Summary of the Discussion of the Expert Panel on BioethicsOrganization of the Expert Panel

The Expert Panel and Task Force members were selected and convened by the Secretariat of the Expert Panel. These two committees always have at least 10 members and are organized according to their operating rules. According to the operating rules, the Expert Panel must have experts in the relevant fields and, indeed, medical, legal, and ethics experts participated in the committees. All of them are required to be experts, but they are not in a position to represent the organizations. They included members of the biomedical research community. There is also a need for members to express their opinions from the general standpoint and, therefore, journalists participated in the Expert Panel and representatives of patient organizations participated in the Task Force. The “general standpoint” here is intended to incorporate the viewpoints of non-professionals into the discussion, but is not representative of the general public.

There was no extreme bias in the male-to-female ratio of the participants throughout the study period. At the 98th Expert Panel (first meeting of the study period), of the fifteen members, seven were men, and eight were women; at the first Task Force, of the fourteen members, ten were men, and four were women.

Course of Discussion

The analysis covers four years of discussion in the Expert Panel on Bioethics. Based on the composition of the meeting body and timing of the report formulation, the entire period under analysis can be divided into four periods. Here, we mainly present the course of the discussions on the ethics review system and refer to some other discussion topics (Table 1).

Table 1 Four phases of meetings of the Expert Panel on Bioethics

In April 2016, the Expert Panel on Bioethics formulated a report titled “Research on the Use of Genome Editing Technology on Human Fertilized Embryos (Interim Summary).” At this time, no national guidelines for basic research on the use of genome editing technology in human embryos existed; therefore, this report became the starting point for discussion. At the 98th Expert Panel on Bioethics held immediately after the formulation of the Interim Summary, it was pointed out that the ethics review system for genome editing research should be discussed. In the ensuing discussion, methods such as using a two-step review process or involving academic societies were suggested, since the quality of the review process is not always sufficient for institutional ethics review boards. The period during which these discussions were held by the Expert Panel on Bioethics is referred to as the first period.

At the 104th meeting of the Expert Panel on Bioethics, the establishment of a Task Force was decided. The period up to the formulation of the First Report (107th meeting) is referred to as the second period. The Task Force discussed the policies for an ethical review system. It was decided that a consistent system that is not divided according to research purpose should be established, and the system should be regulated by guidelines rather than by law. It was also confirmed that a “two-step review” has been conventionally used for human embryo research; however, a review system other than this should be considered. Based on this discussion, the First Report concluded that it is appropriate to adopt a “two-step procedure” for the review system. This term is distinct from a “two-step review” in that it leaves open the possibility of adopting methods other than ethics review, such as notification to an administrative agency, as the second-step procedure. In addition, during this period, The Expert Panel discussed whether it is permissible to use human embryos for basic medical research using genome editing technology. The discussion was carried out step by step for different purposes of research, and whether surplus or newly created embryos were used. The first topic of discussion was research on assisted reproduction using surplus embryos, and the First Report stated that such research should be permitted provided that the individual research protocol is properly reviewed. A separate paper is currently being prepared for policy development in human embryo research.

In the third period, a wide range of proposals, not limited to the “two-step procedure,” were put forward. The use of third-party organizations and establishment of a central IRB were discussed, and an example of HFEA in the UK was repeatedly referred to. The Second Report stated that it would be appropriate for MEXT and MHLW to promptly develop guidelines and establish a rigorous review system that can make appropriate judgments regarding the acceptability of individual research plans and can pay attention to the actual situation in Japan and overseas, especially the current status of operation of the genome editing guidelines and other guidelines for research using human fertilized embryos. Moreover, disease research using surplus embryos and assisted reproductive medical research using embryos created for research purposes were discussed. The Second Report stated that such research should be permitted, provided that the individual research protocol is properly reviewed.

Subsequent discussions were held by the Expert Panel on Bioethics. The subject was the review system, and the report “Summary of Opinions on the Review System for Basic Research Using Genome Editing Technology on Human Fertilized Embryos” was compiled. This is referred to as the fourth period. In this period, an appropriate review system for basic research using genome editing technology on fertilized human embryos was discussed with reference to the existing ethics review system. It is also noteworthy that the government’s involvement in the review system has been discussed.

Thus, the ethics review system for research on the use of genome editing technologies in human embryos has been discussed intermittently over the four years.

