Provisions For Review of Genetic Research in Japan

- Takashi Tsuchiya, M. A.
Associate Professor, Department of Philosophy
Faculty of Literature and Human Sciences
Osaka City University, Osaka 558-8585, JAPAN

E-mail: tsuchiya@lit.osaka-cu.ac.jp

Eubios Journal of Asian and International Bioethics 13 (2003), 127-130.


Following is an outline of Japanese regulation provisions for reviewing genetic research based on The Ethics Guidelines for Human Genome/Gene Analysis Research, promulgated by the Japanese Government in 2001. Then, three major problems in them will be discussed. First, since a framework of human research is absent in Japan, genetic research regulations are individual and isolated similar to other regulations of medical research. Second, since the Ethics Guidelines were needed and promulgated urgently for the national research development, protection of human subjects is apparently neither the primary purpose nor seriously pursued. Third, the regulations depend entirely on institutional ethics review committees and the Japanese Government has made no effort to control their quality.

1. Background of the Provisions

In Japan, genetic research with gene analysis is regulated under The Ethics Guidelines for Human Genome/Gene Analysis Research (2). This was issued jointly by three Japanese Ministries, namely the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Ministry of Economy, Trade and Industry, on March 29, 2001.

The Ethics Guidelines are based on The Fundamental Principles of the Research on the Human Genome (3), which were issued by the Council for Science and Technology Bioethics Committee on June 14, 2000. These Principles in turn were based on such documents as the UNESCO's Universal Declaration on the Human Genome and Human Rights and The Guidelines for Bioethical Problems Associated with Genetic Analysis Research (the so-called "Millennium Guidelines") of the Ministry of Health and Welfare, the latter of which were first issued on April 28, 2000 but replaced by the present Ethics Guidelines.

The need for these Japanese Principles and Guidelines were recognized when the Japanese Government declared a new national policy for the development of science and technology for the new millennium. "The Millennium Project" was proposed and passed through the Diet in 1999. About half of the entire budget of the project (6 billion and 4 thousand million yen of 12 billion yen) was for biomedical and biological research. This would be funded for five years (2000-2004) for (1) human genome/gene analysis research particularly of single nucleotide polymorphisms (SNPs), (2) development of the "order-made (tailor-made) medicine," namely medicine based on recognition of personal physical differences as the result of SNPs analysis, (3) development of tissue engineering, and (4) identifying sequences of the rice genome. In the Millennium Project the Japanese Government has been trying to improve the current international competition of biomedical industries. However, as there were guidelines for gene analysis research, the Government issued them in haste. First, the Ministry of Health and Welfare promulgated the Millennium Guidelines, which were applied only for research in the Millennium Project. Then the Japanese Government published the Fundamental Principles and the Ethics Guidelines, which cover all human genome/gene analysis research in Japan, not only for those in the Millennium Project.

2. The Scope and Structure of The Ethics Guidelines

The Ethics Guidelines cover all human genome/gene analysis research performed in Japan. The term "human genome/gene analysis research" means "research conducted by using human specimens for the purpose of elucidating structures or functions of the human genome and genes that commonly exist in cells of a donor and possibly inheritable." [14-(3)] In more concrete terms, it is "research intending to analyze structures or functions of base sequences of DNA or complementary DNA derived from mRNA or the like by using a tissue, such as leukocytes, of a donor, a main example of which is research that analyzes what is called germline mutation or polymorphism." [14-(3) Subrule] They also apply to provisions of human specimens for such research. However, the Guidelines do not apply to research that analyzes somatic mutation alone, such as those of cancer cells. They also do not apply to the human genome/gene analyses in the course of medical treatment such as routine clinical examinations, clinical trials and post-marketing surveillance that are covered by the Medical Act, or genetic analysis for educational purposes.

The Ethics Guidelines are consisted of five parts and 16 chapters as indicated in Table 1. They declare seven basic principles on which all provisions of the Ethics Guidelines should be based. They can be summarized as in Table 2.

Then they provide duties of researchers and directors, requirements to protect research subjects ("donors"), and proper handling of human specimens.

