Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
FRAMEWORK FOR ADDRESSING ETHICAL DIMENSIONS OF EMERGING AND INNOVATIVE BIOMEDICAL TECHNOLOGIES A SYNTHESIS OF RELEVANT NATIONAL ACADEMIES REPORTS
DISCLAIMER: This derivative document was prepared by Leah Rand and Neal Dickert with the assistance of Board on Health Sciences Policy board members R. Alta Charo, Jeffrey Kahn, and Patricia A. King, and with input from staff members in the Health and Medicine Divisionâs Board on Health Sciences Policy and the Division on Earth and Life Studiesâ Board on Life Sciences: Katie Bowman, Caroline Cilio, Rebecca English, Cathy Liverman, Andrew Pope, and Fran Sharples. This synthesis does not necessarily represent the views of the National Academies of Sciences, Engi- neering, and Medicine. Funding for this project was provided by the National Academy of Sciences Biology and Biotech- nology Fund and the National Academy of Sciences Frank Press Fund for Dissemination and Outreach. The Greenwall Foundation provided support for the 2018 Greenwall Foundation Fellow in Bioethics at the National Academies. REVIEWERS: To ensure that it meets institutional standards for quality and objectivity, this derivative document was reviewed by Eli Adashi, Brown University; Jeffrey Botkin, The University of Utah; Barry Coller, The Rockefeller University; Kathleen Hall Jamieson, University of Pennsylvania; Valerie Gutmann Koch, The University of Chicago; Bernard Lo, The Greenwall Foundation; Carol Scott-Conner, The University of Iowa; and Matthew Wynia, University of Colorado. Wylie Burke, University of Washington, served as the review coordinator. Copyright Â© 2019 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. SUGGESTED CITATION: National Academies of Sciences, Engineering, and Medicine. 2019. Framework for address- ing ethical dimensions of emerging and innovative biomedical technologies: A synthesis of relevant National Acade- mies reports. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25491.
INTRODUCTION ing policy recommendations and advising policy makers.2 Because of their dual scientific and policy advisory role, Over the past 15 years, the National Academies of National Academies projects often have a broad scope. Sciences, Engineering, and Medicine (the National Acad- Committees address questions ranging from what ave- emies) have convened multiple committees of leading nues of research should be pursued and how studies experts in the biomedical sciences and in ethics to should be conducted or regulated to how biotechnology address ethical challenges related to innovative and should be implemented within a health system. Frame- emerging biomedical technologies.1 Some committees works addressing only one piece of this process or the have been specifically charged with addressing ethical ways that these pieces fit together will likely be incomplete issues; others have addressed ethical issues as part of for the purposes of the National Academies and similar a broader scope of work. These committeesâ high-im- evidence-based groups working on policy and program- pact reports have shaped policy, practice, and discus- matic efforts. sion around core ethical issues. Some committees have developed project-specific ethical frameworks to guide A well-designed framework can provide a clear and practi- their studies; others have referred to extant frameworks. cal structure that is accessible to and useful for ethicists Given the impact of the reports and the different ethical and non-ethicists alike and provides insights applicable to principles applied in each, this paper seeks to synthesize a wide range of stakeholders, including policy makers and ethical principles in order to arrive at a framework for relevant organizations and communities. An articulation of addressing some of the social and ethical challenges of general ethical commitments or principles can be useful, emerging biomedical technologies. but a framework to guide projects at the policy or pro- grammatic level needs to be practically oriented in order This framework is different from ethics principles for to help identify important ethical issues and ensure that researchers or philosophical discussion because it they have been effectively addressed. These goals can focuses on ethical challenges relevant to science policy help to ensure that health sciences policy guidance efforts rather than particular research projects or conceptual relevant to biomedical technologies are comprehensive problems. Though there is overlap among relevant consid- and consistent in their approach. It can also increase erations, policy bodies, like the National Academies, face efficiency by providing a starting point for discussions particular challenges with new biomedical technologies when addressing new policy considerations. and making evidence-based recommendations that are pragmatic and address ethical concerns. This paper is The framework proposed in this paper was developed by the first attempt to derive a coherent framework of ethical the 2018 Greenwall Foundation Fellow in Bioethics at the considerations synthesized from published reports. National Academies, Neal W. Dickert; Board on Health Sciences Policy (HSP) staff member Leah Rand; and three National Academies reports have an explicit policy focus HSP board members who have significant committee expe- because committees are often charged with answering rience and ethics expertise, R. Alta Charo (University of policy-level questions on specific topics. Although National WisconsinâMadison), Jeffrey Kahn (Johns Hopkins Univer- Academies reports frequently acknowledge existing eth- sity), and Patricia A. King (Georgetown University). Based ics frameworks and guidance documents such as the on a review of National Academies reports published over Belmont Report or the Helsinki Declaration, the reports the past 15 years that address key topics in biomedical include adaptations or additional principles focused on innovation and research, this framework is a derivative