Genetic diagnosis of familial cancer in Japan and the proposed Ethical Guidelines of 1998

For many years, the Japanese word "Iden Byo" (genetic disease) has had a rather negative connotation. Some people believe that the appearance of genetic disease in a family member indicates some sort of wrong-doing in the previous generation. This belief is based on a traditional Japanese idea which may originate from the Buddhist notions of Karma or destiny.⁵
__Genetic disease was regarded as shameful to the family and something to be hidden and kept secret, in particular because genetic diagnosis and disease might result in social discrimination against a particular "family clan" when it comes to marriage, employment, schooling, etc. One important aspect of genetic disease in Japan is that it is not only a matter for the individual and the immediate family members, but also for the whole generational family.

Ethics of familial cancer research in Japan

Serious bioethical issues are raised by familial cancer diagnosis. Openness among family members is often not the norm in the case of serious disease. Misdirected efforts to cure the patient are made, and false hopes for recovery are proclaimed. In the case of terminal illness, such as cancer, the patient would not be told the truth that he or she is dying. However, if the situation is not terminal, but involving genetic defects or diseases like breast cancer or familial polyposis coli, the individual patient would be told the facts, but he or she would usually not tell the truth to other family members who might be affected by similar genetic defects in the future. This illogical contrast in not telling the truth to the patient in the terminal stage of cancer (not telling the truth to a dying patient) while presenting the genetic diagnosis of familial cancer (but not telling the truth to other family members at risk) might be interpreted as a psychological protection mechanism in Japanese culture. This mechanism aims at preserving a gentle feeling of loving-kindness without telling the "truth" in order to avoid the harmful reality.
__However, the traditional ethos of the Japanese people has been changing during the last twenty years, at least slowly.

Patients and the formation of the "Family Support Group"

One example of slow change is the formation of the patient and family self-help group called "Harmony Line."⁶ This organization had around 40 members at its establishment in 1998. Two thirds of its members are patients themselves; the rest are relatives. The purpose of this organization is to share and exchange various kinds of information regarding their disease, living conditions, medication, surgery, alternative treatment, etc.⁷
__In this social and cultural context, the Ethics Committee of The Japanese Society for Familial Tumor (JSFT) in 1998 presented its draft guidelines for familial cancer research and clinical trial.⁸ JSFT was originally formed to be a key research station for Familial Cancer and Prevention Project of UICC (Unio Internationalis Contra Cancrum) in the Asia-Oceania region.⁹

The outline of Genetic Diagnosis Research Guidelines

JSFT's Ethics Committee had been working on these draft cancer research guidelines since 1996. Below follows a brief summary,¹⁰ which I have paraphrased to denote the main elements of each clause in the original Japanese text.¹¹
__In the Introductory Notes, the guidelines explain the purpose of familial cancer research and other relevant issues, such as the meaning of susceptibility, the protection of privacy, the guarantee of human rights and dignity of patients and family, and the necessity of ethical consideration in order to carry out scientific work.
__In addition, the following nineteen recommendations are put forward.

I. Fundamental Principle of the Guidelines.
__1. The priority of genetic diagnosis and research in familial cancer should be the protection of the human rights of the concerned participants and family members as it relates to the whole lineage of the family.

II. Purpose and Conditions of Research.
__2. The research should only be performed for the advancement of diagnostic, therapeutic and prophylactic procedures, as well as the understanding of the etiology and pathogenesis of disease. Medically non-relevant research should not be performed.
__3. Prior to carrying out a genetic test, it is necessary for the participants and society in general to make a comparative medical, psychological and social study of the balance between expected advantages and disadvantages. The test will be carried out when its advantage is confirmed and the informed consent has been obtained from the subjects.
__4. The selection of participants should only be based on those individuals who have a probable genetic susceptibility due to various familial and clinical data. Moreover, in the case of carrying out genetic tests on minors, the tests should be beneficial directly to them.
__5. Genetic diagnosis should be performed by a physician who has an understanding of the meaning and limitations of genetic testing.
__6. The research should be in accordance with ethical principles expressed in the Helsinki Declaration of the World Medical Association. Justification of the research should be stated clearly and in detail in the protocol.
__7. The protocol for research and application of genetic diagnosis in medical services should be reviewed by a proper institutional ethics board.

