approval of new drugs for pediatric indications, we would also like to discuss their evaluation in terms of NHI drug prices. As shown in Figure 7, in FY2024, the number of cases of special exceptions (pediatric addition) in the calculation of inter-standard adjustment only increased. In addition, as shown in Figure 8, the distribution of the addition ratio of the number of cases that received the addition for children at the time of the NHI price revision was different before and after FY2024. In terms of the addition rate, the pediatric addition is stipulated in the range of 5-20%, but until FY2023, 5% was applied to the majority of items, and rates exceeding this were rarely applied9). However, the reform of the NHI drug price system in FY2024 has led to more flexible decisions, and higher additional rates are being applied more frequently. In other words, it is thought that incentives for pediatric drug development have been improved, and it is expected that pediatric drug development will be progressively promoted as a result of a boost to profitability, which is one of the challenges in pediatric drug development. We believe that the development environment for pediatric drugs should continue to be improved in the future, along with the verification of the effects of such development.

Conclusion

The survey in this report indicates that the number of pediatric drug approvals has been increasing, although it is only about 30% of the total in the most recent year. In FY2024, there was a new framework to promote the development of pediatric drugs and a reform of the NHI drug price system. The number of approvals is expected to increase due to these effects. It is expected that the number of approvals will increase due to these effects, and that the environment will continue to improve based on verification of the effects of these reforms.

Return to News List

Share this page

TOP

Site Search