Topics Drug lag: Characteristics of unapproved drugs for pediatric use in Japan
Part 2 -Anticancer Drugs

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

1. Introduction

The Pharmaceuticals and Industrial Policy Research Institute (PIIPRI) has conducted a series of analyses of the current status of drug ^{lag1, 2, 3, 4, 5)}. The drug lag refers to the problem that it takes many years for a drug already approved overseas to obtain regulatory approval in Japan, and has two aspects. There are two aspects to the drug lag: the "lag" aspect, in which a drug is approved in Japan but takes longer than in other countries; and the "unapproved in Japan" aspect, in which a drug is approved in other countries but not in Japan. If left unchecked for a long period of time, this unapproval in Japan can lead to "drug loss" and become a serious problem.

It has been reported that many of the pediatric diseases associated with unapproved drugs in Japan are rare diseases, and that cancer is one of the most common unapproved disease ^areas3). The Ministry of Health, Labour and Welfare (MHLW) is also focusing on the promotion of drug development for pediatric oncology and is conducting ^surveys6). In this report, pediatric oncology drugs are defined as anticancer drugs that have been approved for pediatric indications, and the status of drug approval and indications in Japan and the United States are investigated. In addition, in order to clarify the causes of the drug lag, we analyze and report on development leaders and pivotal studies (validation studies to obtain the data necessary to apply for regulatory approval) in the United States.

Survey Methodology

In this paper, we report on the status of drug approvals and pediatric indications in the U.S. for 40 drugs listed in the PediatricOncology Drug ^Approvals7) published by the U.S. Food and Drug Administration (FDA) on its website, from 2000 to 2022. The survey covered information on 40 drugs that received pediatric indications between 2000 and 2022.

The approval status and pediatric indication status of the relevant drugs in Japan were collected and analyzed mainly from the list of approved new drugs, review reports, interview forms, etc. published by the Pharmaceuticals and Medical Devices Agency (PMDA).

Clinical trial information that included the U.S. was obtained from ClinicalTrials.gov, a clinical trial registration system operated by the National Institutes of Health (NIH) of the U.S., and clinical trial information for Japan alone was obtained from review reports published by the PMDA.

The major pharmaceutical company responsible for the development of the drug was Evaluate Pharma, which had consolidated group sales of at least US$5 billion at the time the drug was approved for pediatric use.

The term "not approved in Japan" refers to products for which a new active ingredient has not yet been approved, including for adults, while the term "not approved in Japan" refers to products that have been approved but not yet approved for pediatric indications. Information as of March 31, 2023 was used for the approval and pediatric indications in Japan.

3. status of pediatric oncology drugs in the U.S.

3-1. Status of U.S. Pediatric Oncology Drugs Approved for Pediatric Use in Japan

In the U.S., 40 anticancer drugs were approved for pediatric indications from 2000 to 2022. We investigated the approval status and pediatric indications of these 40 drugs in Japan (Fig. 1). Sixteen (40%) were approved in Japan and indicated for pediatric use, 16 (40%) were approved in Japan but not indicated for pediatric use, and 8 (20%) were not approved in Japan (as of March 31, 2023). In other words, of the 40 products approved in the U.S. for pediatric oncology, 24, or 60%, are not approved for pediatric use in Japan.

3-2 Comparison by U.S. Development Leader Category

We identified the US developers of the 40 products with pediatric indications in the US (Fig. 2). Of the 16 products with pediatric indications in Japan, 11 (69%) were developed by a major pharmaceutical company and 5 (31%) were developed by a non-pharmaceutical company.

Of the 16 drugs approved in Japan but not indicated for pediatric use, 11 (69%) were developed by major pharmaceutical companies and 5 (31%) by non-pharmaceutical companies.

Among the 8 drugs not approved in Japan, 1 (12%) was from a major pharmaceutical company and 7 (88%) from a non-pharmaceutical company.

Among the drugs approved in Japan but not indicated for pediatric use, many were developed by major pharmaceutical companies, while the majority of the drugs not approved in Japan were developed by non-pharmaceutical companies.

3-3. Status of Inclusion in Pivotal Studies in Japan

In the Policy Research Institute News No. 66, we reported that one of the reasons why anticancer drugs are not approved in Japan is the lack of inclusion of Japan in international clinical ^trials3). 3) In order to investigate the relevance of the pediatric indication, we examined the inclusion of Japan in the clinical trials (pivotal trials) listed in the Pediatric Oncology Drug Approvals (Fig. 3), which were the basis for approval. The age of the patients included in the Japanese studies was not specified as either adult or pediatric.

Of the 16 products with pediatric indications in Japan, 5 (31%) were included in clinical trials in Japan, 10 (63%) were not included, and 1 (6%) was unknown. On the other hand, most of the unapproved and not approved for pediatric indications in Japan were not incorporated in Japan, with all 8 unapproved and 14 (88%) not approved for pediatric indications in Japan being not incorporated in Japan.

