Sciences. All rights reserved. Human Genome Editing: Science, Ethics, and Governance OVERSIGHT OF HUMAN GENOME EDITING 25 PREPUBLICATION COPY—SUBJECT TO FURTHER EDITORIAL REVISION In U.S. regulation, these principles underlie the insistence on voluntary, informed consent from competent persons; special protections for those lacking competence; a reasonable balance between the risks of harm and potential benefits; attention to minimizing risks whenever possible; and equitable selection of research participants. REGULATION OF GENE THERAPY IN THE UNITED STATES Both somatic and germline human genome editing would be regulated in the United States within the framework for gene transfer research and, once approved, for gene therapy, which applies to work with human tissues and cells from the early stages of laboratory research through preclinical testing, human clinical trials, approval for introduction into medical therapy and postapproval surveillance. At the national level, regulation may be mandatory in all cases—for example, when the work is to be submitted to the U.S. Food and Drug Administration (FDA) for approval—or it can be mandatory only for those who are using federal funds. Oversight also can proceed according to voluntary self-regulation pursuant to professional guidelines. In addition to national rules, individual states have at times issued rules on specific topics, such as embryo research, or attached restrictions to the use of state funds, such as for embryonic stem cell work. As a result, unlike some jurisdictions, such as the United Kingdom, in which work with embryos generally falls under a single statutory framework or regulatory body, the United States has individual rules related to stage of work and source of funding that overlap and interact in a manner that, in the end, provides fairly comprehensive coverage. In general, laboratory work is subject to local oversight by institutional biosafety committees (IBCs) whose focus is on safety, and in many cases to federal oversight for quality assurance under the Clinical Laboratory Improvement Amendments as well.15 In some cases, laboratory work using cells from identifiable living donors also is subject to review by institutional review boards (IRBs), whose focus is on protecting donors from the effects of being identified, and on ensuring appropriate informed consent. Laboratory work using human embryos does not fall within IRB jurisdiction unless the progenitor-donors are identifiable, but this work may be overseen by voluntary oversight bodies, such as embryonic stem cell research oversight committees (ESCROs) created pursuant to NAS/IOM recommendations or the embryo research oversight committees (EMROs) recently created pursuant to recommendations of the International Society for Stem Cell Research (ISSCR, 2016a). Preclinical animal work is subject to regulation and oversight by institutional animal care and use committees pursuant to the Animal Welfare Act. Clinical trials may be the subject of discussion and advisory protocol review by the National Institutes of Health (NIH) Recombinant DNA Advisory Committee (RAC), but will nonetheless require approval by an IRB and permission from the FDA. Human genome editing technologies are considered to be gene therapies with regard to FDA oversight, and the agency regulates human genome editing under the existing framework for biological products, which includes gene therapy products. The FDA has authorized a number of gene therapy trials but has not yet approved a gene therapy for market. If one is approved, it will still be subject to the FDA’s ongoing monitoring and, if necessary, restrictions on their use. This 15See https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html?redirect=/clia (accessed January 5, 2017). Copyright © National Academy of Sciences. All rights reserved. Human Genome Editing: Science, Ethics, and Governance 26 HUMAN GENOME EDITING PREPUBLICATION COPY—SUBJECT TO FURTHER EDITORIAL REVISION FDA oversight entails review under rules governing biologics and, in many cases, under rules governing drugs. Once gene therapies are introduced into clinical care, not only will the FDA maintain surveillance to detect safety concerns, but formal studies of the labeled uses also may be conducted to take a fresh look at the safety and efficacy of the therapy. Postmarket use may also encompass uses that go beyond the indications for which a therapy was approved. Formal studies of an approved biologic for a use other than specified in the labeling would generally not be considered off-label use and would require FDA oversight. But outside of a study, “off label” use in clinical care is entirely legal, and has become a common practice among physicians with respect to drugs, and might be available for a gene transfer product using genome editing once it is approved. Physicians use their own expertise and sources of information, as well as the advice of professional societies. They are regulated at the state level by their licensing and disciplinary bodies, may be limited by availability of patients' insurance coverage for novel interventions, and are constrained by the prospect of tort liability for medical malpractice should they be deemed negligent or reckless.