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Heritable Human Genome Editing (2020)

Chapter: 5 National and International Governance of Heritable Human Genome Editing

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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"5 National and International Governance of Heritable Human Genome Editing." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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5 National and International Governance of Heritable Human Genome Editing A responsible translational pathway toward potential clinical uses of heritable human genome editing (HHGE) requires that national and international governance foundations be in place prior to any clinical use. Chapter 5 discusses the elements that would need to be part of such systems. This chapter begins by discussing how HHGE intersects with, and poses challenges for, current oversight systems for medical technologies. The chapter then describes the mechanisms that a country would need to establish to ensure responsible oversight of any future clinical uses of HHGE. Finally, the chapter emphasizes the need for international coordination around developments that affect HHGE. The chapter does not delve into detail on how national and international governance systems for HHGE would ultimately be implemented by countries and by the international community—ongoing dialogues including the work of the World Health Organization’s expert advisory panel are exploring this area in greater depth. However, this chapter concludes with recommendations for core components of these efforts. A RESPONSIBLE GOVERNANCE SYSTEM FOR HERITABLE HUMAN GENOME EDITING HHGE would entail a form of assisted reproductive technology used to generate an embryo with an altered genome with a view to establishing a pregnancy. A governance system for the use of HHGE would need to include the ability to oversee all stages of the translational pathway described in Chapter 4. These stages include basic and preclinical research to develop methodologies for HHGE that can sufficiently control and characterize the effects of genome editing; national legislative, advisory, and regulatory decision-making charged with determining whether a clinical use of HHGE could be considered; and evaluation of outcomes resulting from any clinical use of a genome-edited embryo to establish a pregnancy. Considerations for Societal and Stakeholder Engagement on Heritable Human Genome Editing PREPUBLICATION COPY | UNCORRECTED PROOFS 148

Prior to the clinical use of HHGE in any country, one important requirement is for public engagement on whether it would be acceptable to use HHGE in that country, and, if so, for what purposes and with what governance mechanisms. Genome editing in human embryos should not proceed past preclinical laboratory research unless it is deemed acceptable by a country and unless there are approvals by the relevant bodies to consider it for potential clinical use. The question of precisely how such discussions should proceed was beyond this Commission’s charge; however, presentations and submissions to the Commission’s call for evidence emphasized a number of additional points to inform future deliberations (see Box 5-1). Box 5-1 Societal Considerations to Inform Future Discussions about HHGE* Engagement with Genetic Disease, Disability, and Minority Communities • It is critical to engage directly with people who have conditions that might be considered for HHGE. Views on HHGE among genetic disease and disability community members differ. Attitudes reported in a 2016 consultation by Genetic Alliance U.K. ranged from welcoming the potential ability to eradicate a condition to serious reservations, and the view that a genetic condition is a fundamental part of the person’s identity.** Communities expressing concerns include the deaf community and the autism community. Many submissions to the Commission’s call for evidence emphasized that any demand for HHGE must come from communities of people who are living with the particular condition under consideration. • It is critical to recognize historical experiences with stigmatization and eugenic practices concerning disease and disability. Concerns expressed by respondents over any use of HHGE included that it will “undermin[e] the equality of value and worth of all human persons in society”. Other concerns expressed included that the development of HHGE could reduce the accommodations a country provides to people having genetic conditions. • It is critical to engage with other communities whose voices have not always been considered in medical decisions, including minority and indigenous communities. For example, the incidence of sickle cell disease in the African American community is substantially higher than in the U.S. population overall. It would be technically possible to consider HHGE to prevent inheritance of sickle cell disease, but past unethical and abusive medical conduct has left a legacy of mistrust of the medical establishment for this community. It would be essential to extensively and systematically engage with and incorporate input from African Americans before advancing toward any clinical use of HHGE for sickle cell disease. Engagement with Civil Society PREPUBLICATION COPY | UNCORRECTED PROOFS 149

• A need for discourse among civil society about human genome editing. As stated by one respondent, “society must have the opportunity to shape the way in which the science develops.” There are diverse levels of understanding about the meaning of scientific terms such as “genome,” “somatic cell,” and “germline;” what types of genome editing uses are currently being developed; and how HHGE would be undertaken should it be permitted. As a result, there is a role for education to underpin informed public consultations. • A need to include an expansive array of topics in societal discussions of HHGE. The focus of public engagement and civil society discussions will need to be on more than scientific and clinical dimensions and will need to include diverse voices as well as expert input from the humanities, social sciences, ethics, and faith communities. Issues that will need to be debated by a country include the potential for HHGE to prevent disease transmission, the implications of HHGE for exacerbating inequities and social justice concerns, the value placed on genetic relatedness of a child or on parental freedom to pursue reproductive preferences, potential social and psychological consequences for parents, children and the wider family, privacy considerations, and others. Some respondents stated that HHGE had no possible path to legitimate use, while others could envision its use in certain circumstances, and still others noted that it currently conflicts with existing laws and international treaties. All of these issues will need to be openly debated by a given country. • A need to develop and support processes by which societal discourse can be undertaken. This would include how to undertake societal engagement, how to engage diverse views, and how to support and sustain such efforts at national and international levels. It would be valuable to draw on expertise from the social sciences to develop effective engagement strategies. • A need for transparency and accountability associated with the development and potential use of HHGE. Transparency can give legitimacy to decisions about HHGE and would include making available information on what evidence exists on the safety and efficacy of HHGE technologies, how (and by whom) this evidence is assessed and how (and by whom) decisions are made about whether HHGE could be undertaken, and the outcomes of any clinical use of HHGE. This information needs to be regularly updated. _________ * The information in this box is based on submissions to the Commission’s call for input and presentations and comments during public information-gathering sessions. ** See https://geneticalliance.org.uk/wp-content/uploads/2016/05/nerri_finalreport15112016.pdf. HERITABLE EDITING IN THE CONTEXT OF CURRENT REGULATORY SYSTEMS A governance system for HHGE would share similarities with the oversight structures that currently guide appropriate conduct in other areas of biomedical research and clinical practice. Because HHGE entails the use of genome editing technologies as a form of assisted PREPUBLICATION COPY | UNCORRECTED PROOFS 150