Of the products with pediatric indications in Japan, 31% were found to have Japan as part of a global clinical trial, but interestingly, some products were approved even if Japan was not included in the clinical trial. The results suggest that data packages other than participation in global clinical trials may be used to obtain approval for pediatric indications.

In other words, the data showed that there were few products not approved in Japan or not approved for pediatric indications that were incorporated in Japan, suggesting that, at the very least, participation of the Japanese region in global clinical trials is a useful approach to obtaining approval.

4) Increase in the number of unapproved and off-label drugs in Japan

4-1. Rapid Increase in the Number of Pediatric Indications in the U.S. in Recent Years and Widening Differences between Japan and the U.S.

The number of pediatric indications for anticancer drugs in the U.S. since 2000 was analyzed (Fig. 4). The survey of the year of pediatric indication acquisition and the number of items for which pediatric indications were obtained showed that 31 items (78%) obtained pediatric indications in 2017 or later, compared to 9 items for which pediatric indications were obtained from 2000 to 2016, showing a rapid increase.

Looking at the status of approval in Japan of items in and after 2017, while some items obtained pediatric indications in Japan, 21 items (53% of the total) had no pediatric indication in Japan or were not approved in Japan as of the end of March 2023, indicating that many items cannot be used in Japan.

The study also examined the characteristics of changes in the number of products since 2017. The changes in the initial approval and the number of pediatric indications in the U.S. showed that the number of pediatric indications has increased rapidly while the progress of initial approval has steadily increased without much change from the previous year (Fig. 5).

Furthermore, Figure 6 shows the cumulative number of pediatric oncology products approved in Japan and the U.S. While the number of products approved in the U.S. has increased significantly since 2017, there has been no significant increase in the number of products approved for pediatric indications in Japan. As a result, the difference in the cumulative number of products between the U.S. and Japan widened from only 3 in 2016 to 24 in 2022, confirming that the number of unapproved and off-label drugs for pediatric cancer has been increasing in Japan in recent years.

In other words, the widening gap between Japan and the U.S. in the acquisition of pediatric indications after 2017 was not due to a change in the overall approval of anticancer agents, but rather to a change in the status of pediatric indications in the U.S.

4-2. initial indication or additional indication

We investigated the timing of obtaining pediatric indications for products approved in the U.S. (Figure 7). The data were categorized by whether pediatric indications were obtained at the time of initial approval or after initial approval as an additional indication, and were disaggregated by timing (pre-2010, 2011-2016, and 2017 or later).

Prior to 2016, many drugs were developed as anticancer drugs for adult patients and obtained additional pediatric indications after initial approval (9/12 and 10/12 drugs, respectively).

In contrast, after 2017, the ratio reversed, with more drugs obtaining pediatric indications at the time of initial approval, with 14 of the 16 drugs obtaining the indication at the time of initial approval; of the 14 drugs, only one was a primarily pediatric anticancer drug, which is not often used in adult patients.

Characteristics of products with pediatric indications in Japan

5-1. clinical trials for pediatric indications in japan

In order to understand the status of global clinical trials in obtaining pediatric indications, we investigated the status of clinical trials for 16 drugs with pediatric indications approved in Japan at the time of obtaining pediatric indications in Japan from the PMDA review reports (Fig. 8). In particular, we focused on whether or not Japanese children were enrolled in the clinical trials. As a result, we identified 9 products for which domestic independent clinical trials were conducted separately from international clinical trials, including pediatric patients, and 4 products for which Japan participated in international joint clinical trials including pediatric patients. Of the remaining three, one was based on a public knowledge application using mainly overseas data, and the remaining two were approved by extrapolation from foreign pediatric data, even though there were no Japanese pediatric data at the time of ^{application8)}.

In other words, in many cases, it became clear that independent domestic clinical trials in pediatric patients were conducted to obtain pediatric data from Japanese pediatric patients, in addition to the international clinical trials.

5-2. time from initial approval in the u.s. to pediatric indication in japan

For those products that were approved in Japan for pediatric indications, we checked whether the approval timing was delayed or not (Fig. 9). There were 16 products that were approved for pediatric use in both Japan and the U.S. All of these products were first approved in the U.S. between 1997 and 2020.

There were multiple patterns of approval for each product, with some products having a longer period of time from initial approval to pediatric indication in the U.S. (Pattern 1: A, E, G) and some products having a longer period of time from initial approval to pediatric indication in Japan (Pattern 2: A, E, I). In addition, items that took a long time between initial approval in the U.S. and initial approval in Japan (Pattern 3: B, C) were delayed from the U.S., even if the initial and pediatric indications were simultaneous in Japan.

Looking at the chronological order, in recent years, many items have received pediatric indications at the time of initial approval in the U.S. These items also received pediatric indications relatively at the time of initial approval in Japan, and the delay from the U.S. was about 2 years for the items from 2017 (4 items/5 items). In other words, the results suggest that in order for pediatric indications to be obtained in Japan without delay from the U.S., it is extremely important to obtain pediatric indications at the time of initial approval in the U.S. and at the time of initial approval in Japan. This analysis was conducted for products that have already received pediatric indications in Japan, and it is possible that other unapproved or off-label products not shown in the figure will receive pediatric indications in the future. In addition, the data evaluation periods are not aligned for each product, making comparisons of older products with newer products unsuitable.