practical issues and often on broad policy-oriented con- product and does not contain findings, conclusions, or rec- siderations (HHS, 2016; U.S. National Commission for the ommendations, except those drawn from and referenced Protection of Human Subjects of Biomedical and Behav- to original National Academies reports. After reviewing ioral Research, 1979). Other existing frameworks do not prior National Academies reports, individual ethics princi- incorporate, for example, considerations from political ples and considerations were identified and grouped into theory or other domains that are often essential in mak- sets of related considerations. These considerations were then refined through iterative discussions. The resulting framework is a synthesis of principal ethical commitments 1 Emerging and innovative biomedical technologies are defined for this paper as novel uses, modifications, or creations of biological sys- tems or processes (Nuffield Council on Bioethics, 2019); this paper 2 âPolicy makersâ is used broadly to indicate groups or individuals focuses specifically on the applications of these technologies in health involved in making recommendations or proposing policies relevant sciences, medicine, and public health. to biotechnologies; it is not constrained to legislators. 3
reflected across published reports, but it is not an exhaus- The following section presents the eight key ethical tive catalog. Some considerations or recommendations considerations of the framework. Each consideration is offered within particular reports are specific to the con- defined. Examples from National Academies reports are tent focus of those reports. In addition, this framework used to demonstrate the kinds of considerations relevant (and the reports synthesized in its development) is limited to emerging and innovative biomedical technologies and to human applications. to research on them. In the final section, next steps and concluding thoughts are offered regarding operational- Consistent with the goals of this process, it is important izing and refining the ethical considerations. to acknowledge that the commitments and values within this framework do not represent an articulation or spec- ification of a particular ethical theory. The elements of the framework represent shared commitments or values FRAMEWORK FOR ADDRESSING ETHICAL that can be justified within many theoretical orientations. DIMENSIONS OF EMERGING AND INNOVATIVE The framework is designed to be of value to individuals BIOMEDICAL TECHNOLOGIES with different theoretical commitments and, perhaps most importantly, is intended to be practically useful Eight core considerations or commitments make up the in structuring policy work and communicating findings proposed framework for approaching ethical issues in to the public and to all users of evidence-based policy emerging and innovative biomedical technologies (see recommendations. It is important to recognize that an Box 1). These considerations often overlap with each implicit commitment to rigor and carefulness undergirds other; however, each consideration reflects a discrete and the application of this framework and the treatment of important area of emphasis. The first commitment, the ethical considerations generally, just as a commitment to promotion of societal value, clearly informs the other con- independence, high-quality evidence, and rigorous peer siderations. For this reason, it is listed first. The remaining review characterize National Academies reports more seven are not listed in any hierarchical order. generally and ensure their independence and integrity. Those providing policy advice and making policy decisions on matters of biomedical science have a special respon- BOX 1 sibility to consider the full range of risks and implications Framework for Ethical Dimensions of of innovation when advising scientists, legislators, and the Emerging and Innovative Biomedical nation on research activities. This commitment to rigor Technologies necessitates, as much as possible, an evidence-based approach that considers both the proximate and the long- â¢ Promote societal value term impacts of biomedical technology or research while eschewing non-data-driven slippery-slope arguments that â¢ Minimize negative societal impact sometimes characterize discussions of contentious eth- ical issues. â¢ Protect the interests of research participants â¢ Advance the interests of patients While the framework is intended to guide consideration of the ethical dimensions of emerging and innovative â¢ Maximize scientific rigor and data quality biomedical technologies, the proposed framework is not, however, intended to restrict what any particular group â¢ Engage relevant communities should address, and each application will raise topic- â¢ Ensure oversight and accountability specific issues. Additionally, this framework is likely to evolve. As biomedical research and innovation evolve, the â¢ ecognize appropriate governmental and R ethical considerations that guide progress may change. policy roles Finally, this framework is designed to guide a process, facilitate discussion, and facilitate comparisons; it is not intended to pre-specify outcomes or recommendations. 4