reproduction to enable prospective parents to have a child with an altered genome, it shares some characteristics with existing oversight systems in both somatic gene therapies and assisted reproductive technologies (ARTs). However, the clinical use of HHGE would also pose challenges to current systems. How Heritable Human Genome Editing Would Relate to the Regulation of Gene Therapies Many somatic cell gene therapies currently undergoing clinical development rely on using genome editing technologies. Somatic cell gene therapies have a history of highly regulated oversight in the countries in which they have been carried out, including the United States, Japan, China, India, and countries in Europe. In the United States, the European Union, and China, for example, somatic genome editing is regulated primarily using the frameworks established for prior generations of gene therapies (NASEM, 2017). A number of clinical trials based on somatic genome editing have been initiated in the United States. The regulatory process involves the institutional reviews required for human clinical trials as well as additional institutional oversight by biosafety committees and federal review. Federal oversight includes requirements for prospective approval from the national regulatory authority, the U.S. Food and Drug Administration, via an Investigational New Drug license or its equivalent. Once clinical trials commence, centralized reporting of adverse events and longitudinal data collected during the clinical trial phases are required for submission of an application to the Food and Drug Administration for approval as a therapeutic to be marketed in a clinical context. Other countries have similar regulatory systems intended to ensure the safety and efficacy of somatic gene therapies tested or approved for use in humans. Regional organizations, such as the European Medicines Agency, promote the development of scientific guidelines in areas such as gene and cell therapy products, and there are other ongoing international dialogues aimed at improving the consistency of somatic gene therapy regulations. 29 In addition, countries including Chile, Colombia, Mexico, and Panama have incorporated explicit prohibitions on the use of somatic genome editing for purposes that might be perceived as enhancement (Abou-El-Enein et al., 2017; NASEM, 2017). While somatic genome editing shares a similarity with heritable 29 See http://www.iprp.global/working-group/gene-therapy. PREPUBLICATION COPY | UNCORRECTED PROOFS 151

genome editing in that both types of uses rely on genome-editing technologies, there are important differences that challenge the applicability of its regulatory frameworks to HHGE. Somatic therapies fit within an oversight paradigm in which medical interventions are developed and deployed to treat an existing patient with a genetic condition. The effects of the editing are limited to that individual’s cells and tissues and are not inheritable, and the largely individual-level harms and benefits can be assessed and explained as part of gaining informed consent. HHGE, on the other hand, provides a reproductive option for prospective parents to have a potential future child without transmitting a disease-causing genotype. The heritable genomic alteration and the potential harms, benefits, and uncertainties that arise may affect not only that child, but also any offspring of that child, raising societal concerns and leading to effects that may not be apparent until subsequent generations. How Heritable Human Genome Editing Would Relate to the Existing Regulation of Assisted Reproductive Technologies As noted above, HGGE would constitute a form of assisted reproductive technology, and ARTs have a very different history of regulatory oversight from that of somatic gene therapies. Laws regarding the use of ART vary substantially among countries. While there are important lessons to be gleaned from such regulatory experiences (Cohen et al., 2020), this variation will make it difficult to achieve coordinated oversight of HGGE using current ART regulatory systems. A survey conducted in 2018 by the International Federation of Fertility Societies, that spanned 89 of the 132 countries believed to be offering ART, found that 64 percent of countries that responded to the survey had legislation regulating the use of these technologies, with a focus on licensing clinics, physicians, and laboratories. Penalties for violating regulations ranged from admonishment to imprisonment, with the most frequently used sanctions reportedly being financial penalties, loss of license, and threat of criminal prosecution (IFFS, 2019). One of the ARTs most relevant to the discussion of HHGE is preimplantation genetic testing (PGT), in which cells removed from an early embryo created through in vitro fertilization (IVF) are genetically analyzed and only embryos having specified genotypes are transferred to establish a pregnancy. The majority of countries responding to the International Federation of PREPUBLICATION COPY | UNCORRECTED PROOFS 152

