Oversight framework over oocyte procurement for somatic cell nuclear transfer: comparative analysis of the Hwang Woo Suk case under South Korean bioethics law and U.S. guidelines for human embryonic stem cell research
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- Kim, M. Theor Med Bioeth (2009) 30: 367. doi:10.1007/s11017-009-9113-5
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We examine whether the current regulatory regime instituted in South Korea and the United States would have prevented Hwang’s potential transgressions in oocyte procurement for somatic cell nuclear transfer, we compare the general aspects and oversight framework of the Bioethics and Biosafety Act in South Korea and the US National Academies’ Guidelines for Human Embryonic Stem Cell Research, and apply the relevant provisions and recommendations to each transgression. We conclude that the Act would institute centralized oversight under governmental auspices while the Guidelines recommend politically-independent, decentralized oversight bodies including a special review body for human embryonic stem cell research at an institutional level and that the Guidelines would have provided more vigorous protection for the women who had undergone oocyte procurement for Hwang’s research than the Act. We also suggest additional regulations to protect those who provide oocytes for research in South Korea.
KeywordsHuman oocytesHuman embryonic stem cell researchSomatic cell nuclear transferThe Bioethics and Biosafety Act of South KoreaThe National Academies’ Guidelines on Human Embryonic Stem Cell Research
After the Seoul National University Investigation Committee concluded that the data published by Dr. Woo Suk Hwang and his colleagues were fabricated, the Investigation Committee and subsequently the National Bioethics Committee examined the oocyte procurement procedures used in their attempt to derive stem cells from a cloned human embryo. The committees found that Hwang’s team had committed the following four potential transgressions in the oocyte procurement.
First, a number of women had allegedly not been fully informed about the risks of the procedure or the usage of their oocytes, nor had they been asked to sign the consent forms approved by an institutional review board (“IRB”) . Second, the team had retrieved oocytes from two of its junior members for research [2, 3].1 One of the two junior researchers was a Ph.D. student who was listed as one of the co-authors for the paper published in 2004 . Here, the transgression would have occurred if those junior members had undergone oocyte procurement under undue influence or coercion or without being fully informed about the risk of the disclosure of their personal information or if Hwang’s team had not instituted a measure to safeguard their personal information throughout the experiments. Third, most women underwent oocyte procurement for either monetary payment or a discount in medical fees for an infertility treatment procedure [5–7].2 Finally, concerns about a conflict of duties have been raised concerning the role of the team’s physician–researchers. The oocytes had been procured at four institutes where Hwang’s collaborators were working as obstetrician-gynecologists. Those clinician-collaborators co-authored Hwang’s 2004 and 2005 Science articles [4, 8].
The potential transgressions in the procurement procedure described above were committed when there was no legal control or restrictions or while the new legal and ethical regime with respect to human embryonic stem cell research was about to be tested in South Korea and in the United States. In 2003, South Korea enacted a national bioethics law, called the Bioethics and Biosafety Act (“Act”), which would regulate human cloning and stem cell research . The Act has been in effect since January 1. In the United States, the National Academies proposed the Guidelines for Human Stem Cell Research (“Guidelines”) in April 2005 . All of the research reported in 2004 and most of the research reported in 2005 was done before the Act was put into effect. Hwang’s proposal to generate and study cloned embryos for the research reported in 2005 had been licensed by the Ministry of Health and Welfare in January 2005, only about 4 months before his 2005 report was published.
It is interesting to consider whether the current legal and ethical regime established in South Korea and in the United States would have prevented such transgressions. In this article, first, general aspects and the oversight framework of the Bioethics and Biosafety Act of South Korea and the National Academies’ Guidelines for Human Stem Cell Research will be described. Second, the Act and the Guidelines will be respectively applied to each transgression described above to determine whether the Act and Guidelines would have prevented such transgression. Third, an analysis of two regimes will be made to determine the extent to which each regime offers protection for human oocyte donors in the context of human embryonic stem cell research. Fourth, suggestions will be made on how to institute further protection for potential oocyte donors for research, which will be followed by a conclusion.
The Bioethics and Biosafety Act of South Korea and the National Academies’ Guidelines for Human Stem Cell Research
The Bioethics and Biosafety Act of South Korea
The Bioethics and Biosafety Act was enacted to promote health and quality of life by fostering life sciences and biotechnology, and to preserve human dignity and prevent physical harm to human beings in the process of such developments . The Act obligates the central and regional governments to implement necessary measures to effectively deal with bioethical and safety problems that may arise in the process of developing and utilizing life sciences and biotechnologies. It also obligates anyone who intends to research, develop, or utilize life sciences and biotechnologies to endeavor not to infringe on human dignity and value so as to maintain bioethics and biosafety. The Act states that anyone who could be affected by the application of life science and biotechnology has the right to be fully informed and withhold consent to the application.