Promote Societal Value such technologies as heritable, germline editing (NASEM, Biomedical innovation is principally justified by its 2017a). potential to benefit society and individuals through In many reports, societal value considerations are explic- improving health and well-being. While scientific itly invoked to balance against other kinds of consider- knowledge production alone may have intrinsic value, ations, as they are in the Belmont Reportâs principle of it is ultimately the ability of biomedical research and beneficence (U.S. National Commission for the Protec- discovery to promote health and well-being that justifies tion of Human Subjects of Biomedical and Behavioral its pursuit, especially in the face of potential risks or Research, 1979). This framework separately considers harms (Emanuel et al., 2000). The goals of the National societal value, negative social impact, and the advance- Academies include advancing science and its capacity ment of patientsâ and research participantsâ interests. to contribute to human welfare and to increase health These considerations are interrelated and need to be equity. In evaluating emerging biomedical technologies, balanced in order to avoid exploitation in the process of a central task of National Academies committees is thus promoting and advancing science (Emanuel et al., 2000). to identify the potential for practical benefit in health This framework does not specify exactly how this balanc- and well-being, i.e., the âsocietal valueâ of a biomedical ing should be achieved and is not a checklist. Rather, it technology. Importantly, this includes not only direct is designed to clarify distinct considerations and to make health benefits but also potential positive impacts of the the task of balancing more explicit. This enhances its technology on health equity. practical value (by getting relevant considerations âon the tableâ) and facilitates policy recommendations. This consideration is listed first within this framework for two reasons. First, innovations that cannot lead to improvement in health and well-being are unlikely to be justified if they raise any significant concerns regard- Minimize Negative Societal Impact ing risk or harm. A second, and related, reason is that Just as biomedical innovation should be directed toward understanding the potential for an innovationâs ability the production of societal value, avoiding negative socie- to produce societal value is essential for contextualizing tal impact is also essential. The impact of biotechnological subsequent considerations and to balancing various risks innovations can be widespread, and a commitment to and benefits to participants or society. minimizing negative societal impact requires that decision makers consider the potential consequences of biomed- Multiple reports have emphasized the importance of soci- ical innovation beyond its direct impact on research par- etal value. Reports addressing ethical implications related ticipants and future patients. Potential negative societal to embryonic stem cell research specifically described the impacts include a broad range of consequences that are potential of this research to address important health particularly important in the context of making policy- problems within society, and potential risks or harms oriented recommendations. While research ethics guid- are explicitly balanced against that potential to promote ance traditionally addresses harms to research partici- societal value (NRC/IOM, 2005, 2010). In a 2014 Insti- pants, policy makers need to consider broader questions tute of Medicine (IOM) report on human health risks about what harms may arise across society as a result and exploration spaceflight, the committee stated that of a program of biomedical innovation. These concerns National Aeronautics and Space Administration (NASA) could arise during the process of research, but they can must always consider what benefit it seeks to gain from also arise in the context of downstream implementation. a particular mission from the perspective of its current Specific areas of focus in the National Academies reports research agenda and the advancement of future space- addressing innovative biomedical technologies have been flight (IOM, 2014a). The report Human Genome Editing: driven by a commitment to avoid negative societal impact, Science, Ethics, and Governance reflects an emphasis on including stigma, discrimination, and increasing health societal value in articulating the ethical value of âpromot- inequities. ing well-beingâ and in recommending that gene-editing technologies be used only for the treatment or preven- Committees routinely consider whether new biomedical tion of disease or disability for somatic genome editing technologies have the potential to increase stigma or dis- and only for the treatment or prevention of serious dis- crimination against certain groups, and concerns about ease or disability should it be deemed permissible to use stigma have featured prominently in National Academies 5
reports addressing these innovative technologies. These access to important benefits. In this respect, disparities concerns arise, for example, when technologies have the are not all the same; some are more problematic than potential to reduce the prevalence of certain disabilities others. The case of MRTs highlights the importance of as a result of screening, prevention, or treatment. The paying special attention to situations where inequitable report on mitochondrial replacement techniques (MRTs), access can produce a demonstrable negative impact on Mitochondrial Replacement Techniques: Ethical, Social, those who lack access. and Policy Considerations, explicitly acknowledges con- cerns about eugenics and a language of âfitnessâ that There are additional forms of potential societal impacts may develop with the adoption of technologies to modify of research on individuals and communities. Research embryos (NASEM, 2016a). Such a social shift could poten- in a particular area may affect clinical care, for instance, tially stigmatize disability and those who do not make use and it is also important to consider the effects of research of new technologies, and the report argues for vigilance on non-participants. This set of issues was addressed in against shifting biologic or genetic ideals of fitness that the report Opportunities for Organ Donor Intervention might diminish the dignity of individuals with disabilities. Research: Saving Lives by Improving the Quality and Quan- In the report on human genome editing, there is a similar tity of Organs for Transplantation (NASEM, 2017b). A fair commitment to human dignity, rooted in the principle of allocation system for organs is essential and should not be respect for persons: âAll people have equal moral value, jeopardized by clinical research. Plans for organ donation regardless of their genetic qualities.