Fertility Societies survey reported that they allow PGT for prevention of monogenic disease. These countries were split almost equally with respect to whether laws or regulations permitting the use of PGT were accompanied by further guidelines restricting how it could be used. Research analyzing national approaches to the use of PGT found that they were typically based on the seriousness of a condition (Isasi, Kleiderman, and Knoppers, 2016). For example, Mexican legislation prohibits PGT for any purpose other than “the elimination or reduction of serious diseases or defects,” while other countries require a “substantial risk” of the disease occurring or that the disease is “untreatable” or “incurable” (Isasi, Kleiderman, and Knoppers, 2016). The United Kingdom is an example of a country that utilizes “seriousness” in its evaluation of PGT applications and where the use of IVF with PGT is permitted only to prevent specific genetic conditions that have been approved by the Human Fertilisation and Embryology Authority. Its list of permitted conditions now totals more than 600 and includes the use of PGT to select an embryo that is immunologically matched to a sibling with a disease (savior sibling PGT). 30 In France, only couples at high risk of having a child affected by a “particularly serious and not curable” genetic disease are allowed to use PGT under the national public health code, with oversight by the country’s biomedical agency (Agence de la Biomédecine). Requests for PGT are evaluated on a case-by-case basis rather than against a list of allowed uses. A review committee at each major reproductive medicine center evaluates the requested use and reports annually to the Biomedical Agency on its decisions. This enables retrospective analysis of the criteria by which such requests are judged, which take account of factors such as risk of disease, anticipated disease manifestation, and family medical history. In China, regulations on ARTs were published by the Ministry of Health in 2001 and were amended in 2003 into a document titled “Technical Standards, Basic Requirements, and Ethical Principles on Human ARTs and Related Technologies and Human Sperm Bank.” Any medical institutions permitted to carry out human ARTs are required to meet these regulations and standards and to obtain an approval certificate from the Ministry of Health. Medical institutions offering these technologies are required by law to have ethics committees, which review certain proposed methods or some specific cases. PGT has been used for those couples that are at high risk of having a child with single-gene disease, chromosome disorders, or sex-linked genetic disease, but it is not allowed 30 See https://www.hfea.gov.uk/treatments/embryo-testing-and-treatments-for-disease/approved-pgd-and-ptt- conditions/. PREPUBLICATION COPY | UNCORRECTED PROOFS 153

for sex selection. In the United States, assisted reproductive technologies are offered in the context of the practice of clinical medicine without a requirement for regulatory approval. There are no federal restrictions on the conditions for which PGT can be used. Instead, PGT use is guided by any state laws that may restrict uses, professional guidelines, and the choices of clinicians and prospective parents (Bayefsky 2016, 2018). Mitochondrial replacement techniques (MRT) represent a novel form of ART, which are currently permitted for clinical use in the United Kingdom. The approach taken by the United Kingdom to develop a translational pathway and oversight regime for this technology can provide an informative model to help guide the development of national oversight systems relevant to HHGE. As described in Chapter 1, the characteristics include a controlled step-wise process under the auspices of appropriate national regulators; limitation to cases involving parents wishing to have a genetically-related child unaffected by serious disease; limited licensure to use in single cases rather than blanket approval, with ongoing review before subsequent licenses are issued; a comprehensive informed consent process; long-term follow up of offspring and prohibition of uses beyond the permitted indication. Lessons Applicable to the Creation of an Oversight System for Heritable Human Genome Editing As with other medical technologies, an oversight system for HHGE would need to address all stages of a research and clinical translation pathway. Because multiple actors contribute to any translational pathway, responsibilities at individual, institutional, national, and international levels will be required. Investigators and clinicians will need to adhere to relevant norms, guidelines, standards, and policies. For example, these may include or draw on policies developed for governance of gene therapies and for governance of assisted reproductive technologies. Well-specified processes will need to be established for institutional boards to review clinical use protocols, including appropriate protections for participants. Prior to the initiation of any clinical use, approvals will be required from relevant national advisory bodies and national regulatory authorities that assess the context of proposed use, preclinical evidence, clinical protocols, and plans for follow up. Processes will need to be implemented for national and international discussion, coordination, and sharing of results on relevant scientific, ethical, PREPUBLICATION COPY | UNCORRECTED PROOFS 154

and societal developments impacting the assessment of HHGE’s safety, efficacy, and societal acceptability (see Box 5-2). Box 5-2 Experience Conducting Independent Assessments of Safety and Efficacy of Mitochondrial Replacement Techniques The pathway toward clinical use of mitochondrial replacement techniques (MRT) in the United Kingdom included detailed assessments in 2011, 2013, 2014, and 2016 of the state of the science and preclinical evidence on safety and efficacy (HFEA 2011, 2013, 2014, 2016). This experience, described below, can inform the creation of systems for regular reviews of developments relevant to HHGE. As can be seen from the chronology, multiple reviews were undertaken as knowledge progressed, with evidence requested by one panel being generated by the scientific community and reviewed by a subsequent panel. The latest evidence on preclinical safety and efficacy also informed recommendations on which patients might be considered for initial human uses and what types of clinical follow-up and outcome assessments should be undertaken. The MRT Scientific Assessments Over the course of four scientific reviews, expert panels examined preclinical data on the use of MRT in model organisms and in human research embryos, scrutinizing both published and unpublished data. One of the key issues evaluated was the ability to produce animals using MRT that had normal development and adult health, and in which mitochondria were predominantly derived from the donor egg. Pronuclear transfer had been used in mice successfully since the 1980s, and mouse experiments allowed an examination of the degree of genetic distance between the donor’s and mother’s mitochondrial DNA (mtDNA) haplotypes that could be safely tolerated. Experiments in macaques using maternal spindle transfer were also successful; offspring lacked detectable maternal mtDNA and were healthy at the time of reporting. The 2016 panel also reviewed a limited amount of clinical data, most of which were unpublished. A report at the time of the review indicated that a baby had been born in Mexico following MRT. This suggested that MRT could be used to generate a healthy child but in the absence of full details (scientific and clinical) being made available, the panel was reluctant to rely on such data. Crucial pre-clinical data came from human embryos that were generated using pronuclear transfer and maternal spindle transfer by different groups. The carryover of mtDNA from the mother’s egg was usually very low and embryos had developmental parameters that were comparable with control embryos (using measures such as fertilization rates and the proportion forming blastocysts). Transcript profiling suggested that the embryos generated through MRT and control embryos had comparable gene expression. The expert panels prior to 2016 determined that it would be useful to examine the proportion of carried-over mtDNA in embryonic stem cells (ES cells) derived from such embryos in order to model the post-implantation embryo when mtDNA replication may be a factor. Three research groups independently observed that levels of carried-over mtDNA could elevate after extended ES cell passaging in vitro and come to predominate in around 20 percent of the cultures—a phenomenon called reversion. These data were important in the panel’s cautious approach to introducing the PREPUBLICATION COPY | UNCORRECTED PROOFS 155