The Act covers the generation of and research on human embryos created through either in vitro fertilization (IVF) or somatic cell nuclear transfer (SCNT) along with genetic testing, protection and the use of genetic information, and gene therapy. The Act bans reproductive human cloning by prohibiting the implantation of a cloned human embryo created through SCNT in a uterus and the maintenance or childbirth of the implanted cloned human embryo. The Act explicitly bans cross-fertilization and cross-implantation between humans and non-human animals, SCNT between humans and non-human animals, fusing a human embryo with a non-human embryo, and fusing human embryos with non-identical genetic information [9, 11]. It also prohibits the implantation of the product from any of those banned acts in a human or non-human uterus. The Act has no provisions regarding the derivation or use of hESC lines from procedures other than IVF and SCNT. For instance, the Act does not mention parthenogenesis and androgenesis.
Unless inconsistent with the Constitution, the Act is the primary law in South Korea concerning bioethics and safety issues related to life sciences and biotechnologies. The Act allows provisions from other laws to be relied upon as well so long as those provisions concern the bioethics and safety issues in the context of life sciences and biotechnologies . Therefore, other relevant laws such as medical practice law and organ transplantation law could complement the Act.
The Act requires relevant institutes to meet certain conditions related to facilities and personnel. It also makes relevant institutions subject to inspections by the Ministry of Health and Welfare. The Enforcement Decree and Enforcement Guidelines of the Act prescribe necessary measures and details to implement or enforce the provisions of the Act [12, 13].
The National Bioethics Committee reviews and the South Korean president determine what constitutes permissible hESC research using embryos generated through IVF or SCNT. The committee consists of 16–21 members, including seven ministers, and may include up to seven members from the scientific and non-scientific communities, respectively. The committee is not responsible for the review and approval of specific proposals.
Medical or research institutes that are registered to generate or to use human embryos created via IVF or SCNT must establish an IRB pursuant to the Bioethics and Biosafety Act or the Enforcement Guidelines of the Act. The IRB consists of five to nine members, including one who is not engaged in the field of life sciences or medical science, as well as another who is external to the particular institute. Pursuant to the Enforcement Decree of the Act, the names and qualifications of the IRB members and the minutes of its meetings are to be documented and retained for public review.
The Act mandates that IRBs review the following: the ethical and scientific validity of a research proposal; the consent process with patients and donors; the measures to ensure the safety of the patients, donors, and subjects of genetic information; and the measures to protect personally identifiable information. The IRB is obligated to immediately review any claim of serious harm or threat to bioethics and safety arising from research, development, and utilization of life sciences and biotechnologies. The IRB is required to report its findings to the Minister of Health and Welfare.
It is unclear whether an IRB must review the provenance and procurement process of all hESC lines that its researchers intend to use in their research. The Act mandates IRB reviews “related to the research, development, and utilization of life sciences and biotechnologies carried out by its institution” . Where the Act has no provisions explicitly requiring the IRB review and documentation of the provenance process of hESC lines derived at other institute, it is uncertain whether the Act mandates IRB reviews on the procurement process of hESC lines supplied or imported from other institutes with respect to informed consent, safety measures, and protection of privacy.
Individual research proposals that intend to use surplus embryos or SCNT should be approved by the Minister of Health and Welfare after the IRB review. The proposals should include the following: the objective, method, and duration of the research; the names of principal and associate investigators; the IRB’s decision on the proposal; how many surplus embryos or cloned embryos will be used in research; and which institutes will supply the embryos. A revised proposal requires re-approval by the minister.
To be approved, the proposal should be permissible under the Bioethics and Biosafety Act and should intend to develop a new treatment when no treatments are currently available or one that is expected to be conspicuously superior to the other treatments. Currently, only research directed toward developing therapies for one of the 17 rare and incurable diseases specified by the Enforcement of Decree of the Act may be permitted if the Minister of Health and Welfare finds that the subject and extent of the research are within the scope of permissible research as determined by the President. If the type, subject, or extent of a research proposal is out of the scope, the proposed research is not permissible until the National Bioethics Committee considers the case and, subsequently, the President approves it.
The Ministry of Health and Welfare provides oversight at both the national and institutional levels. At the national level, the minister, as the Chief Executive Secretary, must oversee all affairs of the committee. The minister appoints all government official members for the subcommittees. The ministry designates the institutes that may generate embryos via IVF or SCNT or may use embryos created by IVF or SCNT in research, based on the facility and personnel requirements set by the ministry itself. The creation, donation, storage, transport, disposal, and use in the research of every embryo generated through IVF in those institutes are supervised by the ministry. In certain circumstances, the ministry may do any of the following: inspect or fine an institute; revoke the authorization, registration, or license of an institute; or order the institute to close its facilities.