Ethics Review SystemNew Proposals for the Ethics Review System

The discussion on human embryo genome editing not only explored the possibility of applying the existing research ethics review system, but also extended it to the possibility of establishing a new review system based on unprecedented ideas, such as cooperation with academic societies and a centralized review. Existing ethics review systems in Japan include a method in which only an institutional ethics review board reviews the research plans and a “two-step review” method in which the national government, in addition to the institutional review board, conducts a review. However, in the former method, it is difficult to ensure the quality of the IRB's review, while in the latter method, the complexity of the procedure has been an issue. The Expert Panel has sought a way to resolve these issues.

During the first period, a proposed review structure involving academic societies was discussed with the Japan Society for Gene and Cell Therapy and other academic societies. The Japan Society for Gene and Cell Therapy has a strong interest in human genome editing, and in 2015, it issued a joint statement with the American Society for Gene and Cell Therapy (Friedmann et al. 2015). In addition, the society called on three other Japanese societies that may be involved in human embryo genome editing research. On April 22, 2016, it issued a “Statement from Four Societies on Human Genome Editing,” which assumes the need for discussion on ELSI for human genome editing and clarified its stance to actively engage in information and awareness-raising activities in collaboration with each other.Footnote 2 The statement also argued that guidelines should be carefully and promptly prepared for the implementation of basic research on genome editing using human germ cells and embryos. In Japan, guidelines for basic research have served the function of prescribing details of the ethics review system. Representatives of these four relevant academic societies, which include many members who utilize genome editing technology, attended the 98th Expert Panel on Bioethics (June 1, 2016) to provide an explanation of the statement and comment on the interim summary from the standpoint of the societies. At this time, the Expert Panel and representatives of the four societies confirmed that there are areas in which the government should be involved and areas in which academic societies and others should be involved in the regulatory framework for human embryo genome editing. Representatives of the four societies reiterated the point made in the statement that the national government should first establish guidelines.

Conventional regulation of medical research in Japan has been carried out in various ways, including through laws and regulations, administrative guidelines, and self-regulation by academic societies. In discussions of the Expert Panel, it has been pointed out that while self-regulation by academic societies is more flexible than laws and administrative guidelines, there are some issues, such as the fact that they are not effective for those who are not members of an academic society. The four societies argued that both regulations prepared by the government and self-regulation by academic societies should be used to strengthen the overall governance of technology.Footnote 3 The representatives of the societies stated that the government should prepare broad guidelines and the societies should be involved in scientific matters, so that both parties can play complementary roles.Footnote 4 The Expert Panel on Bioethics agreed to this policy, and thereafter, a collaboration between the government and academic societies was sought.

The Expert Panel repeatedly pointed out the current lack of assurance of the quality of IRB reviews and the difficulty of achieving a certain level of review in all IRBs. Therefore, the first method of collaboration was to create a manual or guidelines to support IRB reviews. As the second method of collaboration, a proposal was made for a system in which academic societies are directly involved in the review process to ensure the quality of the review. This new review system had not been considered previously. In addition, the idea of the two-step review process involved establishing a central ethics review board (CRB). On the other hand, the actual discussion also reaffirmed the importance of the IRB, which is in a position close to the researchers and research facilities.

At the 101st Expert Panel on Bioethics meeting (October 21, 2016), three proposals were discussed regarding the division of roles between the government and academic societies.Footnote 5 All three proposed establishing a CRB involving academic societies. One of them also proposed utilizing the conventional IRB in addition to the CRB. The other two proposed that the IRB observe the progress of the research plans, which they called “monitoring,” rather than conduct ethics reviews. The three proposals were distinguished according to the roles played by the CRB and IRB (Table 2). To implement these proposals, the four societies were preparing to establish a “Joint Committee on Genome Editing Research.”

Table 2 Three proposals for the ethics review system

However, at the 104th meeting, the Expert Panel on Bioethics and the four societies diverged on the policy of the review system, and these proposals were effectively withdrawn on paper. At the 104th Expert Panel on Bioethics, the importance of continuing to consider cooperation with academic societies was pointed out, and the participation of representatives of academic societies was also obtained. The government and the academic societies continued to engage in discussions on the ethics review system.

Furthermore, during the third period, discussions were held with reference to the HFE Act and the HFEA in the United Kingdom. Compared to the Japanese review system, the UK’s review system is unique in that it is centralized in HFEA and comprehensively covers both basic research and clinical applications. In particular, the centralized review system has been an ongoing topic of discussion in the Expert Panel on Bioethics. The CRB included in the proposal for the 101st meeting was expected to play a centralized role, which is the same role that the HFEA plays. In addition to centrality and comprehensiveness, the HFEA provides substantial guidance on the review process.