III. Informed Consent.
__8. Prior to genetic diagnosis research and the taking of samples, the participant should be made aware of the following, orally or in writing: the aim, the procedure, the expected benefits, the potential disadvantage (the possibility of having mental stress), the limitations of genetic testing (i.e. the occurrence of false positives or negatives) and the protection of privacy. Moreover, it is necessary for the physician to obtain the consent of the subject based on his or her free will. The consent should be secured in writing.
__9. In genetic diagnosis and research, detailed discussions concerning the research should be carried out in order to obtain an informed consent from the participant. The premise is that he or she should be informed about the name and condition of the disease.
__10. The participant has a right to refuse genetic sample testing and there should not be any medical disadvantage due to this refusal. Moreover, he or she may also change the decision in due course without receiving any negative outcome.
__11. In receiving genetic diagnosis and testing, the participant should be informed clearly that while there might be potential advantages in terms of better treatment and prevention, there are also potential social disadvantages with respect to marriage and conflicts among the lineage family members.
__12. The participants should be clearly informed whether particular genetic tests and diagnoses are still on the experimental stage or are established procedures of medical practice. It should be explained that at this stage the majority of genetic diagnoses have been carried out for research purposes.
__13. Third parties such as parents, guardians or proxies could be given the right to consent on behalf of non-competent participants if this is in the patient's best interests.
__14. The result of the genetic test and diagnosis should be disclosed to the participant, if he or she wants to know, and should be withheld if he or she prefers not to know. The possible benefits and disadvantages of declining information should be explained to the participant.

IV. Maintenance and Protection of the Genetic Information of the Individual.
__15. The right to have access to genetic information belongs to the participant. Right to have access to the information could also be possible for medical staff members and researchers.
__16. The maintenance and confidentiality of genetic information of the individual should be strictly controlled in order to protect the privacy of the participants.
__17. The maintenance of the individual and the registration of the genetic information of the family lineage of the participants is necessary for the advancement of the study of familial cancer and for securing its scientific quality.

V. Support Systems for the Participants.
__18. It is necessary to provide genetic counseling in keeping with the need of individuals and family members and in response to their psychological changes.
__19. The arrangement of a medical, psychological and social support system in receiving the opinion of the subjects and the support group is recommended.

A break-through for medical research in Japan

As I mentioned above, these guidelines are the result of the continuous efforts by JSFT which began in 1996.¹² We see in them a full recognition of the principle of respect for the autonomy of the participants in research and of the fundamental idea of informed consent in genetic diagnosis, testing and research. After detailed discussions on drafts and amendments, the Ethics Committee finally presented them at a general assembly of JSFT in 1998.¹³
__In our cultural context, the ethical aspects of research on the genetic problems of individuals always raise the complicated question of family relationship and conflict. However, I think that these JSFT guidelines reflect a very well refined sensitivity to the family issues as well as the participant-centered, anti-paternalistic research on genetic diagnosis and testing. This is for many Japanese medical researchers a radical departure. And this is one of the reasons why, after three years of repeated revision, presentation and amendment, these guidelines still remain a "proposal" (a draft) without receiving the official endorsement of the general assembly of JSFT.

Ethical aspects of gene therapy and informed consent in Japan

In this section, I shall focus on the recently emerging gene therapy and some bioethical problems of the research protocol including informed consent documents.

Guidelines for gene therapy in Japan

In February 1994, the "Guidelines for Gene Therapy Clinical Research" (GGTCR) were issued as an official "Notice No. 23" of the Ministry of Health and Welfare (MHW) followed by similar guidelines by the Ministry of Education.¹⁴ By this Notice, a review board, the so-called Central Evaluation Committee for Gene Therapy, was established. Some of its members have assigned memberships in committees of both the Ministry of Health and Welfare and the Ministry of Education.
__According to these guidelines, genetic manipulation for the enhancement of the body or particular abilities by using germ-cells should be discouraged and even prohibited as is the case in many countries in the world. This is also in line with statements issued by international organizations such as WHO, CIOMS, UNESCO and the Council of Europe.
__A 1991 survey carried out by the Prime Minister's Office has shown that more than 50% of the public supports gene therapy.¹⁶ Moreover, professionals argue that the medico-technological intervention on particular genes for the purpose of gene therapy would be justified bioethically and legally if the patient's situation is regarded as incurable, and if the patient agrees to become involved with full informed consent.
__I think that in the public debate on gene therapy, contributions from various disciplines such as bioethics, religion, philosophy, genetics and medicine are extremely important and even necessary. Furthermore, open communication between the general public and the experts should be a basic factor in all public policy-making and regulation.¹⁷
__The first gene therapy protocol in Japan was carried out at Hokkaido University Hospital in 1995. The subject was a patient with ADA deficiency. According to a report published in 1997, after 11 rounds of treatment, the patient's condition had improved. This case received quite a lot of attention in the Japanese media as an innovative new medical technology to be applied to very rare types of disease.