The National Academies’ Guidelines on Human Stem Cell Research
Currently, the United States has a no comprehensive national ethics law. According to Professor Henry T. (Hank) Greely at Stanford University School of Law, there is almost no federal “law” on assisted reproduction or on reproductive cloning. No United States law or regulation prohibits research cloning and these cloning techniques are legal unless prohibited by individual states .
On assisted reproduction, 16 states address issues in gamete and embryo disposition . Initiated by California in 1997, 15 states passed laws pertaining to human cloning as of January 2008 . Thirteen states have enacted statutes to prohibit reproductive cloning, and two other states prohibit the use of public monies for reproductive cloning . Six state statutes, including that of California, do not prohibit “therapeutic” cloning .
Thirty-three states have statutes that address the permissible sources for human embryonic stem cell research, consent provisions to conduct research on a fetus or embryo, and restrictions on the purchase or sale of human tissue for the research . Again, according to Professor Greely, there is no case law regarding hESC research or cloning except for Louisiana and Illinois embryo research litigation from the 1980s.
As mentioned earlier, in June 2005, the National Academies of Sciences proposed Guidelines for Human Embryonic Stem Cell Research to encourage the scientific community’s responsible practices in hESC research. As mandated in its 1863 Act of Incorporation, the academies have investigated and reported on “any subject of science or art” so that the nation’s leaders can turn to the academies’ advice on the scientific and technological issues pervading policy decisions .
The Guidelines apply to the use and derivation of new hESC lines derived from surplus blastocysts, blastocysts produced with donated gametes, or blastocysts produced using SCNT, but not to reproductive uses of SCNT, which should not be practiced. The Guidelines take into account ethical, legal, and policy concerns related to the development and use of human embryonic stem cells for research and therapeutic purposes.
The Guidelines cover the following: donor recruitment; stem cell characterization; handling, storage, and transfer of blastocysts and stem cell material; prerequisites to hESC research; appropriate and permissible uses of human embryonic stem cells in research; and safeguards against misuse. The Guidelines attempt to cover the importation and exportation of biological materials, information exchanges among institutes (such as the transfer of medical data), and multi-national collaboration.
The academies recommend a dual system of oversight at the institutional and national levels in order to achieve the highest ethical, legal, and scientific standards in the derivation, storage, and use of human embryonic stem cells. Moreover, the academies recommend creating a special review body other than the IRB to provide an additional level of review and scrutiny at the institutional level.
Additionally, various aspects of hESC research are governed by many federal regulations. For example, hESC research would be subject to human subject protection for donors, medical privacy protection, the FDA’s laboratory standards, safety reviews of laboratory work if the work involves the genetic alteration of hESC lines, animal care committee reviews, and rules governing the importation of biological material or the transfer of medical data from other countries. Even the National Institute of Health’s (NIH) Best Practices for the Licensing of Genomic Inventions as well as the National Academies’ Recommendations for the NIH on Intellectual Property rights in genomic and protein related innovation  could be adopted to resolve intellectual property issues arising from hESC research.
The National Academies’ Guidelines recommend establishing a national body that would initiate a national effort to provide a formal context in addressing the moral and oversight questions. The national body will continuously consider new issues arising from the field of hESC research, which is in a state of flux, and periodically assesses the adequacy of guidelines proposed in light of changes in science and the emergence of new issues. However, the national body may not review or approve specific research protocols. The body, which is not under governmental auspices, should be respected by the lay and scientific communities, should be politically independent without conflicts of interest, and should have suitable expertise. Its membership should include authorities familiar with the various issues associated with hESC research and should include representatives of the public in order to pay careful attention to evidence and argumentation and to take into account the diverse views of the public. The national body will not review or approve specific research protocols.
The National Academies recommend that all research institutes engaged in hESC research are to create a special review body, called the Embryonic Stem Cell Research Oversight (ESCRO) committee, in addition to the IRB. IRB reviews procurement procedures, in terms of voluntary informed consent free of inducements, adherence to standards of clinical care, and compliance with all applicable federal regulations for the protection of donors. The ESCRO committee provides another level of review and scrutiny, which is distinct from that of IRBs.
The ESCRO committee is to have suitable scientific, medical, and ethical expertise to provide local oversight for all issues related to the derivation and use of hESC lines. It maintains registries of investigators conducting the hESC research at the institution, the types of hESC research conducted, and the human embryonic stem cells in use. Most importantly, the ESCRO committee is to document the provenance of all hESC lines derived or imported by institutional researchers. It is also to document evidence that the procurement process was approved by an IRB to ensure adherence to the principles of informed consent, minimization of risks to donors, and protection of confidentiality. An ESCRO committee with suitable scientific and ethical expertise is to conduct its own reviews on whether the research is well justified. In order to ensure that inappropriate or frivolous research is not conducted, it may require more than simply a good scientific reason as the justification of research. The ESCRO committee is to coordinate the various other reviews that may be required for a particular protocol. It is to review the compliance of hESC research with all applicable regulatory requirements and guidelines, and to facilitate the education of investigators involved in hESC research.