Those who bear the final legal responsibility of conduct of research are the directors of institutions, namely the hospital director, the public health center director, the dean of the medical school, or the director of the laboratory. They must oversee researchers and penalize them in cases of abuse. To prevent divulgence of subjects' personal information, the directors have to designate a personal information custodian. They must also establish an ethics review committee as an advisory board for review of research protocols, and approve or reject the protocols according to the committee's decision. In addition, they shall always be informed about the performance of approved research in a report from the principal investigator or by asking external specialists to investigate on site at least annually. For research subjects and their blood relatives they shall provide genetic counseling.


Table 1. Contents of the Ethics Guidelines

INTRODUCTION
PART I: BASIC IDEAS
1. Basic Principles
2. Scope of Application
PART II: DUTIES OF RESEARCHERS AND EQUIVALENT PERSONS
3. Basic Duties of All Researchers and Equivalent
Persons
4. Duties of Directors of Research Institutions
5. Duties of Principal Investigators
6. Duties of Personal Information Custodians
7. Duties and Composition of Ethics Review
Committees
PART III: BASIC STANCE TOWARDS DONORS
8. Informed Consent
9. Disclosure of Genetic Information
10. Genetic Counseling
PART IV: HANDLING OF HUMAN SPECIMENS
11. Use of Existing Specimens
12. Methods of Human Specimen Preservation and
Disposal
PART V: REVISION
13. Revision
PART VI: DEFINITIONS OF TERMS
14. Definitions of Terms
PART VII: SUBRULES
15. Subrules
PART VIII: DATE OF ENFORCEMENT
16. Date of Enforcement

Table 2. The Basic Principles of the Ethics Guidelines

(1) Respect for human dignity
(2) Free and adequately informed consent
(3) Confidentiality of personal information
(4) Conduct of socially beneficial research that contributes to the knowledge, health and welfare of humanity
(5) Priority of an individual's human rights over scientific or societal benefits
(6) Propriety of research through observation of the Guidelines in making and executing research protocols and their prior review by an independent Ethics Review Committee
(7) Transparency of research through on-site investigation by third parties and publication of research results


The ethics review committee takes a key role in this system. In reviewing protocols, it sometimes makes a judgment on critical issues such as allowing proxy consent, disclosing genetic information to the donor's blood relatives without donor's consent when it indicates serious but curable disease, and permitting research with existing specimens. To evaluate protocols both from ethical and scientific points of view, it shall be composed of natural scientists, humanists or social scientists (including specialists in ethics and law), and persons from the general public. It cannot discuss or decide without the attendance of a humanist, a social scientist, or a person from the general public. The guidelines recommend that at least half of all the members come from outside the institution. At least half of the external members shall be humanists, social scientists, or persons from the general public. The committee must be composed of both male and female members. Its composition, names, affiliations, and backgrounds of the members, and committee proceedings should be disclosed to the public.

As for provisions of a specimen to a human cell, gene or tissue bank, the donor's personal information must be completely removed so that he/she can never be identified.

Figure 1: Constellation of Some Japanese Guidelines for Medical Research (see below)

(Cited from the document "Concerning the Drafting of The Ethics Guidelines for Clinical Research," prepared by the Division of Research and Development, Department of Medical Policy, The Ministry of Health, Labor and Welfare, for the 12th meeting of the Division of Science and Technology of The Health Science Council on January 29, 2003. http://www.mhlw.go.jp/shingi/2003/01/s0129-7g.html)

3. Problems in the Present Provisions

The enforcement of the Ethics Guidelines appears to have changed the behavior of Japanese researchers in genetics. They have been compelled to learn that free and informed consent of the subject is necessary and essential. In addition, every research institution has been establishing an ethics review committee and new administrative system including a personal information custodian and making preparations for genetic counseling in haste. The situation might be similar to that of the United States in the middle of the 1970's, when the National Research Act required every institution performing human research with federal funds to establish an Institutional Review Board. However, although the ethical standard of genetic research in Japan appears to have been improving, it is not yet sufficient. There are three main problems as follows.

First, the Ethics Guidelines are based on individual and isolated provisions for human research, and there is no systematic constellation among these specific provisions. In Japan, there are no universal regulations for human research such as in the U.S. Common Rule that is applied to both biomedical and behavioral research with the U.S. federal funds (4). For human research in medicine, the Ministry of Health, Labor and Welfare is currently drawing up general guidelines, The Ethics Guidelines for Clinical Research. However, these new guidelines will not apply to specific fields of research which have already been regulated, such as pharmaceutical research, organ transplantation, embryonic stem cell research, epidemiological research, gene therapy, and human genome/gene analysis, and will apply only to research that has not be covered by the present provisions. (See Fig. 1) This situation of individualization and isolation is a result of competitions between ministries and divisions within Japanese bureaucracy.

