Pediatric Clinical Studies in Japan: Regulations and Current Status

The ICH Guideline E11, Clinical Investigation of Medicinal Products in the Pediatric Population,¹ was introduced and implemented as a Japanese pharmaceutical regulation in December 2000. Prior to the introduction of the E11 guideline, there were two guidelines for pediatric clinical trials, the rather old Guideline for Pharmaceutical Development of Pediatric Use,² and a brief description in the Pediatric Application section of the General Considerations for Clinical Trials on New Medicinal Products³ (later replaced by the ICH E8 guideline). However, the ICH E11 guideline is more comprehensive and detailed. Therefore it is now the principal guideline for pediatric clinical trials.

The regulation has been adopted, but it has not been easy to activate clinical trials for children. This article will describe the current situation for pediatric clinical studies in Japan.

Status of pediatric indications
A report, written by S. Morita of the Kagawa University School of Medicine⁴ on the current status of descriptions of pediatric usage in package inserts, examined all prescriptions during 1997 and 1998 for pediatric patients in five university hospitals and one general hospital. For outpatients and inpatients under 18 years old, 371,832 prescriptions covering 1490 drugs (National Health Insurance drugs only) were written during the investigational period. In the report, Morita classified the instructions for pediatric usage found in package inserts into several categories, and demonstrated the poor condition of package inserts for children.

Morita found sufficient dose and usage description in package inserts for only 236 drugs (15.8% of all drugs) in this investigation. The description, Safety is not established in children, was in 573 drugs (38.5%). Among those drugs, the description in 360 drugs provide the reason for this as No data or little data for pediatric use, and the description for 215 drugs had no explanation. Seventy drugs (4.8%) were Contraindicated or not recommended in children. No clear guidance on usage in children or the simple statement dose can be adjusted was present for 332 drugs (22.3%). No useful description whatsoever for pediatric application was given for 164 drugs (11%).

Although off-label use is not legally prohibited in Japan, it causes various medical and legal problems for physicians. Physicians must inform their patients if the drug use will be off-label. However, for convenience of therapy, in many cases they do not give such information to the patients or their parents. Furthermore, hospitals, and clinics cannot be reimbursed by the National Health Insurance for off-label drug use; they have to compensate such expenditure from their own budget. If patients experience serious adverse reactions during off-label drug use, they are not afforded any form of compensation allowed for reactions from on-label uses. Usually, patients who experience serious adverse drug reactions may be compensated under the public rescue program. However, the public rescue program does not cover off-label drug use, and patients are not entitled to receive any compensation. Under-labeling of pediatric drug use creates problems for patients, pediatricians, and medical institutions.

Obstacles to pediatric clinical trials
In Japan, few clinical trials are conducted for pediatric indications. According to J. Satos investigation,⁵ in 1998, 54 drugs were approved for new indications, but among those only 8 included pediatric indications. Again, in 1999, only 8 out of 84 approvals had pediatric indications.³ Many reasons, on both the investigator side and the industry side, lead to this small number of pediatric trials.

Few investigators. There are few specialists for pediatric clinical trials in Japan. Lack of educational programs and fewer opportunities for clinical trial experience in pediatric populations are major reasons that this situation continues.

Recruitment difficulties. Difficulties in subject recruitment also make it difficult for the number of pediatric clinical trials to advance. Obtaining informed consent from parents is especially difficult. Clinical trials are not yet well established in daily medical practice. Parents, who understand the necessity of clinical trials, hesitate to consent for their own children to participate.

Onerous data requirements. The Japanese regulatory authority requires a data package for pediatric indications similar to that for adults. It is important to review sufficient clinical data when considering an approval, but this makes pediatricians and the pharmaceutical industry lose their incentive to develop pediatric drugs.

Market considerations. Low drug prices, a small market size, and the need for various formulations are other factors discouraging industry from developing pediatric drugs. Considering this difficult situation for conducting pediatric clinical trials, both industry and the regulatory authority need to create some efficient way to get approvals with a minimum of clinical trials.

The overall situation is still critical, but the introduction of the ICH E11 guidance and incentive programs are expected to increase the number of pediatric trials.

Incentive programs
There are two major incentive programs for pediatric clinical studies. Both of them were established as notifications of the Ministry of Health, Labor, and Welfare (MHLW). One is the notification on Medicinal Drug Use with Off-label Indications,⁶ published in 1999. Indications for which there is substantial evidence and experience outside of Japan and a recommendation by the relevant physicians association may be approved without domestic clinical trials. This notification is applicable to marketed drugs (both adult and pediatric indications) in Japan. Medical societies classify off-label indications commonly used in Japan into several classes. Class 1a drugs already have sufficient evidence for their indications. The indication of theophylline for apnea attacks in premature infants is a good example of this notification. The MHLW, the pediatrics association, and the relevant manufacturers have been discussing this indication quite a long time. The health authority initially required manufacturers of theophylline to perform clinical trials using premature infants to obtain the indication, but they could not do so because of the difficulty of subject recruitment and low profitability. Recently the MHLW agreed to allow submission of this application without clinical trial data in premature infants according to the notification described above because of a strong request from the pediatricians society.