â This entails a âcom- research, for example, must address the risk of alienating mitment to destigmatizing disabilityâ (NASEM, 2017a, the public and reducing donor organ availability. Society p. 34) and takes into account negative impacts to indi- can be made worse by the presence of some disparities, viduals and society. so attention to the potential for negative societal impact is important when making recommendations about new The potential for new technologies or research to increase technologies. inequities requires careful attention. Though broader dis- tributive justice issues in health care are beyond the scope of work for many policy makers or programs, the identi- fication of potential inequities and how to address them Protect the Interests of Research Participants indicates a commitment to minimizing societal impacts. The report on MRTs specifically addresses the potential The goal of protecting the interests of research partici- for the introduction of MRTs to increase health inequities pants focuses specifically on clinical research, an essen- because MRTs will likely be highly expensive and initially tial stage in the development of innovative biomedical available only to relatively well-off individuals with health technologies. It is rooted in long-held positions in bioethics insurance that covers them (NASEM, 2016a). Difficulties about the importance of avoiding harm to and exploita- in access may exacerbate health and social inequities tion of research participants. In considering novel bio- because those with means may be able to have children medical technologies, it is important to recognize the without a devastating disease, while individuals who are moral constraints of using individuals (typically humans, less well-off or too distant from sites offering the tech- although similar considerations are relevant for animals) nology might either have to forgo having children or risk as research participants (IOM, 2003).3 The primary goal of the child having a serious illness. The report explicitly the research process is the generation of knowledge, and advises that inequitable access that is a function of the a principal ethical goal is to avoid compromising individu- current health care system should not derail advance- alsâ interests or well-being in that process. When evaluat- ment but also advises that the implementation of this ing new technologies and research, it is important to take technology must include efforts to identify individuals who into account the rights and interests of participants and can benefit most. This example illustrates not only an to identify and account for issues that affect their welfare. attention to issues of potential negative social impactâ the societal harms caused by limited accessâbut also a Ethical commitments to protect research participantsâ need to consider these impacts against potential socie- interests are the focus of multiple guidelines and regula- tal benefitsâthe promotion of societal value. Addressing tions, ranging from the Nuremberg Code to the Belmont disparities and inequities is complex. It is often the case 3 The scope of this paper is limited to human research and the effects that access to new technologies or therapies is initially of biomedical technologies. The National Academies have addressed limited by financial or other resource considerations that, the protection of animals in research in several reports, including IOM, over time, may attenuate, allowing broad and affordable 2011; NAS/IOM, 1991; NRC, 1998, 2011. 6
Report and the Federal Common Rule (45 C.F.R. Part 46 as spouses or family members. These considerations are HHS, 2016; U.S. National Commission for the Protection of distinct from issues related to bystander effects or societal Human Subjects of Biomedical and Behavioral Research, impact (addressed in a prior section on avoiding negative 1979). Broadly, there are two kinds of protections that are societal impact) because they directly affect individuals critical to consider. One form of protection focuses on indi- connected to the research. vidual welfare. The potential risks of research participation must be taken seriously and weighed against both poten- It is important to recognize that individualsâ participation tial benefits to individual participants and potential soci- in research is often driven not only by a desire to assist etal value. A second form of protection that follows from in research but also by clinical goals, and participants this commitment is the focus on rights and other inter- frequently occupy the roles of patient and research par- ests that participants have. The reports of the National ticipant simultaneously. As research participants, they are Academies frequently call attention to the importance of involved in knowledge generation, and it is ethically nec- informed consent and other measures to ensure respect essary to protect their interests in the design and conduct for persons. While attention to these considerations may of studies. As patients, individualsâ involvement may be advance participantsâ welfare interests, a primary motiva- primarily oriented toward clinical benefit. In many cases, tion is also to ensure the protection of rights and interests these interests may align, but they can exist in tension. that extend beyond participantsâ health or welfare (e.g., Protecting research participantsâ interests is thus a com- protection of privacy interests). This commitment can mitment that has distinct features from the advancement be found in reports recommending consent for human of patientsâ interests. embryonic stem cell research, which have recognized the additional moral significance that some people attach to embryos (NRC/IOM, 2005, 2010). Advance the Interests of Patients In contrast to the protection of research participantsâ Steps that researchers should take to protect research interests, a commitment to advancing patientsâ interests