The Pharmaceutical Industry at a Glance Comparison of pediatric indications of new drugs between Japan and the U.S.

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

Introduction

The characteristics of pharmaceutical products are such that the expected benefit of efficacy and the risk of adverse health effects coexist, and it is important to optimize the balance between benefit and risk for the patient. In recent years, there have been increasing reports of drug interactions among multiple drugs administered to treat multiple diseases in elderly patients suffering from multiple diseases, resulting in adverse events. In order to avoid such cases, further promotion of the proper use of medicines among the elderly is considered to be particularly important.

On the other hand, off-label use of pharmaceuticals has long been a major issue for children, who are the opposite of the elderly, from the viewpoint of proper use of pharmaceuticals. This is due to the fact that some approved drugs that can be prescribed to adults are used for pediatric patients even though they are not indicated for pediatric use or do not have pediatric dosage and administration information in their package inserts. Children, who are still growing both mentally and physically, react differently to pharmaceuticals than adults in many cases, and therefore require a more rigorous optimization of the risk-benefit balance based on medical and pharmacological evidence. In other words, the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) Guideline E11 (Guidance on Clinical Trials of Medicinal Products in Pediatric Populations) and E11 (Guidance on Clinical Trials of Medicinal Products in Pediatric Patients) are the most important guidelines for the development and use of pharmaceuticals in pediatric patients. As recommended in ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) Guideline E11 (Guidance on Clinical Trials for Pharmaceuticals in Pediatric Populations) and E11(R1) (Addendum), ¹⁾ information on pediatric usage experience for new drugs under development or approved for adult indications should be collected in an optimal manner, including conducting appropriate clinical trials to obtain pediatric indications, dose levels, etc. The accumulation of information on the pediatric experience is desired.

Off-Label Use in Pediatric Practice in Japan

Off-label use of drugs in pediatric patients is not an issue only in Japan, but has been considered a problem in Europe and the United States since the 1960s. In the U.S., in particular, the government has the right to request companies to develop drugs for pediatric use, and to provide ^incentives2) for companies to develop drugs for pediatric use. As a result, there have been reports suggesting an increase in the number of drugs with additional indications for pediatric use, a corresponding decrease in off-label use, and an increase in clinical trials for pediatric ^use3).

In Japan, efforts by physicians, academia including the Japan Pediatric Society, regulatory authorities, industry associations, and other stakeholders have begun to develop measures to correct off-label use in pediatric patients, and are promoting the correction of such use. As a result, it has been reported that the percentage of approvals for pediatric use in the total number of drug approvals has been increasing every year since ²⁰¹⁰³⁾.

However, according to the European Medicines Agency (EMA), the total number of additional indications for pediatric use for approved and already approved drugs in Japan, the U.S., and Europe between 2007 and 2015 was 50, 249, and 221, ^{respectively4)}. (The figures for Europe are the sum of those approved under the central review system, non-central review system, mutual recognition system, and country-specific review system.) ) This may be due to the possibility that the indication is specific to a certain region, that there are not enough patients in Japan to conduct clinical trials, or that there is a delay in the start of clinical development. In this study, we focused on the status of clinical development and compared the status of pediatric indications and clinical development with that of the U.S., a single country region, to investigate the status of clinical development efforts for pediatric indications in Japan.

Survey Method

Of the ethical drugs approved in the U.S. (biopharmaceuticals are not listed) listed in the Orange Book (collection of ethical drug quality information) ⁵⁾ electronic data file (May 2019 edition) available on the FDA (Food and Drug Administration, U.S.) website, those with an extended exclusivity period based on clinical trial implementation for pediatric indications (pediatric indications) are listed. The products were included in the list of U.S.-approved ethical drugs (biopharmaceuticals were not listed) for which the exclusivity period was extended (Pediatric Exclusivity) based on clinical trials for pediatric use.