Second, Japanese provisions for genetic research were enforced as a part of a national research development policy and do not appear to regard protection of human subjects as the primary purpose. As explained above, these provisions were prepared for the Millennium Project. The Japanese Government promulgated the Millennium Guidelines, the Fundamental Principles, and the Ethics Guidelines all in Japanese fiscal 2000, the year of the beginning of the Project. As the Millennium Guidelines were made BEFORE AND WITHOUT the Fundamental Principles, the drafting process was irregular since the more general and fundamental ones (the Fundamental Principles) came after the more specific ones (the Millennium Guidelines). If protection of the human subject was truly the primary purpose, provisions should be based on principles derived from investigation of problematic cases of subject abuse. However, partly because of a shortage of time the drafting committees did not review such cases, for example the so-called "Suita Study." This was an epidemiological study with gene analysis of blood samples of about 5,000 residents in Suita City, near Osaka, performed by researchers of the National Cardiovascular Center. These samples were gathered at regular public health check-ups. Gene analyses were performed without any informed consent of the subjects. Only after being reported in the press, the researchers apologized to the subjects, asked them to consent, and discarded samples of subjects who refused participation. However, the drafting committees of the guidelines never discussed nor investigated this kind of case. Their stance suggests urgent need for these provisions, not for subject protection, but for research development.

Third, although the provisions allow ethics review committees to play a key role, the Japanese Government has made no effort to maintain their quality. Research institutions are not required to assure to the Government about their ethics review committee's quality. On the other hand, the Government has made neither a guidebook to articulate review standards and to explain essential review points, nor an educational program to improve the committee member's competence. This might be gross negligence, since levels and standards of research review are different among committees and poor protocols can pass examination. However, in the current provisions the Ministries bear no responsibility to administer each ethics review committee to control quality. This is another example of the Japanese Government's disregard of subject protection. As a consequence each institution finds some difficulties in administering the ethics review committees, as discussed in the following paper by Shirai on the situation of ethics review committees in Japan.


Figure 1:  Constellation of Some Japanese Guidelines for Medical Research

 

 

臨床研究倫理指針:The Ethics Guidelines for Clinical Research (forthcoming)

疫学研究に関する倫理指針:The Ethics Guidelines for Epidemiological Research (2002)

ヒトゲノム・遺伝子解析に関する倫理指針:The Ethics Guidelines for Human Genome/Gene Analysis Research (2001)

遺伝子治療臨床研究に関する指針:The Guidelines for Clinical Research in Gene Therapy (1994/ 2002)

ヒト幹細胞を用いた臨床研究に関する指針(検討中):The Ethics Guidelines for Clinical Research with Human Stem Cell (currently being drafted)

投薬等を伴う介入研究等:intervention studies with medication etc.

治験(薬事法):pharmaceutical clinical trials (covered by The Medicine Act)

医師主導の治験:pharmaceutical clinical trials directed by physicians

企業主導の治験:pharmaceutical clinical trials directed by companies

 

 



Notes

1) This paper was presented at the conference "What are the Common Grounds: An American and Japanese Dialogue on Genetic Disease Linked to Racial and Ethnic Groups," May 8-9, 2003, at the Center for Global Partnership Office, the Japan Foundation, Akasaka, Tokyo, Japan.

2) Hereinafter mentioned as the Ethics Guidelines. Numbers of the chapters and sections indicated as [x-(y)] as cited from their articles. An English translation of their full text can be found on the Eubios Ethics Institute website (http://eubios.info/eghgr.htm), although in this paper another translation was used which was prepared by the working group delegated by the Ministry of Health, Labor and Welfare and will be the official translation.

3) English translation is http://www.mext.go.jp/a_menu/shinkou/seimei/gensokue.pdf

4) An explanation of this lack of human research framework in Japan was presented in Tsuchiya, Takashi, "In The Shadow of the Past Atrocities: Research Ethics with Human Subjects in Contemporary Japan," EJAIB 13, No. 3 [2003], 100-1.


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