The ESCRO committee at each institute will determine whether the proposed research will be categorized as permissible research. It is to divide research proposals subject to its approval into three categories: (1) research that is permissible after notification of an ESCRO committee and completion of the reviews mandated by the current requirements; (2) research that is permissible only after additional review and approval by an ESCRO committee or its equivalent; and (3) research that should not be permitted at this time. For example, purely in vitro hESC research using pre-existing anonymous cell lines is permissible if notice of the research, documentation of the provenance of the cell lines, and evidence of compliance with any mandated reviews such as IRB are provided to the ESCRO committee. In contrast, the ESCRO committee will evaluate the scientific merit of all research proposals to generate new hESC lines by any means, proposals involving the introduction of human embryonic stem cells into non-human animals, and proposals in which personally identifiable information about the donors of the blastocysts or gametes is readily ascertainable by the investigator. Moreover, the ESCRO committee will not permit research involving in vitro cultures of any intact human embryo for longer than 14 days or until the formation of the primitive streak begins. It will also not permit research in which human embryonic stem cells are introduced into non-human primate blastocysts or in which any embryonic stem cells are introduced into human blastocysts. No animal into which human embryonic stem cells have been introduced at any stage of development will be allowed to breed.
The ESCRO committee would presumably review individual research proposals case-by-case holistically, with no restriction solely based on a target disease. It is possible for a research proposal to be found permissible at one institute, but not at another. The ESCRO committee could change its position on a proposal from time to time because it will regularly review and reconsider its categorization quickly and flexibly as the field matures and the experiences of the institute accumulate.
Summary of regulatory differences between South Korea and the United States
The South Korean bioethics law and the National Academies’ Guidelines use different approaches to provide adequate oversights on hESC research. The Bioethics and Biosafety Act in South Korea would institute centralized oversight under governmental auspices. The National Bioethics Committee in South Korea will review the types, subjects, and extent of the research that may employ surplus embryos or SCNT. Following the National Bioethics Committee review, the President will determine the limitations on the permissible research using embryos generated through IVF or SCNT. The Minister of Health and Welfare is responsible for the review and approval of specific proposals. The institutes that are licensed to generate or to use human embryos created via IVF or SCNT must establish an IRB pursuant to the Act or the Enforcement Guidelines of the Act. An IRB is to provide institutional oversight under the supervision of the Minister of Health and Welfare.
In contrast, all oversight bodies that the National Academies recommend are politically independent and composed of experts and representatives of public. With respect to hESC research, the national body will consider new issues arising from the research and periodically review whether the proposed Guidelines would be adequate to address those issues. The National Academies recommend all research institutes engaged in hESC research create an ESCRO committee. An ESCRO committee is to provide oversight for all issues related to derivation and use of hESC lines. An ESCRO committee at each institute determines whether individual hESC research proposal is permissible.
Protection against potential transgressions in human oocyte procurement under the Bioethics and Biosafety Act of South Korea and the National Academies’ Guidelines for Human Stem Cell Research
Analysis of the Hwang Woo Suk case under the Bioethics and Biosafety Act of South Korea
Lack of informed consent
The lack of informed consent would have been in violation of Articles 5 and 9 of the Act. Pursuant to the principle of self-determination, Article 5 of the Act states that potential human subjects are entitled to full explanation of bioethical and safety issues that may arise from relevant biotechnology. Thus, the Act would require that the IVF clinics and research institutes provide to women who will undergo oocyte procurement all material information about bioethical and safety issues related to oocyte retrieval and future research uses of retrieved oocytes and cloned embryos created from retrieved oocytes.
The material information presumably includes possible negative ethical and medical consequences of ovarian hyperstimulation and oocyte donation to research using SCNT, and foreseeable future uses of their oocytes. In addition, to avoid the danger of the “misconception of therapeutic use,” potential donors must have been clearly informed that any oocytes they donated were not to be used for patients right now, but instead would be used for an experiment with a very low probability for any successful outcome .
The Act provides specific requirements in consenting to IVF. It requires the obtainment of informed consent from donors of gametes, the IVF patient and her spouse (the “Consenters”), when their surplus gametes or surplus embryos that were originally obtained or created for reproductive purpose are being used in research instead of being disposed. When obtaining written permission from the Consenters, the medical institute that will generate embryos for pregnancy should inform the Consenters about the purpose of generating embryos, the preservation period, storage and disposal of sperm, oocytes, and embryos generated in the institute, how to withdraw consent, the Consenters’ rights, the protection of the Consenters’ private information, and whether the Consenters would also consent to donate their gametes to research.