technique into the clinic. It was recommended that only women with consistently high levels of pathogenic mtDNA in their oocytes—for whom preimplantation genetic testing would likely not be successful—should be eligible for treatment when considering potential benefits and harms. Moreover, it was recommended that women be offered pre-natal testing to assess mtDNA levels in the fetus to check for the possibility of reversion in vivo. Similarly, there had been, and still are, concerns about the possibility of functional mismatch between the mother’s nuclear genome and the donor’s mtDNA. At the time of review, there was no direct evidence for this. But the panel recommended that mtDNA haplotype matching be considered to mitigate any risk because what would be undertaken represented first-in-human uses of the technology and data were scarce. Legal and Regulatory Frameworks The legal and regulatory status of HHGE varies considerably among countries. HHGE is currently prohibited by law in dozens of countries including many in Europe as well as the United States, where federal budget provisions currently prevent the US Food and Drug Administration from considering any application for clinical use of HHGE (Kaiser, 2019). Any clinical use of HHGE in these countries would require changes to the relevant legislation. All countries in which HHGE research and clinical applications may be pursued will need regulatory mechanisms to oversee use of HHGE and impose sanctions where appropriate, as well as a clearly communicated way for concerns about possible violations of regulations to be reported. Because HHGE would be deployed within an existing culture of in vitro fertilization and assisted reproductive technology clinics, it will be important to engage with this community on the issues posed by HHGE prior to any clinical uses. However, relying on professional conduct guidelines and self-regulation for an emerging and controversial technology such as HHGE may be insufficient. At a minimum, laws or regulations incorporating penalties for any unauthorized use of HHGE should be considered in countries that do not currently have them. Each country that considers the development of HHGE will end up drawing on the regulatory infrastructure and oversight authorities available under its laws and regulations. For a country such as the United Kingdom, the Human Fertilisation and Embryology Act could be further amended to permit HHGE, as it was in 2008 to enable the Authority to evaluate applications for MRT. If the U.S. government were to decide to permit clinical use of HHGE, it would also need to consider whether the U.S. Food and Drug Administration or other state and federal regulatory bodies need additional authorities to oversee the practice of assisted reproductive medicine, since HHGE would take place in ART clinics. Other countries may PREPUBLICATION COPY | UNCORRECTED PROOFS 156

similarly need to wrestle with how HHGE could fit within or challenge national medical oversight systems and determine whether they need to create new oversight paradigms or whether existing oversight mechanisms could be modified to sufficiently address the oversight needs for HHGE. REQUIREMENTS FOR NATIONAL OVERSIGHT SYSTEMS FOR HERITABLE HUMAN GENOME EDITING Regardless of the details of the regulatory systems that a country may design for HHGE, national regulatory authorities or their equivalents would need to establish the specific criteria that must be met for any translational application of HHGE to proceed in their jurisdictions. To address the characteristics for responsible governance of HHGE identified above, all countries in which it is being considered would need to have mechanisms in place to oversee translational progress toward potential clinical use of HHGE, to prevent unpermitted uses and to sanction any misconduct. The issues that will need to be addressed through national systems wherever HHGE is proposed to be undertaken include: • giving clear and unambiguous direction to researchers and clinicians about the legality of HHGE; • ensuring that researchers and clinicians adhere to norms of responsible science, including relevant human rights and bioethics principles (see Box 5-3) and applicable guidelines, standards, and policies; • providing transparency on any applications for HHGE under consideration; • providing transparency to the world community of any intention to allow an approved clinical use of HHGE; • creating clear processes and mechanisms for review, approval, and oversight of any initial human clinical uses of HHGE; • establishing mechanisms to circumscribe the clinical use of HHGE, including to limit and control any uses beyond the scope of a permitted indication; and • being responsive to international scientific consensus regarding the current state of HHGE technologies, especially in areas of safety and proposed uses, with the goal of coordinating protocols and sharing data to the maximum extent possible. PREPUBLICATION COPY | UNCORRECTED PROOFS 157