For these products, whether or not they are approved in Japan and whether or not they have pediatric indications were investigated using search tools available on the PMDA (Pharmaceuticals and Medical Devices Agency) website and information in the package inserts of ethical drugs. The status of clinical development in Japan was also surveyed using the ClinicalTrials.gov (provided by the National Library of Medicine; U.S. National Library of Medicine), a web-based information search tool for clinical trials, or Japic Clinical Trials Information (provided by the General Public Foundation), a web-based information search tool for clinical trials. Clinical Trials Information, provided by the Japan Pharmaceutical Information Center).

Status of Pediatric Indications or Clinical Trials of U.S. Approved Drugs in Japan

As shown in Figure 1, of the U.S. approved prescription drugs (small molecule drugs) listed in the May 2019 Orange Book, 185 products were covered by pediatric exclusivity.

Of these 185 products, 117, or approximately 60%, were approved in Japan, while the remaining 68 products were not approved in Japan. Of the 117 products, one-third (39 products), or about 20% of the total, were indicated for pediatric use.

A survey of the status of pediatric clinical trials in Japan for 68 unapproved products and 78 approved products without pediatric indications showed that only 1 of 68 unapproved products and 2 of 78 approved products (without pediatric indications) have started pediatric clinical trials (Figure 1). In other words, of the 185 US-approved drugs that have undergone clinical trials in pediatric patients, only 42 (or 23%) have obtained pediatric indications or have initiated clinical trials in Japan.

Figure 1: U.S.-Approved Drugs Approved for Pediatric Use in Japan

Conclusion

In Japan, from the perspective of promoting the proper use of pharmaceuticals, efforts to correct the off-label use of pharmaceuticals by children include extending the reexamination period when conducting clinical trials of approved drugs for pediatric patients, adding an additional drug price when pediatric indications, dosage and administration are included, establishing a review committee for unapproved drugs and off-label drugs with high medical necessity The establishment of the Study Council for Unapproved Drugs and Indications with High Medical Needs, the construction of a pediatric drug development network based on the AMED Clinical Research Trials Promotion Project "Research on Drug Selection to Promote New Drug Development in the Pediatric Field," and the clarification of the application of priority review for drugs for specific uses based on the partial revision of the Act on Quality, Efficacy and Safety Assurance of Pharmaceuticals, Medical Equipment and Other Drugs and Related Matters. The time is ripe to evaluate the effects of these measures. Although it is too early to assess the effectiveness of some of these measures, it is undeniable that the number of clinical trials conducted especially for pediatric patients has lagged behind that of Europe and the U.S. ⁴⁾.

In order to further correct pediatric off-label use, all stakeholders must continue to work together to come up with ideas for more effective measures and put them into action.

Acknowledgments

For the purpose of this survey, we asked volunteer members of the Intellectual Property Committee of the Japan Pharmaceutical Manufacturers Association (JPMA) to assist in reviewing the results of the survey on ClinicalTrials.gov and Clinical Trial Information for the purpose of providing up-to-date information on the status of clinical development of the subject drug for pediatric patients in Japan, to the extent possible. We thank them for their cooperation.

1) Number of reports and countries from which data was obtained

Ministry of Health, Labour and Welfare Website ICH-E11 Clinical Trials (see 2020/01/20)
2)

For example, in the U.S., the exclusive marketing period is extended for 180 days on the condition that a pediatric clinical study report is submitted, etc. In Europe, the patent term for a new drug is extended for 180 days on the condition that a pediatric clinical study protocol is submitted, etc.
3)

Masao Nakagawa, et al. "Proposals for the Promotion of Pediatric Drug Development in Japan," Journal of the Japanese Pediatric Society, Vol. 120, No. 10, 1453-1461 (2016).
4)

EMA 10-year Report to the European Commission, General report on the experience acquired as a result of the application of the Paediatric Regulation, 27 27 October 2016 (see 20/01/20)
5)

FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) (See 20/01/20)

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