The Act has no prescription for the procurement or consenting process for SCNT, but it has a general prescription focused on IRB review under Article 9 of the Act discussed earlier. Thus, where women undergo ovarian hyperstimulation to donate their eggs to research employing SCNT, IRBs at research institutes designated to perform SCNT should review whether consent had been obtained with appropriate measures from all donors, whether the safety measures and the measures to protect personally identifiable information had been taken, and whether research protocol were ethically and scientifically valid. The Act imposes no additional requirements or higher standards for the consenting process where eggs are retrieved from donors in order to be used specifically for SCNT. Unlike the case of donating gametes to IVF or donating embryos created by using IVF to research, the Enforcement Guidelines of the Act would not have provided any standardized consent form.
Oocyte procurement from junior researchers for SCNT
Here, particular dangers include: (1) donation by junior researchers done involuntarily under undue influence or coercion and (2) inadequate protection of the donors’ personal information from disclosure to other team members.
The Act would not have mandated IRBs to find the oocyte donation by junior members of the research team prohibited per se because of potential undue influence and coercion. The Act would not have explicitly provided the detailed measures of how to safeguard personal information of women who undergo procurement for hESC research. It would not have required obtaining any authorization from those women for any transmission of specific health information. Instead, the Act would have mandated IRBs to review the consent process with junior researchers and the measures to safeguard their personal information. Thus, the IRBs should have determined whether the donation by junior researchers for SCNT had been done voluntarily or under undue influence or coercion. The IRBs also would have reviewed how Hwang’s team was proposing to safeguard the personal information of those researchers throughout the experiments and whether those researchers had been fully informed about the risk of disclosure of their personal information during the consent process.
It was possible for the junior researchers to donate their oocytes out of sheer altruism and patriotism. In fact, the Ph.D. student mentioned a desire to help sick children and her love for South Korea in her interview with Nature. Since Korean culture tends to place greater stress on serving the common good, this may partly explain her motivation. Students involved in such a project with great causes might want to donate their oocytes despite all the inconveniences and risks in undertaking the procedure, desiring to help sick patients and to demonstrate that South Korea is capable of world-leading research. At the same time, in the strict hierarchy of a scientific laboratory in a Confucian society like South Korea, junior members might often feel great pressure to please their superiors. In Confucianism, teachings of filial piety and respect for and obedience to elders, bosses, and teachers are central. Thus, the IRBs should have considered the whole set of circumstances, such as the culture of the laboratory, the nature of her relationship with the principal investigator or other colleagues, and evidence of any relevant financial or non-financial incentives or penalties. For example, the earning of a Ph.D. or getting help from the principal investigator in finding a job in exchange for her donation would be regarded as suspicious.
Considerations for oocyte procurement
The Act would have flatly banned providing or utilizing gametes that are procured for IVF in return for financial rewards, payment-in-kind, profit, or other considerations, as well as inducement or assistance to do such activities. Under the Act, gamete donors may donate surplus gametes that are no longer needed by couples being treated for infertility to research. However, the Act would have prohibited the provision or utilization of surplus gametes for research in return for any consideration. According to the standardized consent form that the Ministry of Health and Welfare is to provide to every relevant institute, the Consenters may not demand any material or monetary compensation for their donation and they relinquish their right to any profit that might be derived from the research. Surplus embryos must be supplied to research institutes for free.
In contrast, Articles 22 and 23 under the chapter titled “Cloned embryos created through SCNT” do not explicitly ban trading or compensation to donors of gametes or somatic cells, including women who undergo ovarian hyperstimulation, in the case of donating specifically to SCNT. No clauses in those Articles suggest Article 13(3) under the chapter titled “Embryos created through IVF” should be applied in SCNT as well as in IVF. However, according to the Ministry of Health and Welfare, Article 13(3) should be read as if it is applicable in any situation where eggs are provided or utilized, and, therefore, the Act prohibits oocyte trading for any purpose, including IVF and SCNT. Thus, the provision of monetary payment or a discount in medical fees for infertility treatment procedure by Hwang’s collaborators to women who underwent oocyte procurement would have been in violation of Article 13(3), which is punishable by up to two-year imprisonment or up to a 30,000,000 won ($24,000 U.S.) fine.
Even if providing monetary payment or payment-in-kind would not have been banned, the IRBs should have reviewed the consent process and considered whether there was any coercion by providing such considerations to women under economic duress under the Act. Moreover, economic duress would have made the oocyte procurement from those women in violation of the principle of self-determination declared in Article 5 of the Act.