Box 5-3 Adherence to Human Rights and to Bioethical Principles Legally binding human rights and established human rights norms have been influential in framing the appropriate use of medical interventions.a Human rights language has long been conflated with biomedical ethics language, but their normative purpose and impact are different. Human rights are universal in their framing, although national translation in individual countries may incorporate cultural and religious differences. Human rights are legally actionable and belong to both individuals and collectivities. The language of policies and guidelines in biomedicine may use “rights” language, such as the “right of the child to an open future;” however, this is an ethical concept and not a legally recognized right of the child. The need to develop governance approaches to encompass HHGE provides a potential opportunity to use and develop the content of internationally recognized human rights to influence future laws, policies, and regulatory responses around HHGE. However, the possibility of using human rights to frame, delimit, or expand concepts such as the freedom to conduct scientific research, the right of everyone to benefit from scientific advances, the right of children to the highest attainable standard of health, or even the rights of future generations has not yet been discussed by international bodies deliberating on HHGE. The feasibility of charging existing international and national supervisory or regulatory bodies with oversight of such rights in this specific context remains to be determined. This is an area that could be further explored as one foundation for future HHGE governance and is an approach being explored by the WHO panel. A foundational aspect for any use of HHGE is consideration of bioethics principles. Since the establishment of the Nuremberg Code in 1947, the field of biomedical research has benefited from international ethical guidance responsive to scientific developments (WMA, 2013; UNESCO, 2015; CIOMS, 2016). These norms, while self-regulatory in nature, have been influential in prospectively addressing areas of public concern, such as deliberate interventions in the human germline. Different reports and organizations present and interpret bioethical principles in slightly different ways, but they share many common features (NASEM, 2019a). In its 2017 report on human genome editing, for example, the U.S. National Academies identified seven principles to guide the development of governance for human genome editing that reflect this set of norms: promoting wellbeing, transparency, due care, responsible science, respect for persons, fairness, and transnational cooperation (NASEM, 2017). The Nuffield Council on Bioethics, in its report on genome editing and human reproduction, stated that two “overarching principles” should guide the use of HHGE interventions for them be ethically acceptable: they “should be used only where the procedure is carried out in a manner and for a purpose that is intended to secure the welfare of and is consistent with the welfare of a person who may be born as a consequence of treatment using those cells”; and they “should be permitted only in circumstances in which it cannot reasonably be expected to produce or exacerbate social division or the unmitigated marginalization or disadvantage of groups within society” (NCB, 2018, p. xvii). The WHO’s Expert Advisory Panel on human genome editing has articulated six values, principles and goals for good governance of these technologies: “a. Clarity, transparency and accountability; b. Responsible stewardship of resources; c. Inclusiveness, solidarity, and the common good; d. Fairness, non-discrimination, and social justice; e. Respect for the intrinsic dignity of the person; and f. Enforcement capacity.”b PREPUBLICATION COPY | UNCORRECTED PROOFS 158

Because decision-making about HHGE is ultimately a function of individual jurisdictions, countries should only permit the use of HHGE if they have engaged in thorough scrutiny of how any proposed application conforms with the human rights and ethical principles discussed above. _________ a Notable legal human rights instruments with regard to HHGE are the Convention on the Rights of the Child (1989); the Convention on Human Rights and Biomedicine (Oviedo) (1997); and the Convention on the Rights of Persons with Disabilities (2006). b World Health Organization, Human Genome Editing: A DRAFT Framework for Governance, July 3, 2020. Available at: https://www.who.int/docs/default-source/ethics/governance-framework-for- human-genome-editing-2ndonlineconsult.pdf?ua=1. NEED FOR A SYSTEM OF GLOBAL COORDINATION AND COLLABORATION While countries have decision-making authority concerning the research toward, or clinical use of HHGE, it is critical to also have international scientific and ethical cooperation on HHGE. A translational pathway for HHGE therefore requires governance systems that extend beyond those of individual countries to enable transparent discussion about any approved clinical uses of HHGE and the resulting outcomes. This is because: • There is a collective interest of humanity in the use of a novel technology that can result in heritable changes to the human genome; • The research and clinical communities developing these technologies are global, and the technologies have implications beyond national borders; • Citizens from different countries seeking access to HHGE will travel to countries where it becomes available; and • Any initial uses of HHGE following the pathways described in this report would involve a small number of people, and it would be important to collect and compare information across national boundaries in order to more fully understand first-in-human safety and efficacy data and to promote common approaches. With respect to both biomedical research and clinical practice, in general, countries have framed licensing powers and accompanying professional duties within their legislation and regulations on health and their health systems, or through the creation of statutory oversight bodies, or, more rarely, via legislation on specific sectors or technologies. The approach varies PREPUBLICATION COPY | UNCORRECTED PROOFS 159

from country to country or it is defined in regional alliances. Any proposed mechanism for international governance of HHGE will need to provide for at least three functions: 1. An international scientific advisory panel to provide ongoing technical assessment and evaluation of developments in the science and technologies on which HHGE depends and to make recommendations about their suitability and readiness for particular clinical uses. 2. An international body for evaluating and making recommendations on crossing major thresholds associated with the clinical use of HHGE, based on consideration of a wide range of societal and scientific perspectives. In the current context, a threshold represents a boundary that distinguishes a currently accepted use from another that is not currently accepted. Before crossing any threshold, it will be important for the global community to assess not only progress in scientific research, but also what additional ethical and societal concerns the circumstances of particular uses could raise, as well as any results, successes, or concerns that had been observed from any human uses of HHGE that had been conducted thus far. 3. An international mechanism by which individuals or organizations in one country can bring forward technical or ethical concerns arising from HHGE work conducted in their own country or in another country. These necessary functions are explored below. An International Scientific Advisory Panel to Monitor and Assess Relevant Scientific and Clinical Developments As emphasized throughout the report, before any country should consider approving the clinical use of HHGE, further technical developments are essential. There is therefore a need for the ongoing technical assessment and evaluation of developments in the science and technologies on which HHGE depends, as well as making recommendations about their suitability and readiness for particular clinical uses. Multiple gaps in the ability to fully characterize such genome editing or assess its effects make it premature to use any HHGE approaches at the time of this writing, and articulating the essential characteristics of a translational pathway does not mean that a country should necessarily permit even initial clinical uses. PREPUBLICATION COPY | UNCORRECTED PROOFS 160