These discussions were not immediately reflected in the ethics review system. However, the Second Report summarized and published these discussions as follows.Footnote 6

“The Expert Panel on Bioethics will consider the review procedures for research that involves genome editing, etc., with a view to utilizing a third-party organization (assumed to be an organization separate from each research institution or the national government) and collaborating with related academic societies, etc. In doing so, it is appropriate to pay attention to the actual situation in Japan and abroad, especially the current status of operation of the Guidelines for Genome Editing and other guidelines for research using human fertilized embryos, etc.”

In the Summary of Opinions, it was mentioned that “the government should prepare guidance (guideline commentary) that better responds to the needs of the fields of review, with reference to the approach of the HFEA in the UK, etc.”Footnote 7

Involvement of the Government

In the fourth period, the pros and cons of government involvement in the ethics review process were discussed. Government involvement in the ethics review process is a conventional practice in Japan. However, there has been insufficient consideration of the advantages and disadvantages of such involvement.

At the 119th Expert Panel on Bioethics (October 9, 2019), a legal scholar and physician pointed out the following:Footnote 8

Although a legal basis is required for guideline conformity review, the language of the Genome Editing Guideline does not provide a basis for granting a comprehensive ethics review authority to a government agency.

As a review by a government agency focusing on the content of research poses a major constitutional problem, in relation to academic freedom, it is necessary to establish very specific and clear criteria for the subject of review, if such content regulation is to be implemented.

According to MEXT’s explanation, the articles of the Genome Editing Guidelines describe the subject matter of the review as specific items, such as the purpose of the research, method of obtaining embryos, and informed consent. However, this explanation did not address all the issues raised. Another panel member who specializes in jurisprudence, while largely affirming the points made by this jurist and physician, touched on the difficulty of writing ethics into the article. He also pointed out the polysemous nature of the term ethics and distinguished between “ethics that enter into the inner mind” and “guidelines for professional conduct.” This led to a discussion of ethics in which the government may be involved, and while there are challenges when they pertain to “ethics that enter into the inner mind,” the “guidelines for conduct” are not considered inappropriate worldwide. After much discussion, the members of the Expert Panel set a goal to determine what is feasible and establish guidelines for conduct that most parties can agree upon. The legal deficiencies pointed out were overcome by this interpretation and did not result in changes in the text of the statute.

Throughout the four years of discussions, matters that had been taken for granted in the existing ethics review system were questioned from various aspects. As a result, a new ethics review system was not immediately established. However, new ideas were included in the report, and the issues raised provided fresh interpretations of the existing system.

Involvement of Various Stakeholders in the Overall Discussions of the Expert Panel

The previous sections analyzed the discussions regarding the roles of various stakeholders in the review system. In this section, we analyze the roles of various stakeholders in the overall process of discussions by the Expert Panel on Bioethics. We focus on the research community and the general public, including patients, as new ways of engaging with them have been observed.

Research Community

The Expert Panel on Bioethics is an expert panel established by the Council for Science, Technology, and Innovation and the Cabinet Office, Government of Japan. In this Panel, discussions were held with the participation of a wide range of positions, from experts in diverse fields, including medicine and law, to those who represent the views of the general public, such as journalists. However, these experts were not necessarily able to represent the views of the professional organizations, such as academic societies.

More active involvement of the research community is expected in the discussion regarding research on the use of genome editing technologies in human embryos. The Interim Summary formulated on April 22, 2016, states, “We expect the research community to actively lead the discussion in an open manner from a broad scientific, ethical, and social perspective.”

On the same day, the four relevant academic societies published their statements on human genome editing. This led to the involvement of representatives of the four societies in discussions that followed the 98th Expert Panel on Bioethics. Although the proposed review system discussed at that time was scrapped relatively early, the relationship between the Expert Panel on Bioethics and academic societies was sustained thereafter. In the second period, the President of the Japan Society for Gene and Cell Therapy and the President of the Japan Society of Human Genetics were appointed as extraordinary members of the Task Force.