The Ministry of Health and Welfare as well as each IRB at the eight institutions where Hwang’s research was performed could have insisted on establishing a recruitment and procurement system in order to make oocyte procurement more accountable and transparent.3 Under the Enforcement Guidelines of the Act, the IRB at an institution where SCNT is proposed should review the research proposal, which must include specific methodology for the research. Moreover, the ministry is also required to review the SCNT research proposal before granting the license to generate and study cloned embryos, and the research proposal must include the estimated number of oocytes that will be used for the research. Thus, the ministry and each IRB at the eight institutions should have independently reviewed Hwang’s research proposal for how he was planning to secure enough number of human oocytes in order to generate cloned embryos.
Although the Act leaves no room for debate, it has been debated whether the oocyte procurement in return for financial rewards or other consideration is ethically acceptable. Some scientists have called for payment for human oocytes to stimulate nuclear transfer research . It has been argued that society should recognize women’s labor of ova extraction as a Lockean property and provide proper protection over women from whom ova are taken for SCNT . Some commentators have opposed such payment based on either documented cases of exploitation of disadvantaged women , or the argument that women without power will more likely be exploited when the bioethicists attempt to ensure that those women have no rights once an informed consent has been given . Moreover, a commentator has called for an international moratorium on oocyte procurement for SCNT because of the risks to women undergoing such procurement and concerns related to such procurement, which include conflicts of interest, misleading language, and exploitation of young women .
Conflicts of interest and substandard care
The Act would not have prevented the obstetrician-gynecologists who procured oocytes from participating in the research as co-authors. However, pursuant to the principle of self-determination declared in Article 5 of the Act, the medical providers performing the retrieval procedure at the IVF clinics should have disclosed to the donors the providers’ research and financial interests in the experiments for which procured oocytes were provided. For example, an obstetrician working for one of Hwang’s collaborators should have informed women that underwent the procedure that he or she was retrieving oocytes to be supposedly used for his or her employer’s research. Moreover, the IRBs at four institutions where Hwang’s clinician-collaborators procured oocytes for the research could have made extraordinary efforts to avoid potential institutional conflicts of interests when reviewing the proposal.4
Although the Act mandates the IRBs at the relevant institutes to review the safety measures, it is unclear whether the donors are entitled to the standards of clinical care under the Act. Pursuant to the 2008 Amended Act, an institute that intends to create embryos has a duty to give a potential oocyte donor a medical check-up prior to the oocyte retrieval procedure. The number of retrieval procedures per donor is also limited under the Amended Act. However, the Act, including its enforcement decrees and enforcement guidelines, makes no comment on the applicable standards of care for the donors. Therefore, the Act would not have provided any legal recourse against substandard care provided to women who underwent oocyte procurement for SCNT.
Analysis of the Hwang Woo Suk case under the National Academies’ Guidelines for Human Stem Cell Research
In all the situations described below, the National Academies’ Guidelines would have required the review and approval of Hwang’s research proposal, which intended to create new hESC lines by employing SCNT from both IRB and ESCRO committees. Initially, an IRB should have reviewed whether oocytes were obtained after voluntary and informed consent had been obtained through a process ensuring minimized risks. Once an IRB had approved the procurement procedure for Hwang’s research, further research with the derived hESC line would not have needed additional IRB review unless the cell line was used in violation of the principle of privacy protection, and the ESCRO committee should have ensured adherence to the basic ethical and legal principles of informed consent and protection of confidentiality by documenting evidence that the procurement process of human embryonic stem cells was approved by an IRB.
Lack of informed consent
Under the Guidelines, the IRBs most likely would not have waived the requirement for obtaining voluntary informed consent from any person whose oocytes were used in hESC research. During the consent process, potential oocyte providers for hESC research should have been informed about the risks involved, all options concerning the handling and usage of their blastocysts, and the array of future research uses. Written informed consent should have been secured from all oocyte providers.
The informed consent would have been evaluated during the consenting process using the comprehensive list of obligatory information stipulated by the Guidelines. For example, if a donor had not been told that her oocytes were used to derive human embryonic stem cells, as an egg donor for Hwang’s research claimed, it would have been a clear violation of the principle of informed consent promoted by the Guidelines. The health risks involved in oocyte retrieval, such as serious discomfort and complications, including death, must have been provided to all women who underwent retrieval.
Oocyte procurement from junior researchers
Regarding oocyte procurement from junior researchers, the Guidelines would have held the research team and the research institution to a higher standard in order to protect the autonomy and privacy of those junior researchers. Such procurement could have been considered an ethical breach under the Guidelines since those junior researchers were supposed to have no possibility of medical benefit from the hESC research, and one of them, a Ph.D. student, might have felt pressured or coerced to donate eggs. The identity or other private information of those researchers could have been disclosed easily to other team members conducting the experiments using their oocytes, for instance, through re-identification. Thus, the Guidelines would have required telling the donors that neither consenting nor refusing to donate eggs for research would affect the evaluation of their professional performance, the determination of authorship, or future recommendations for jobs. The Guidelines also would have mandated informing the junior researchers that the identities of the donors were readily ascertainable to those who derive or work with the resulting hESC lines.