There is, therefore, a need for an international advisory body to regularly review the latest scientific evidence and to evaluate its potential impact on the feasibility of HHGE. The necessary functions of such scientific review include: • assessing or making recommendations on further research developments that would be required to reach technical or translational milestones as research on HHGE progresses; • providing information to national regulatory authorities or their equivalents to inform their own assessment and oversight efforts; • facilitating coordination or standardization of study designs to promote the ability to compare and pool data across studies and trans-nationally; • advising on specific measures to be used as part of the long-term follow up of any children born following HHGE; and • reviewing data on clinical outcomes from any regulated uses of HHGE and advising on the risks, benefits, and uncertainties of possible further applications. There are existing international activities that play a valuable role in contributing to the technical assessment of the science and technologies underlying HHGE. The two international summits on human genome editing convened by various scientific academies (including the U.S. National Academies of Sciences and Medicine, the U.K.’s Royal Society, the Chinese Academy and the Hong Kong Academy, and others) have brought together the scientific community for scientific presentations relevant to HHGE. A third summit is planned for 2021. Professional societies in science or medicine can also play a role in scientific review and standards development. In stem-cell research, the International Society for Stem Cell Research has an ongoing mechanism for the creation and revision of guidelines (ISSCR, 2016) for research and clinical practice in the stem cell field. In the ART field, the U.S. Society for Assisted Reproductive Technology (SART) provides access to data from IVF clinics for research and comparison, and is developing a standardized document for informed consent in collaboration with the American Association of Law Schools. 31 31 See www.sart.org. Recent SART clinic reports are available at https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2017 for 2017, and preliminary 2018 data at https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2018. PREPUBLICATION COPY | UNCORRECTED PROOFS 161

However, these activities are largely informal and ad hoc. The examples demonstrate that although existing structures and processes can fulfill some of the functions necessary, none do or can perform the collection of functions recommended for ongoing technical assessment and evaluation of the technologies foundational to HHGE. For this reason, the Commission recommends the creation of an International Scientific Advisory Panel (ISAP) that would provide regular scientific and technical assessments as part of the international governance efforts for heritable human genome editing described above. (Figure 5-1). An ISAP would need the endorsement of national governments to have the standing and influence required to perform these functions. It would also need to be flexible given the potential for rapid advances in areas of science that contribute to the feasibility of HHGE. The panel would need to convene regularly in person or virtually, likely at least once per year, with additional meetings and discussions as needed. To be most effective, such a panel would need to have diverse, multidisciplinary membership and include independent experts who can assess scientific evidence of safety and efficacy of both genome editing and associated assisted reproductive technologies. It should include international experts from multiple disciplines including genetics, genome editing, reproductive medicine, pediatric and adult medicine, bioethics, law, and other fields. This combination is similar to that for Data Safety and Monitoring Boards (DSMBs) or Data Monitoring Committees (DMCs) for large, often multi- site, clinical trials, which seek to ensure relevant expertise in clinical specialty areas, clinical trial methodologies and analysis, biostatistics, and often in the ethics of design, conduct, and interpretation of clinical trials. 32 Because the panel would be assessing evidence that could be used to support progress toward initial use of HHGE for serious monogenic diseases, the panel would also greatly benefit from including representatives of the public, such as members of genetic disease and disability communities. Existing national and international networks could be drawn on to identify members who could be nominated to such a panel. For example, national academies of sciences and medicine, the global network of science academies (the InterAcademy Partnership), national and international professional societies in relevant areas, genetic disease and disability communities, 32 See FDA guidance at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishment- and-operation-clinical-trial-data-monitoring-committees; and NIH guidelines at https://www.nidcr.nih.gov/research/human-subjects-research/toolkit-and-education-materials/interventional- studies/data-and-safety-monitoring-board-guidelines. PREPUBLICATION COPY | UNCORRECTED PROOFS 162

and scientific, medical, and technical experts in relevant government ministries might all serve to identify colleagues who are leaders in their disciplines and could bring the expertise and cooperative spirit required to this task. National and international discussions would be needed to agree on the panel’s terms of reference, its convener, and how its activities would be funded. The Commission is not wed to any particular body or organization for establishing an ISAP, but emphasizes its recommendation that any translational pathway toward HHGE requires establishing a systematic and rigorous way to fulfill the five functions described above in order to enable independent expert review of scientific and clinical evidence to inform national and international governance. Advances in areas of science relevant to HHGE, as well as in the practice of in vitro fertilization and preimplantation genetic testing, will have implications for whether the translational pathway criteria specified in Chapter 4 can be met. As this pathway was developed for the very first possible uses of HHGE considering the current state of science, it will be important to be open to scientific developments that could alter the methodologies employed to meet the requirements. It will also be important to assess evidence gained from further basic research and preclinical testing and from any future initial human uses. The Commission strongly believes that successfully carrying out these functions requires more than the current informal and ad hoc systems. PREPUBLICATION COPY | UNCORRECTED PROOFS 163

Figure 5-1. An International Scientific Advisory Panel (ISAP) would provide regular, independent assessments along the clinical translational pathway, as envisioned in Chapter 4, toward HHGE for certain circumstances of serious monogenic diseases. These assessments would include reviewing advances in preclinical research, providing advice on whether sufficient methodologies to support evaluating a proposed use had been developed, informing the deliberations of a country’s own advisory or regulatory bodies if requested, and analyzing the outcomes of any permitted clinical uses of HHGE. International Body for Evaluating and Making Recommendations before Crossing Heritable Human Genome Editing Thresholds PREPUBLICATION COPY | UNCORRECTED PROOFS 164