6. discussion and summary

In summary, 60% of pediatric oncology drugs approved in the U.S. since 2000 were unapproved or off-label in Japan (as of the end of March 2023). In detail, one-third of these drugs were unapproved and two-thirds were off-label. In addition, while many of the companies responsible for drugs not approved in Japan were not major pharmaceutical companies, many of the companies responsible for drugs not approved in Japan were pharmaceutical companies, and even large companies had not obtained pediatric indications for their products in Japan. Furthermore, since 2017, pediatric indications in the U.S. have been obtained at the time of initial approval, and the number of items has increased rapidly. As a result, the difference in the number of pediatric indications between Japan and the U.S. widened from 3 to 24 items and the drug lag in pediatric indications for anticancer drugs expanded.

First, we would like to discuss the changes in the U.S. in 2017 from the perspective of drug regulation. Pediatric indications for anticancer drugs are expected to require additional investments in clinical trials and drug formulation development in addition to those for adult indications, as the number of eligible patients is small. The development of pediatric indications has undeniably tended to be delayed, and the government has taken measures to promote ^{development9, 10).} In the U.S., the Best Pharmaceuticals for Children Act (BPCA) ¹¹⁾ was enacted in 2002 to provide incentives (6-month exclusive marketing rights and priority review), and the Pediatric Research Equity Act (PREA)12) was enacted in 2003 to mandate pediatric development. (PREA) ¹² ) was enacted in 2003. In 2012, the Creating Hope ^Act13) allows transferable Priority Review Vouchers (PRVs) to be granted as incentives. 2017 saw the enactment of the Research to AccelerateCures and Equity (RACE) for Children Act was enacted. ¹⁴⁾ The RACE for Children Act newly allows companies developing such molecularly targeted anticancer drugs for adults, based on the FDA's list of molecular targets that have been established as highly relevant in pediatric cancer, to The increase in the number of pediatric indications in the U.S. since 2017 may be due to both the incentives and mandates described here, considering the development time from the enactment of the law to the acquisition of the indication. The publication of the list of molecular targets in the RACE for ChildrenAct may be one of the reasons for the acceleration of pediatric indications in the U.S.

Meanwhile, Japan has also taken measures to promote development, such as extending the post-approval reexamination period (not to exceed 10 years) and revising it to clarify the period (2038-2 years), and increasing the NHI price for pediatric patients (5-20% increase) ¹⁵⁾. In addition, a system for the designation of drugs for specific ^{indications16)} has been established, and measures have been taken to encourage the development of drugs for pediatric use, such as priority consultation and priority review. However, it is not difficult to imagine that more effective measures will be needed in the current situation where the number of unapproved and off-label drugs is increasing compared to the United States and the gap in the number of drugs approved for pediatric use is widening.

As shown in section 3-2, many of the unapproved drugs in Japan were developed by companies other than major pharmaceutical companies. This is not an event limited to unapproved drugs for pediatric oncology, but rather a factor that can be seen in recent years in drug lag and drug loss in ^general3). In other words, the hurdles for startups (which in this paper fall into the category of non-pharmaceutical giants) to conduct clinical trials in Japan are high, and the Japanese drug market may be less attractive for them when investing in the Japanese region. There is a limit to what can be inferred from publicly available information regarding actual corporate behavior and thinking, and deeper scrutiny is needed, including interviews with individual companies.

In addition, there were many drugs (16 drugs) that were approved in Japan but not yet approved for pediatric use, and the majority of these drugs were developed by major pharmaceutical companies. Although the major pharmaceutical companies have development and sales functions and know-how in Japan, they are not expected to recoup their additional investment in pediatric development because they have not yet started development. In addition, in the area of anticancer drugs, molecular-targeted drugs that target gene mutations are becoming the mainstream. They are becoming a kind of rare fragments, and the difficulty of collecting data is increasing as well as the difficulty of recovering the investment. Strong support for development is highly expected, both in terms of financial support by the government to reduce the investment burden in pediatric development and support for the pharmaceutical affairs system, such as increasing the number of cases where approval is granted by extrapolation of existing data, including overseas data, and re-examination with actual clinical data in Japan after approval.

Although the point is somewhat off topic from this paper, there are other issues to be considered for pediatric cancer compared to adult cancer. For example, there are schooling support issues associated with long-term hospitalization, and the National Cancer Center has published a "Guideline for Consultation on Childhood Cancer ^Schooling17). There are also issues such as late ^{complications18)} and fertility ^{preservation19)}. As a person involved in the pharmaceutical industry, I can only hope to increase the number of children in Japan who can be saved, cured, and live better lives by increasing treatment options.

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