Review of scientific and ethical quality

In the spring of 1997, the National Commission on Health and Welfare Policy¹⁸ was officially established at the Ministry of Health and Welfare. Its Subcommittee for the Evaluation of Advanced Technology of Medicine has been functioning as a national review board for gene therapy research since 1997 when it replaced the former Central Evaluation Committee for Gene Therapy.
__As a member of this National Commission and its Subcommittee for the Evaluation of Advanced Technology of Medicine,¹⁹ I have been involved in the public review of scientific and ethical aspects of several gene therapy protocol applications.
__In 1998, the Subcommittee reviewed applications of gene therapy protocol for kidney cancer at the Hospital of Tokyo University's Medical Research Institute, for lung cancer at the Hospital of Okayama University Medical School, for esophageal cancer at Chiba University Hospital, and for breast cancer at the Cancer Research Society's Hospital in Tokyo.
__Common to many of the applications were insensitive and immature phrases used without serious attention to the patient's and family's feelings, and this in spite of the emphasis of the Guidelines on the "protection of patient's rights and respect for human dignity".²⁰ For example, one research protocol justified its purpose by mentioning that "this experimental gene therapy treatment is not quite verified yet because of lack of data about the cure of disease and because the risk factors are not known in detail. But, this would not be of any obvious harm to a patient who is in the terminal stage of life." This can be interpreted as: "The researcher still does not know the degree of risk or safety of this gene therapy. However, the patient is going to die soon anyway. So this could be justifiable."²¹ The patient, the family, and the general public would certainly be much offended by these so-called "scientifically and medically accurate and objective phrases."
__According to GGTCR, the subject must be confronted with lethal and fatal sickness such as severe hereditary disease, cancer, AIDS and other life-threatening diseases. Moreover, in Chapter 1, section 2 and 3 it is stated that the expected benefits of this clinical research should be superior to those of presently existing alternative methods, and that the benefit to the patient should outweigh the foreseeable disadvantages.
__In accordance with the GGTCR, the insensitive ways of writing research protocols, disregarding the rights and dignity of the patients, should be avoided. This is particular important in the Japanese cultural context.
__A scientifically oriented mind sometimes leads researchers into hasty expectations of positive results in an "If it works, it's O.K." mentality without serious consideration of the fact that the patient places his or her last hope in gene therapy. However, this mentality could also be regarded as a result of a cultural tradition of medical paternalism in Japan.²²
__It is very important to mention here that the GGTCR state their objectives to be both to ensure scientific and ethical validity and to promote the proper conduct of gene therapy clinical research.

The difference between "claim" and "revoke"

In the research protocol documents of various institutions, it is stated that the patient is "able to claim" to stop the experimental procedure anytime he or she wants. This expression might seem quite acceptable to a medical expert. However, as a lawyer-bioethicist, I have pointed out in the committee that there is a problem with the phrase "able to claim" to stop and insisted that this vague statement should be revised. I proposed an amendment which changes this phrase to "the experimental treatment of gene therapy should be definitely halted due to the claim of the patient". Otherwise, I stressed, there would be cases of patients being "able to claim" to stop the experimental treatment but not being able to actually stop it. And, once it has begun, patients and family are usually not "claiming" since there is no guarantee of "halting" the treatment.²³
__The GGTCR state more accurately that any subject who has consented to gene therapy can "revoke" his or her agreement anytime.²⁴ The difference between "able to claim" and "revoke" is obvious from the patients' point of view.
__In addition to the lack of sensitivity expressed in research protocols, Subcommittee members have also recognized the limited number of references to the variety of existing and possible alternative treatments. Moreover, the protocols sometimes lack detailed description of the nature of the disease to which the experimental treatment of gene "therapy" would be applied. Even among medical experts the application of the word "therapy" for this gene transfer is questioned due to the present limited success rate for the cure of disease by this procedure. Particularly in the case of a "clinical research trial of gene therapy", a balanced description of the benefit to patients is vital.
__After evaluating several gene therapy protocols, a majority of the Subcommittee members including myself concluded that many of them were not written well enough to be understood by lay-people such as patients and their families. The majority also concluded that sometimes they were written in a manner that was insensitive to the patient's and family's states of mind which are usually characterized by a hope for complete cure.
__As mentioned above, there is in Japan a cultural difficulty of having straight communication between patients and physicians with respect to disease. However, in accordance with international trends of research ethics and protocol review process, the Japanese Gene Therapy Guidelines of 1994 state the full assurance of "informed consent." The rapid development of high-technology medicine and its application to the cure of diseases has various implications in our particular cultural, social context. However, we also have to recognize the positive challenge to change traditional values in this particular cultural context, especially in the ethics of medical research.²⁵