This report has categorized possible clinical uses of HHGE according to the assessment of the potential harms and benefits they present, with a focus on initial clinical uses. However, decisions about whether to allow HHGE, and, if so, for what purposes, should be based on a wider set of considerations than just scientific assessments. Initial human use of HHGE beyond preclinical development represents a decision that should be based on science, ethics, and societal implications. It will be important for countries to engage in discussions about when, if ever, it is acceptable to move forward with HHGE within their countries and, if so, where to set thresholds on allowable uses. Subsequent decisions about whether to cross additional thresholds to allow further uses of HHGE will similarly require transparent international discussions convened by an institution responsible for ensuring that these discussions are held regularly and that they engage a diversity of viewpoints (Figure 5-2). There is already a range of international bodies whose responsibilities include convening international discussions on the development and regulation of medical technologies. Organisations such as the World Health Organisation (WHO), the Organisation for Economic Cooperation and Development (OECD), and the United Nations Educational, Scientific and Cultural Organization (UNESCO), for example, all have the requisite experience that could enable an inclusive and transparent debate about whether and how to proceed with HHGE. Other organizations could also be selected for this purpose. Regardless of where housed or how structured, this international body would need a wide range of perspectives, including from (i) stakeholder communities that could be affected by future uses of HHGE, such as members of disability and disease communities; (ii) scientific fields, including medicine and social sciences; and (iii) law, ethics and regulation. This should include experts from countries where there are communities that have increased incidence of genetic disease due to factors such as founder mutations or high rates of consanguineous union. As with the current Commission, assessments from this process would inform and be advisory to national and international decision making. If initial clinical uses of HHGE were ever permitted, those uses would only be considered in a carefully prescribed set of circumstances and would likely entail only a small number (on the order of 10-20) of cases. Assuming analysis of the outcomes of any initial uses did not raise further concerns about the safety and efficacy of HHGE, it might be deemed appropriate to consider uses in circumstances beyond those initially envisaged by this Commission. Before PREPUBLICATION COPY | UNCORRECTED PROOFS 165

progressing beyond those initial cases toward any further clinical uses of HHGE, it would be important for the global community to pause and reassess not only the state of the science, but also what additional ethical and societal concerns new circumstances of uses could raise. New classes of use may or may not precisely align with the six Categories defined in Chapter 3. Making recommendations on whether it is appropriate to cross subsequent thresholds in the use of HHGE would be a key role for an international body with responsibility for convening the international debate on HHGE. Potential uses of HHGE beyond the circumstances set out by this Commission open the door to impacting reproductive options for a significantly larger group of people. Making HHGE available to couples in Category B beyond the narrow circumstances described in Chapter 3 would represent a significant expansion in the possible scope of this technology. As a result, a respected body would be needed that can assess whether it is feasible to envision new responsible translational pathways and what these pathways should entail. This process should be complemented by other efforts by civil society to promote international cooperation on approaches to responsible development of medical technologies. For example, the Global Observatory on Genome Editing is being set up to foster international, interdisciplinary discussions on genome editing (Hurlbut et al., 2018). Similarly, the Association for Responsible Research and Innovation in Genome Editing (ARRIGE) was launched in 2018 to promote global governance of genome editing. 33 Both ARRIGE and the Global Observatory promote cross-sector discussions of whether genome editing technologies should be used and if so, for what purposes. There are also international processes that focus more on promoting responsible scientific conduct, for example, the Good Clinical Practice guidance for clinical trials developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), whose members and observers include national regulatory agencies, industry, and international organizations. 34 The ICH develops its guidelines through a process that includes formation of an expert working group to draft a technical document on an issue, followed by development by regulatory members of a draft guideline. The draft guideline undergoes a process of consultation and revision before being adopted by ICH. Although 33 See https://www.arrige.org. 34 See https://www.ich.org. PREPUBLICATION COPY | UNCORRECTED PROOFS 166

governance of HHGE would require engaging a broader and more diverse community than encompassed by ICH, this step-wise process encourages input and buy-in from the represented stakeholders. The launch by the World Health Organization in 2019 of initial phases of a global registry for genome editing clinical trials also represents an important step in the ability to monitor advances in HHGE and to maintain awareness of actions being taken within national jurisdictions. 35 Figure 5-2. International discussions would be required to determine whether it would be possible to cross significant thresholds and describe translational pathways for potential uses of HHGE. 35 Information on the registry is available at https://www.who.int/health-topics/ethics/human-genome-editing- registry/. The registry collects information on clinical trials using somatic genome editing as well as any clinical trials that would be conducted using HHGE. PREPUBLICATION COPY | UNCORRECTED PROOFS 167

A Mechanism to Bring Forward Concerns about Research or Clinical Use of Heritable Human Genome Editing After the announcement in 2018 that children had been born in China following the use of HHGE, an important question posed was how individuals who may have known about the work being conducted could have raised concerns, particularly if they were in one country and the investigator and the research being undertaken were in another. The Commission is not aware of a precise precedent for such an international mechanism that is accessible to anyone who would like to raise a concern. Future governance of HHGE requires an international mechanism for individuals and groups to raise concerns about possible violations of regulations or activities related to any clinical practice of HHGE in jurisdictions without regulations. There should be a highly visible, easily discoverable entity to which people everywhere may direct their concerns about activity in any country. In developing this mechanism, it will be important to keep in mind that raising concerns about scientific or clinical practices can have personal and professional ramifications for the person making the complaint. It is therefore important to maintain anonymity for anyone using this service. Similarly, details of a complaint should not be made public without prior investigation to protect individuals, institutions, and businesses from false accusations. Such investigations would be the responsibility of national regulatory authorities where available. These authorities would be informed by the international mechanism that a complaint had been made against someone within their jurisdiction. Although there is no exact precedent, there are relevant examples that can inform the design of such a mechanism. The World Anti-Doping Agency (WADA) has a means by which anyone can report an “alleged anti-doping rule violation or any act or omission that could undermine the fight against doping.” Some research funders have also developed mechanisms to facilitate the investigation of complaints made against researchers they fund. CONCLUSION AND RECOMMENDATIONS The pursuit of a translational pathway toward the clinical use of HHGE would represent the controlled alteration of a human embryonic genome using genome-editing tools, offered as PREPUBLICATION COPY | UNCORRECTED PROOFS 168