In the second period, an analogous process can be noted in the relationship between the Science Council of Japan, a Japanese academy, and the Expert Panel on Bioethics. On September 27, 2017, the Science Council of Japan released a statement entitled “The State of Genome Editing Technology in the Medical and Pharmaceutical Fields in Japan.” At the 4th Task Force held immediately after, the chairperson of the committee who took charge of preparing this statement was invited to the meeting. This person became a member of the Expert Panel on Bioethics and the Task Force in the third period.

The involvement of the medical community was confirmed during the third period, when human embryo genome editing for disease research was the subject of discussion. In February 2018, the Expert Panel on Bioethics inquired into the Japanese Association of Medical Sciences on research using genome editing technology in human fertilized embryos. The Vice President of the Japanese Association of Medical Sciences presented a progress report at the 12th Task Force (October 22, 2018) and a final report at the 18th Task Force (April 15, 2019). Based on the current state of research, the report focused on the scientific rationale for the use of genome editing technology in fertilized human embryos to potentially contribute to the etiology and developmental mechanisms of diseases, focusing on specific diseases or groups of diseases. According to the Japanese Association of Medical Sciences, the research community involved in disease research, there are disease groups for which the scientific rationale for using genome editing technology may be recognized. In light of this, members of the Expert Panel on Bioethics reiterated the importance of ethical considerations in individual research and the review system for such considerations. The findings reported here by the Japanese Association of Medical Sciences served as one of the key factors leading to the Second Report that permits disease research using surplus embryos.

As described above, in the discussions of the Expert Panel on Bioethics regarding human genome editing, we were able to see the unprecedented multilateral and deep involvement of the research community, including new proposals from their standpoint and contributions to the discussion by organizing the research possibilities using genome editing from their experienced perspective.

Patient and Public

Patients and the public also played an important role in the discussions at the Expert Panel on Bioethics. The Task Force included members of the Japan Patient Association. Hearings were also held with the representatives of patient associations. Public dialogue events have also been actively held.

Hearings with patient association representatives were held twice in the third period when human embryo genome editing for disease research was the subject of discussion. This was groundbreaking since the previous hearings at the Expert Panel on Bioethics focused on sharing expertise with the so-called experts. First, at the 110th Expert Panel on Bioethics (July 27, 2018), a representative of the Japan Patients Association and a member of the Task Force made a presentation. The presenter pointed out the current situation in which biotechnology, including genome editing, has penetrated the general public without understanding its risks. At this time, a member of the Expert Panel pointed out that the government should seriously consider supporting funding and human resources in efforts to increase public understanding. Second, at the 16th Task Force (February 25, 2019), the president of the Japan Fabry Disease Patients and Family Association gave a presentation, in which he expressed expectations for research and treatment using genome editing from the perspective of patients and their families. He expressed his hopes for the careful and positive development of advanced medical technology, not only regarding genome editing, but also regarding medicine as a whole and even social equity and fairness. The following is a quote from the president’s remarks.Footnote 9

“As is the case with our diseases, there are individual differences in symptoms even though they are the same disease. In the age of genomics, we will move away from conventional evidence-based medicine to so-called tailor-made, individualized medicine, and even the structure of medicine and methods of treatment will have to change. It can be said that the genome is changing not only the medical field but also the state of society. I hope that the way of medical care will be reexamined, one person at a time.”

“For the sake of patients and families who need genome editing technology, I hope that basic research using genome editing technology for hereditary and congenital diseases will be conducted carefully and without regret in the future, so that patients can enjoy fair and equitable medical services in the clinical research that follows. I would like to see such a state of affairs.”

In addition, several public dialogue events were held by the Cabinet Office (the administrative body supervising the Expert Panel on Bioethics), in cooperation with the National Museum of Emerging Science and Innovation (Miraikan), Science Council of Japan, and Japan Association for Bioethics. The Expert Panel on Bioethics members were closely involved in these events, and members who were involved in each event had a dialogue with the public and patients and reported their experiences to the Expert Panel on Bioethics. For example, at the event co-hosted with Miraikan, participants commented, “I felt the importance of discussing what kind of society we want to envision,” “It is a problem that many people do not know that this kind of discussion is taking place,” and “I hope that similar events will be held on the same theme on an ongoing basis.” This was reported at the 116th Expert Panel on Bioethics.Footnote 10 In addition, one Expert Panel member participated in discussions at the Society of Intractable Disease Centers and the Japan Patients Association Board of Directors. Experiences from these occasions were also shared with the Expert Panel on Bioethics. The public and patients were involved and played a role in the discussions of the Expert Panel on Bioethics through these dialogue efforts.