a careful balancing of cultural norms, the physical and emotional well-being of children, parental autonomy, and the ability of regulatory systems to prevent inappropriate or abusive applications. In light of the technical and social concerns involved, the committee concluded that germline genome-editing research trials might be permitted, but only following much more research aimed at meeting existing risk/benefit standards for authorizing clinical trials and even then, only for compelling reasons and under strict oversight. It would be essential for this research to be approached with caution, and for it to proceed with broad public input. In the United States, authorities currently are unable to consider proposals for this research because of an ongoing prohibition on the U.S. Food and Drug Administration’s (FDA’s) use of federal funds to review “research in which a human embryo is intentionally created or modified to include a heritable genetic modification.”4 In a number of other countries, germline genomeediting trials would be prohibited entirely. If U.S. restrictions on such trials were allowed to expire or if countries without legal prohibitions were to proceed with them, it would be essential to limit these trials only to the most compelling circumstances, to subject them to a comprehensive oversight framework that would protect the research subjects and their descendants, and to institute safeguards against inappropriate expansion into uses that are less 3 OMIM, https://www.omim.org (accessed January 5, 2017); Genetic Alliance, http://www.diseaseinfosearch.org (accessed January 5, 2017). 4 Consolidated Appropriations Act of 2016, Public Law 114-113 (adopted December 18, 2015). Copyright © National Academy of Sciences. All rights reserved. Human Genome Editing: Science, Ethics, and Governance 6 HUMAN GENOME EDITING PREPUBLICATION COPY—SUBJECT TO FURTHER EDITORIAL REVISION compelling or well understood. In particular, clinical trials using heritable germline editing should be permitted only if done within a regulatory framework that includes the following criteria and structures: · absence of reasonable alternatives; · restriction to preventing a serious disease or condition; · restriction to editing genes that have been convincingly demonstrated to cause or to strongly predispose to the disease or condition; · restriction to converting such genes to versions that are prevalent in the population and are known to be associated with ordinary health with little or no evidence of adverse effects; · availability of credible pre-clinical and/or clinical data on risks and potential health benefits of the procedures; · ongoing, rigorous oversight during clinical trials of the effects of the procedure on the health and safety of the research participants; · comprehensive plans for long-term, multigenerational follow-up while still respecting personal autonomy; · maximum transparency consistent with patient privacy; · continued reassessment of both health and societal benefits and risks, with broad ongoing participation and input by the public; and · reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition. Even those who will support this recommendation are unlikely to arrive at it by the same reasoning. For those who find the benefits sufficiently compelling, the above criteria represent a commitment to promoting well-being within a framework of due care and responsible science. Those not completely persuaded that the benefits outweigh the social concerns may nonetheless conclude that these criteria, if properly implemented, are strict enough to prevent the harms they fear. It is important to note that such concepts as “reasonable alternatives” and “serious disease or condition” embedded in these criteria are necessarily vague. Different societies will interpret these concepts in the context of their diverse historical, cultural, and social characteristics, taking into account input from their publics and their relevant regulatory authorities. Likewise, physicians and patients will interpret them in light of the specifics of individual cases for which germline genome editing may be considered as a possible option. Starting points for defining some of these concepts exist, such as the definition of “serious disease or condition” used by the U.S. FDA.5 Finally, those opposed to germline editing may even conclude that, properly implemented, the above criteria are so strict that they would have the effect of preventing all clinical trials involving germline genome editing. 5 While not drafted with the above criteria in mind, the FDA definition of “serious disease or condition” is “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and selflimiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one” (21 CFR 312.300(b)(1)). Copyright © National Academy of Sciences. All rights reserved. Human Genome Editing: Science, Ethics, and Governance SUMMARY 7