1. 1 Ethical Issues Concerning the Protection of Children in Biomedical Research in Japan Takahiro NISHIMURA (PhD, Osaka University, JAPAN)

2. 2 Serious Ethical Dilemma in Pediatrics Pediatric research must balance two important social and ethical goals. (1) Social goal Scientific progress that includes issues important to children necessitates that children be involved in research. (2) Ethical goal As children cannot themselves consent to participation in biomedical research and must depend on adults to protect their interests, it is essential that the well-being of individual children who participate in a research projects be protected.  This is a serious ethical dilemma in pediatrics.

3. 3 The Current Japanese Situation Regarding Biomedical Research in which Children will participate as Human Subjects Recently research on the problems of childhood mental developmental disorders such as ADHD from a medical and neuroscientific perspective has been pursued in Japan. Accordingly, opportunities for children to participate in clinical research as human subjects are rapidly increasing. And, as such, the problems of protecting children involved as human subjects in clinical research are becoming considerably important. The reasons stem from the fact that children, because of their age, have reduced capacity to comprehend, and lack the legal capacity to consent to enrollment in research as human subjects. Therefore “the protection of children as human subjects” becomes more important in comparison with the adult's case.

4. 4 Backwardness in Embracing the Protection of Children Involved as Human Subjects in Japan Japan has fallen far behind the United States and Europe in implementing the protection of human subjects' rights.  In Japan, there is little regulation, for example, (1) "Guidance on Clinical Investigation of Medical Products in the Pediatric Population" based on the agreement in the ICH" (2) "Ethical Guidelines for Clinical Studies" announced by the Ministry of Health, Labour and Welfare in July 2003.  Unfortunately, there are no ethical guidelines that take into account children as human subjects.

5. 5 The Protection Regulation for Children as Human Subjects in Japan (1) “Guidance on Clinical Investigation of Medical Products in the Pediatric Population” based on the agreement in the ICH“ (2000)  2.6 Ethical Issues in Pediatric Studies The pediatric population represents a vulnerable subgroup. Therefore, special measures are needed to protect the rights of pediatric study participants and to shield them from undue risk. The purpose of this section is to provide a framework to ensure that pediatric studies are conducted ethically. To be of benefit to those participating in a clinical study, as well as to the rest of the pediatric population, a clinical study must be properly designed to ensure the quality and interpretability of the data obtained.  2.6.3 Consent and Assent  2.6.4 Minimizing Risk, 2.6.5 Minimizing Distress

6. 6 The Protection Regulation for Children as Human Subjects in Japan (2) “Ethical Guidelines for Clinical Studies” 2003 (Amended December 28, 2004)  The “Ethical Guidelines for Clinical Studies” have not been decided through analyzing historical events and national debate.  there are no punishments in place if a researcher violates those guidelines.  There is little description of the protection of children in biomedical research.  There is a pressing need to prepare ethical regulations concerning protection for children involved as subjects in research in Japan.

7. 7 The Background to the Development of Legal Frameworks for Children as Human Subjects in Biomedical Research has been delayed in Japan The ambiguity of the legal position of "children" in medical practice in Japan. (1) “Consent” in medical practice is not a juristic act but a factual act in the first place. (2) A medical contract between the physician-patients is a quasi- mandated contract (3) Minors who lack legal capacity to consent for enrollment in research as human subjects must obtain the consent of his/her statutory agent to perform any juristic act.

8. 8 International Movements Concerning the Protection of Children Involved as Human Subjects in Clinical Research (1) WMA “Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects” (2004)  24. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable laws.  25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative.  26. Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population.

9. 9 International Movements Concerning the Protection of Children Involved as Human Subjects in Clinical Research (2) CIOMS “International Ethical Guidelines for Biomedical Research Involving Human Subjects” （ 1982,1993,2002 ） Guideline 14: Research involving children  Before undertaking research involving children, the investigator must ensure that: (1) the research might not equally well be carried out with adults; (2) the purpose of the research is to obtain knowledge relevant to the health needs of children; (3) a parent or legal representative of each child has given permission; (4) the agreement (assent) of each child has been obtained to the extent of the child‘s capabilities; and, (5) a child‘s refusal to participate or continue in the research will be respected.  a 'deliberate objection' by a child to taking part in research should always be respected.