Furthermore, pursuant to federal human subject protection for donors of gametes as well as medical privacy protection that applies through the Health Insurance Portability and Accountability Act (HIPPA), authorization should have been obtained from donors for any use, disclosure, and transmission of protected health information by health care providers. The donation by any member of the research team would have been in clear violation of the principle of privacy protection if the identity or other private information of donors would be eventually known to the team during the experiments using their oocytes.
Considerations for oocyte procurement
The Guidelines would have allowed the reimbursement of women who undergo hormonal induction to generate oocytes specifically for research purposes such as for SCNT only for direct expenses incurred as a result of the procedure as determined by an IRB.5 According to the 2008 Amended Guidelines, direct expenses may include costs associated with travel, housing, childcare, medical care, health insurance, and actual lost wages. Thus, if the IRB had determined a payment of or a discount in medical fees of $1,400, for example, to each donor as the reimbursement of direct expenses, such a payment would not have been prohibited.
In contrast, financial and non-financial incentives should have been avoided in the solicitation for donation under the Guidelines. A potential donor should not have been coerced by anticipated monetary payment. A potential donor who was about to undergo infertility treatment procedures should not have been influenced by anticipated personal medical benefits or concerns about the quality of later care. Thus, oocyte procurement from women under economic duress would have been frowned upon. Also, the potential donor should have been specifically told that there was no obligation to donate and no personal benefit or penalty resulting from her decision.
Conflicts of interest and substandard care
The fact that an attending physician who performed the retrieval procedure was either a co-author of the report or an employee of Hwang’s collaborator would have been frowned upon under the Guidelines. The Guidelines specifically recommend that the attending physician responsible for the infertility treatment and the investigator deriving or proposing to use human embryonic stem cells should not be the same person whenever this is practicable.
Under the Guidelines, clinical staff should have provided appropriate care to patients regardless of their decisions about their oocytes. Researchers should not have pressured the clinical staff to generate more oocytes than necessary for the optimal chance of reproductive success. Payments should have been restricted to specifically defined cost-based reimbursements and payments for professional services in order to discourage the production of excess oocytes during routine infertility procedures if intended for later research.
Summary of case analysis
The analysis of potential four transgressions under the Act and Guideline can be summarized as follows. First, voluntary and informed consent would have been necessary under both the Act and the Guidelines. However, the Guidelines would have prescribed in detail the human oocyte donation procedure solely for the purpose of research while the Act would not have done so. The Guidelines would also have given ample opportunity for potential donors to form a more informed consent by recommending obtaining consent when the embryos were created from oocytes while the Act would not have given such an opportunity to all oocyte donors. Furthermore, the Guidelines would have obligated the ESCRO committee to review and document the provenance and procurement procedures of the hESC lines derived outside of the institute. Second, regarding the potential coercion and privacy issues arising from oocyte procurement from junior researchers, both regimes would have depended upon IRB review on the voluntary informed consent process and measures to protect private information obtained. Under the US regime, federal regulations and laws would have been additionally implemented to protect private information. Third, South Korean bioethics law flatly prohibits oocyte procurement for payment of any kind while the US Guidelines would have allowed payment as long as it could be considered as direct reimbursement for expenses rather than an incentive. Finally, the South Korean regime would not have prevented a conflict of duties and, consequently, the potential for substandard care. In contrast, the U.S. regime would have prevented such situations by recommending that the physician and the researcher should not be the same person, whenever practicable, and by obligating adherence to the standards of clinical care of patients and donors at IVF clinics. For these reasons, the National Academies Guidelines would have provided much more vigorous protection for women who undergo oocyte retrieval than the Bioethics and Biosafety Act.
Further mechanisms to protect oocyte providers for hESC research
Based on the case analysis described above, further protection for women undergoing oocyte retrieval for SCNT can be achieved in South Korea through the following mechanisms: (1) more engagement by the Ministry of Health and Welfare; (2) the recognition of the doctor–patient relationship between a medical provider performing the oocyte retrieval procedure and an oocyte donor undergoing the retrieval procedure; and (3) the promotion of professional ethics among physician-researchers.
Active engagement by the Ministry of Health and Welfare
The Ministry of Health and Welfare in South Korea would be in the best position to integrate the oversight from all levels. The ministry is responsible for the operation of the National Bioethics Committee and for the enforcement of almost all provisions at the institutions involved in hESC research. As mentioned earlier, individual research proposals that intend to use surplus embryos or SCNT should be eventually approved by the Minister of Health and Welfare.