Concluding remarks: towards patient-centered research

Finally, I shall try to explain these attitudes of Japanese scientists doing research on genetic diagnosis and gene therapy. First, there are remains of a paternalistic medical tradition. It has been difficult for many Japanese to ask questions to superiors and authoritative persons such as physicians, teachers and government bureaucrats.
__Second, in Japan there is an "Amae" (sense of dependency) mentality to the superiors and the professionals including parents. This sense of "Amae" is uniquely characterized as one of the components of the Japanese personality which is naturally reflected in the mind of the Japanese patient. According to this interpretation, patients are traditionally expected to be dependent on the physicians, nurses and other medical staff members without asking any questions. They are usually making their decisions in a communal, familial and contextual manner. The decision is usually not based on purely individualistic and autonomous considerations.²⁶ As a matter of fact, the person with a very independent and individualistic behavior would be regarded as an egocentric person, and might be blamed for lacking the sense of dependency which is the basis for communal living in the Japanese cultural context.
__Third, quite a number of Japanese have a feeling of resentment against the arrogant, authoritative professional dominance of medical experts. This could be symbolized in the unhappy memories of the first heart transplants in Japan in 1978, which were a failure and led to accusations of murder against the paternalistic surgeon (although he was not prosecuted).²⁷
__The lack of openness among professionals, particularly in the field of advanced medical science, is a very serious issue, since the public sometimes does not properly understand the application of new medical technology such as organ transplants, genetic engineering, and gene therapy. Therefore, it is good that GGTCR have proposed a more open public review system by gathering experts from different fields such as molecular biology, genetics, clinical pharmacology, pathology, law, and bioethics, and also inviting clinical experts on the particular disease regarding which the gene therapy is to be performed.
__To be sure, the attitudes to informed consent are changing.²⁸ Decision-making becomes more individual and autonomous. However, some traditional family values remain, for instance the practice of not telling the truth to other family members when sharing a common fate such as unexpected disease or terminal disease. But, even though family values and bonding have some positive aspects, I believe that the Japanese should not be encouraged to justify a violation of human dignity and human rights in the name of culture or tradition.
__In the process of application of new medical technology, we need to establish an open, public, and internationally acceptable Bioethics Public Policy. In doing so, traditional attitudes, typical for an Asian cultural context, and in particular for Japan, could be seriously challenged.
__Within the framework of a bioethical reconceptualization, the study of the Japanese situation regarding genetic diagnosis and gene therapy shows a possibility for changes of the Japanese public policy with respect to the cure of patients suffering from genetic disease.²⁹
__Regarding these trends of value change in the Japanese culture, it is very important to note that the background document on clinical gene therapy research issued by the Health Science Council in April 1993 is a positive sign of public understanding. It states: "Thus, researchers and related individuals should make efforts to gain the understanding of the general public by always being aware of social and ethical problems, conducting research with these issues in mind, by explaining clearly what gene therapy is, by informing subjects very well in each case of clinical research, by actively making information open to the public, and actively disclosing it to the public."³⁰
__This is one of the accomplishments of the bioethical input to public policy-making in Japan. Moreover, the Japanese public has also got an opportunity to be present in protocol review sessions, from time to time, which has never been the case before. And all the minutes of the Council meetings, committees and sub-committees are in the public domain and available through the internet homepage of the Ministry of Health and Welfare.³¹
__I conclude by stressing once again that a well-informed public and advanced hi-tech medical experts should work together towards achieving the hope of full care and cure of patients with fatal and hopeless diseases.

Notes

1. Kimura, 1991a.
2. Spinsanti, 1995.
3. Abrecht, 1973.
4. Kimura, 1991b.
5. Ohkura, Kimura, 1989.
6. Fellowship Association for the Patients of Polyposis Coli.
7. Gondo, 1998.
8. JSFT, 1998.
9. Utsunomiya, 1998.
10. A revised version, May 30th, 1998.
11. Ethics Committee, JSFT, 1998.
12. Tsunematsu, Kakee, 1998.
13. JSFT, 1998.
14. MHW, 1994.
15. MHW, 1994. Chapter 1-6.
16. Prime Minister's Office, 1991.
17. National Institute of Health, 1990, pp. 6-7.
18. Kosei Kagaku Shingikai.
19. Sentan Iryo Gijyutsu Hyoka Bukai.
20. NCHW, 1998. Chapter 2, section 3.
21. Tokyo University, 1998.
22. Kimura, 1995.
23. MHW, 1998.
24. MHW, 1994. Chapter 3-5.
25. Kimura, 1995.
26. Doi, 1973.
27. Kimura, 1991c.
28. Kimura, 1993.
29. Kimura, 1990.
30. Kimura, 1993.
31. URL: http://www.mhw.go.jp/

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