At that time, new drugs, or new chemical entities, were required to go through a full development process. The Japanese regulatory authority used to require a full clinical data package, Phase 1 through Phase 3, for pediatric populations. After implementation of the ICH E5 guideline and under the difficult clinical research situation previously described, the MHLW began to consider approval of submission using a bridging strategy based on the ICH E5 guideline. When large pivotal studies have already been performed outside Japan, and the data have been extrapolated to the Japanese population, the company compiles the foreign and domestic clinical data in the Japanese Drug Approval Submission. In recent years, several drugs, including pediatric drugs, have been approved using foreign clinical data without large-scale clinical trials. Flexible handling of the guideline for pediatric indications would also encourage industry.

Another incentive program was included in the announcement of revision of the MHLW Ordinance on Postmarketing Surveillance, published in December 2000.7 It regards extension of the reexamination period: when a company conducts clinical trials for a pediatric indication, the drug will have its reexamination period extended to up to 10 years. This reexamination and reevaluation system is unique to Japan. The reexamination system applies to all newly approved products. The usual reexamination period is six years. During this period, the manufacturer must accumulate postmarketing surveillance data, spontaneous adverse reaction reports, clinical trial data performed during the period, and other clinical data. The company analyzes the efficacy and safety data, then submits it to the regulatory authority. Even if the product has no patent, a generic drug cannot be approved during this period. Orphan drug category products are given a 10-year reexamination period. The reexamination dossier is reviewed and classified into one of three categories:

• approval of continuous marketing with the same indications
• approval of continuous marketing but with modified indications
• non-approval and withdrawal from the market.

After approval of reexamination, the MHLW designates a product for reevaluation when necessary. Many drugs are routinely reviewed for efficacy and safety using literature reports. If a certain drug, or class of drugs, is frequently reported as inefficacious or unsafe, it would be reevaluated. As a result of reevaluation, when the reports are proved to be consistent, designated drugs have to be withdrawn.

This incentive, however, may not be as attractive for pharmaceutical companies as the patent extension in the United States, because the demand for generic drugs is not as critical in the Japanese market as it is in the U.S. market.

Further promotion of pediatric clinical research
In addition to extension of the reexamination period, several incentives to industry are now under consideration. Favorable drug-price setting would be a much bigger incentive for companies. However, under the current severe restriction of medical expenditures, increases in drug prices are unlikely. Priority review may be another incentive for companies, but to implement priority reviews, an increase in human resources within the governmental organizations is necessary. Even under current conditions, the Pharmaceutical and Medical Devices Evaluation Center (PMDEC), which plays the key role for reviewing submission dossiers, has difficulty completing reviews within one year because of insufficient human resources. The third incentive, as described previously, is the most realistic: greater flexibility in accepting a bridging strategy. Recently in Japan, a drug was approved for children only, after approximately 30 infants were recruited to gather the clinical data, mostly for a pharmacokinetics study.

To promote pediatric clinical research, a clinical research network is necessary. The National Center for Child Health and Development (NCCHD) was established in March 2002. This center will take a central role in establishing a network for clinical research in pediatric populations.

Currently, specialists in pediatric clinical trials from both academia and industry are very few. Most pediatricians in big hospitals are too busy with clinical work and have no time for an interest in clinical research, even though they understand the importance of pediatric clinical trials. Education and training programs are necessary to promote clinical studies in pediatric populations. NCCHD will also be expected to take a crucial role in this education.

Clinical trials in general (not only pediatric but adult) are not active enough in Japan. The Japanese government, realizing the importance of clinical research for the future of science and technology in Japan, started a council on renovation of the clinical research system, which will review current regulations and systems and make changes as necessary.

No one in Japan thinks the current situation for pediatric drug use is adequate. However, there are many barriers to activating clinical research for children. Some are common issues worldwide, but some are unique to Japanese society. Further introduction of incentives, education programs, cultivation of the environment for clinical research in general, and renovation of the system are crucial points for the future.

References
1. Clinical Investigation of Medicinal Products in the Pediatric Population, International Conference on Harmonisation, Federal Register 65 (71) 1977719781 (12 April 2000), www.ifpma.org/pdfifpma/E11step4.pdf.

2.N.Kobayashi et al., Guidelines for the clinical evaluation of drugs in infants and children (JP) (1982).

3. Notification by Director No. 43, Pharmaceutical Affairs Bureau, MHW, June 1992, General Considerations for Clinical Trials on New Medicinal Products (JP).

4. S. Morita, Prescription and Package Insert Description Analysis in Pediatric Drug Use, Kosei-Kagaku Research Report, December 2000.

5. J. Sato, Methodology for the Pediatric Clinical Trials, Japanese Journal of Developmental Pharmacology and Therapeutics, 14 (2) (2002).

6. Notification by Director No. 104, Evaluation and Licensing Div. MHW February 1999, On the Handling of Prescription Drugs for Off-Label Use (JP).

7. Notification by Director-General No. 1234, Pharmaceutical and Medical Safety Bureau, MHLW, December 2000 Revision of Post-Marketing Surveillance Practice (GPMSP) (JP).

AcknowledgementThis article is adapted from a presentation given at the fifth EMEA-IFAPP Conference, Clinical Studies at the Extremes of Age, in London, 22 February 2002. The author thanks Dr. H. Nakamura (NCCHD) and, Dr. M. Kuwahara and Dr. T. Iwasaki (members of the Pediatric Clinical Study Project in the JPMA) for their cooperation in providing important information for this article.