10. 10 The Protection Regulation for Children as Human Subjects in the US. (1) The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research “Research involving children ： Report and recommendation” (1977) “The Belmomt Report ： Ethical principle and guidelines for the protection of human subjects of biomedical and behavioral research” (1979) Code of Federal Regulations, Title 45 Public Welfare, Part 46 Protection of Human Subjects ： 45CFR46, Subpart D. Additional Protections for Children Involved as Subjects in Research (1983)

11. 11 The Protection Regulation for Children as Human Subjects in the US. (2) 45 CFR 46, Subpart D. “Categories of Risks”  According to federal regulations (45 CFR Part 46), IRBs must classify proposed research on children into one of four categories. This classification is based on an analysis of probable risks, possible benefits, and associated discomfort. (1) Research not involving greater than minimal risk (404) (2) Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (405) (3) Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition (406) (4) Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (407)

12. 12 The Protection Regulation for Children as Human Subjects in the US. (3) American Academy of Pediatrics “Informed Consent, Parental Permission, and Assent in Pediatric Practice” (1995)  In this statement,the AAP provides an updated analysis of (1) the concept of informed consent; (2) the ethics of informed consent and the concept of the right to refuse treatment (dissent) (3) the concept of “proxy consent”; (4) the concept of parental permission and child assent; and (5) informed consent of adolescents (“legal emancipation”, “emancipated minor”).

13. 13 The Protection Regulation for Children as Human Subjects in the US. (4) NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects (1998)  This document sets forth guidelines on the justifications for exclusions of children from research.  For example, it is expected that children will be included in all research involving human subjects unless one or more of the following exclusionary circumstances can be fully justified: (1) The research topic to be studied is irrelevant to children. (5) Insufficient data are available in adults to judge the potential risk in children.

14. 14 Five Points of View to Consider in Regulations for Protecting Children as Human Subjects in Japan (1) Children's rights and the ethical dilemma of involving them in clinical research. (2) Key concepts such as “ assent”, “ parent's rights permission”, “ proxy consent”, “emancipated minor”. (3) Cases where the parent's consent/permission may be waived. (4) Risk-benefit analysis and conditions where research involving children could be authorized (5) Necessity for a third-party institution that evaluates the fairness in research.

15. 15 The Movement of Legislation for Protection of Human Research Participants in Japan Ministry of Health, Labour and Welfare “Panel on Clinical Trial” (2005)  Various petitions calling for legislation for protection of human subjects in research were submitted to this panel and examined as the subject of future investigation. Cabinet Office, Government of Japan “Council for Science and Technology Policy” (2006)  At this council, the goal to rise "Ethical Guidelines for Clinical Studies (2003)" to the same level ICH-GCP invested with the legal binding force law was indicated clearly. Japan Science and Technology Agency, Center for Research and Development Strategy “The Strategic Recommendations Concerning Clinical Research ： with the aim of radical reform of our domestic system of clinical research” (2006)  This report gives the highest priority to legislation of "the basic law on clinical research".

16. 16 Why Legislation of the Protection Regulation for Children as Human Subjects is Required in Japan. (1) Absence of effective enforcement of the law that prohibits the research using human subject without “his/her consent” (2) Except for the regulations of clinical trials, there are no comprehensive regulations with the binding force that protects human subjects in research, either.  Administrative guidelines without disciplinary regulations concerning misconduct of researchers cannot ensure the protection of human subjects. (3) In Japan, there are no autonomous organizations inside the professional group (Japan Medical Association) that examine and impose disciplinary action.  JMA is a professional profit organization based on voluntary admission.

17. 17 Conclusion: The Importance of the Institutionalization of Research Ethics Education (1) As mentioned above, In Japan, a comprehensive management system that protects human subjects including children in research should be promoted by establishing the research participants protection law. However, by only establishing disciplinary regulations concerning misconduct of researchers, assurance of fairness in biomedical research cannot be expected in Japan. In addition, Japan has to constantly promote the institutionalization of research ethics education to embody the establishment of a human subjects' protection system in the future.

18. 18 Conclusion: The Importance of the Institutionalization of Research Ethics Education (2)  In fact, NIH added a new point of view on the research ethics education to embrace the protection of human research participants in 2000. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS Release Date: June 5, 2000 (Revised August 25, 2000) National Institutes of Health  The guideline states that the NIH requires education on the protection of human research participants for all investigators submitting NIH applications for grants or proposals for contracts or receiving new or non-competing awards for research involving human subjects.