part of an assisted reproduction intervention. All countries pursuing research on or considering the use of HHGE will need to establish oversight systems for this technology, even though national regulatory frameworks for HHGE will differ in their structures and approaches. The governance structures needed for HHGE will also require new models of international coordination. Complex scientific and clinical information will need to be assessed to identify whether the criteria for clinically evaluating a proposed use of HHGE can be met and to incorporate any resulting outcomes into future discussions and decision-making. Achieving national and international coordination will pose challenges. But this is exactly why it will be critical to create robust processes by which there can be appropriate and transparent shared responsibility for moving HHGE forward thoughtfully and cautiously, only if there is clear scientific consensus to continue, and only if a given country decides to permit its use. The Commission recommends the following actions as part of this process. Essential Elements of Oversight Systems for Heritable Human Genome Editing Important national and international governance mechanisms should be established before any clinical use of HHGE. Recommendation 8: Any country in which the clinical use of heritable human genome editing (HHGE) is being considered should have mechanisms and competent regulatory bodies to ensure that all of the following conditions are met: • individuals conducting HHGE-related activities, and their oversight bodies, adhere to established principles of human rights, bioethics, and global governance; • the clinical pathway for HHGE incorporates best practices from related technologies such as mitochondrial replacement techniques, preimplantation genetic testing, and somatic genome editing; • decision-making is informed by findings from independent international assessments of progress in scientific research and the safety and efficacy of HHGE, which indicate that the technologies are advanced to a point that they could be considered for clinical use; • prospective review of the science and ethics of any application to use HHGE is diligently performed by an appropriate body or process, with decisions made on a case-by-case basis; • notice of proposed applications of HHGE being considered is provided by an appropriate body; • details of approved applications (including genetic condition, laboratory procedures, laboratory or clinic where this will be done, and national bodies providing oversight) are made publicly accessible, while protecting family identities; PREPUBLICATION COPY | UNCORRECTED PROOFS 169

• detailed procedures and outcomes are published in peer-reviewed journals to provide dissemination of knowledge that will advance the field; • the norms of responsible scientific conduct by individual investigators and laboratories are enforced; • researchers and clinicians show leadership by organizing and participating in open international discussions on the coordination and sharing of results of relevant scientific, clinical, ethical, and societal developments impacting the assessment of HHGE’s safety, efficacy, long-term monitoring, and societal acceptability; • practice guidelines, standards, and policies for clinical uses of HHGE are created and adopted prior to offering clinical use of HHGE; and • reports of deviation from established guidelines are received and reviewed, and sanctions are imposed where appropriate. Recommendation 9: An International Scientific Advisory Panel (ISAP) should be established with clear roles and responsibilities before any clinical use of heritable human genome editing (HHGE). The ISAP should have a diverse, multidisciplinary membership and should include independent experts who can assess scientific evidence of safety and efficacy of both genome editing and associated assisted reproductive technologies. The ISAP should: • provide regular updates on advances in, and the evaluation of, the technologies that HHGE would depend on and recommend further research developments that would be required to reach technical or translational milestones; • assess whether preclinical requirements have been met for any circumstances in which HHGE may be considered for clinical use; • review data on clinical outcomes from any regulated uses of HHGE and advise on the scientific and clinical risks and potential benefits of possible further applications; and • provide input and advice on any responsible translational pathway to the international body described in Recommendation 10, as well as at the request of national regulators. Recommendation 10: In order to proceed with applications of heritable human genome editing (HHGE) that go beyond the translational pathway defined for initial classes of use of HHGE, an international body with appropriate standing and diverse expertise and experience should evaluate and make recommendations concerning any proposed new class of use. This international body should: • clearly define each proposed new class of use and its limitations; • enable and convene ongoing transparent discussions on the societal issues surrounding the new class of use; • make recommendations concerning whether it could be appropriate to cross the threshold of permitting the new class of use; and • provide a responsible translational pathway for the new class of use. Recommendation 11: An international mechanism should be established by which concerns about research or conduct of heritable human genome editing that deviates from established guidelines or recommended standards can be received, transmitted to relevant national authorities, and publicly disclosed. PREPUBLICATION COPY | UNCORRECTED PROOFS 170

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Heritable human genome editing - making changes to the genetic material of eggs, sperm, or any cells that lead to their development, including the cells of early embryos, and establishing a pregnancy - raises not only scientific and medical considerations but also a host of ethical, moral, and societal issues. Human embryos whose genomes have been edited should not be used to create a pregnancy until it is established that precise genomic changes can be made reliably and without introducing undesired changes - criteria that have not yet been met, says Heritable Human Genome Editing.

From an international commission of the U.S. National Academy of Medicine, U.S. National Academy of Sciences, and the U.K.'s Royal Society, the report considers potential benefits, harms, and uncertainties associated with genome editing technologies and defines a translational pathway from rigorous preclinical research to initial clinical uses, should a country decide to permit such uses. The report specifies stringent preclinical and clinical requirements for establishing safety and efficacy, and for undertaking long-term monitoring of outcomes. Extensive national and international dialogue is needed before any country decides whether to permit clinical use of this technology, according to the report, which identifies essential elements of national and international scientific governance and oversight.

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