In executing its oversight at the institutional level, the ministry needs to be more engaged and creative in order to ensure substantive compliance by the institutes on-site. Hwang’s case clearly shows that the ministry cannot rely on documents submitted by the IRBs. Moreover, the ministry needs to take over the functions performed by the ESCRO committees in the United States. Therefore, the ministry must be capable to evaluate the de novo scientific and ethical validity of research proposals whenever warranted. It must be able to enforce substantive compliance at the institutional level. The ministry also should be able to implement a mechanism to make researchers and research institutes accountable for the provenance and procurement procedures of all hESC lines that they propose to use.
Recognition of the doctor–patient relationship
The relationship between a medical provider performing oocyte retrieval and a woman undergoing the retrieval procedure for any purpose should be recognized as a doctor–patient relationship to safeguard the woman from medical and non-medical harm. Currently, the doctor–patient relationship is instantly recognizable in oocyte procurement for infertility treatment, but not for research purposes. Under the doctor–patient relationship, the ethical obligation of a medical provider is primarily to the woman undergoing the procedure. Under such relationship, the provider is obliged to refrain from divulging confidential information, to become the patient’s advocate in all health-related matters, and to be held to the standard of clinical care. Such a fiduciary relationship is precisely the kind of relationship necessary for women who undergo oocyte procurement for SCNT to protect their physical integrity and privacy.
Promotion of professional ethics among physician-researchers
All co-authors are collectively responsible for the scientific and ethical validity of the research. The three co-authors of the 2004 Science article and at least eight co-authors of the 2005 Science article were practicing physicians in South Korea. Those physician-collaborators are additionally subject to professional ethical codes.6 Thus, they would have prevented the potential transgression discussed above by not breaching their duties toward people in their professional care. Even the physician-co-authors, who were never directly involved in oocyte procurement, would have questioned the provenance of more than 2,000 oocytes and would have tried to ensure the oocyte providers’ well-being since they would have understood perfectly well the inconveniences, discomfort, and risks associated with the oocyte retrieval procedure.
The comparison between the South Korea Bioethics Law and US Guidelines revealed that the Bioethics and Biosafety Act in South Korea would institute centralized oversight on hESC research by the Ministry of Health and Welfare; the National Academies recommend decentralized, politically-independent oversight bodies, including a special review body for hESC research, to be established at each institution. The analysis of the Hwang Woo Suk case under both regimes revealed that the National Academies Guidelines would have provided more protection for the women who had undergone oocyte procurement than the Bioethics and Biosafety Act. Additional means of protecting oocyte providers for hESC research were suggested.
The Summary of the Final Report on Professor Woo Suk Hwang’s Research Allegations by Seoul National University Investigation Committee states, “Regarding the article in 2004, Professor Hwang claimed to have been unaware of the egg donation by the laboratory members. However, the graduate student who donated eggs informed the committee that the act of donation, while voluntary, was approved by Professor Hwang. Egg aspiration was carried out by Dr. Sung Il Roh on March 10 of 2003 at MizMedi Hospital, and notably, Professor Hwang accompanied the student to the hospital himself. In May of 2003, Professor Hwang’s research team circulated a form asking consent for voluntary egg donation and collected signatures from female technicians. This information is based on the testimony provided by eight current and former lab members” .
“One of his collaborators admitted that he had paid at least 21 Korean women about $1,400 apiece for their oocytes” . “Through egg-brokers, 63 women underwent 75 oocyte procurements at MizMedi Hospital and 22 women underwent 25 procurements at Hanna Women’s Clinic” .
These eight institutions are as follows: Seoul National University College of Veterinary Medicine and School of Agricultural Biotechnology, MizMedi Hospital Medical Research Center, Gachon Medical School, Seoul National University School of Medicine, Hanyang University School of Medicine, Sunchon National University College of Natural Science, and Hanna Women’s Clinic.
These four institutions are as follows: MizMedi Hospital, Hanyang University, and Hanna Women’s Clinic MizMedi Hospital, Hanyang University, and Hanna Women’s Clinic.
The Guidelines recommend that no payment, cash or payment-in-kind, may be provided for donating sperm, oocytes, somatic cells, and blastocysts in excess of the clinical need for research purposes. Focusing on hESC research, the Guidelines do not take any position on whether financial or non-financial compensation may be provided for donating gametes or blastocysts for IVF.
Professor Sang Ik Hwang at Seoul National University says the use of traded oocytes by Hwang’s team for its research was a clear breach of ethical medical conduct on the part of Hwang’s physician-collaborator under the Korean Medical Association’s two Guidelines . According to him, Article 8(2) of the Guidelines on Life Cloning Experiments declared in 1999 provides that “life cloning researchers may not be involved in the trading of sperm, eggs, or somatic cells under any circumstances.” Additionally, Article 69 of the Guidelines of Ethics for the Medical Profession declared in 2001 provides that “medical doctors may not exploit the socio-economically vulnerable population because of poverty…by subjecting them to medical research, unless approved otherwise” .