participants and their interests are outlined in the 2003 focuses on the clinical application of innovative biomedical IOM report Responsible Research: A Systems Approach technologies, whether in the health system context or oth- to Protecting Research Participants, which recommends erwise. The reason for the clinical use of any biomedical guidelines for human-subjects research (IOM, 2003). technology is presumably for the benefit of individuals The recommendations include the implementation of with the relevant conditions or, in the case of preventive a systems approach designed to protect autonomous therapies, who may be at risk for developing those con- and informed consent, accountability, and adequate ditions. The aim of this consideration is to advance those resources for sustaining the protection of participants. benefits and patientsâ interests while minimizing risk. This These requirements were particularized to children in is different from protecting research participants from Ethical Conduct of Clinical Research Involving Children the risk of a process aimed at knowledge development. (IOM, 2004). Additional protections that are generally However, as acknowledged previously, research involving relevant and are raised in the context of novel biomed- new biomedical technologies often involves patients, and ical technologies include privacy protections (NRC/IOM, both sets of considerations apply. 2010) and the consideration of returning research results as a part of a commitment to demonstrating respect for The scope of the commitment to advancing patientsâ inter- participants, ensuring transparency, and developing trust ests is broad and involves important policy-level consid- between researchers and participants (NASEM, 2018). erations. For example, this commitment requires careful consideration of justice and fairness issues related to Many of the protections essential to conducting access. These considerations overlap with, but may be human-subject research in general are applicable to bio- distinct from, the concerns discussed earlier regarding medical technologies, but these technologies introduce health inequalities or the exacerbation of disparities. novel challenges as well. Genome editing, for example, Careful consideration of patientsâ interests should also challenges definitions of who counts as a research par- substantially inform and drive decisions regarding the ticipant. Germline genetic interventions have implica- regulation of novel biomedical technology as it emerges tions for future persons, and their interests need to be into clinical use. explicitly accounted for and protected. Many studies of emerging and innovative biomedical technologies may also affect close associates of research participants such 7
The process of respecting and advancing patientsâ inter- when making recommendations on future biomedical ests becomes more complicated when dealing with inno- research. vative reproductive technologies. Germline gene editing and mitochondrial replacement techniques both may Several specific considerations related to scientific rigor make it possible to have genetically related children with- and data quality have been made in previous National out a heritable genetic disease. Both types of therapies, Academies reports. Validity is an important principle guid- however, may also pose risks to the child through unknown ing researchâfor research to be beneficial and produc- effects of genome editing. For this reason, two National tive, it must be valid and should produce findings that Academies reports recommend the research and eventual are accurate and can be applied in real clinical settings use of these new techniques for only the most severe and (NASEM, 2017b). New technologies involving biological debilitating of conditions (NASEM, 2016a, 2017a). specimens also require extra care related to the appropri- ate management of samples. These responsibilities take Protective considerations can, as discussed, exist in ten- on special significance in the context of embryonic stem sion with the advancement of individual patientsâ inter- cell research, for example (NRC/IOM, 2005). ests. Additionally, substantial tension can exist between the advancement of research goals (including the produc- An additional consideration related to maximizing rigor tion of rigorous data) and the advancement of individual and data quality that has been highlighted in prior reports patientsâ interests. Many new biomedical technologies, is the need for increased data sharing. The report Shar- especially those involving genome editing, are likely to ing Clinical Trial Data: Maximizing Benefits, Minimizing remain experimental for a considerable time, so gaining Risk highlights the benefits of working toward increased access to clinical benefits may require involvement in data sharing; among these is the ability to conduct further research (NRC, 2002; NASEM, 2016a, 2017a).4 Patients analyses that may generate additional findings, reframe or patient groups, however, may have a strong desire for conclusions, and protect patients (IOM, 2015). The report clinical access to experimental interventions available identifies important challenges, ranging from individual only in the context of clinical trials. Tensions about access privacy risks to the protection of intellectual property, and to innovative therapy are clearly illustrated by the recent recommends oversight from an independent review panel âRight to Tryâ movement and the resultant federal legisla- and a transparent process for granting access. In a similar tion (Public Law 115-176). It is important to consider how vein, the report on clinical gene transfer protocols recom- a new biomedical technology may advance patientsâ inter- mends that advisory committees overseeing research ests without losing track of its implications for research protocols be used to integrate the capacity to âsurveil, participants or its potential for negative societal impact. aggregate, and analyze adverse events across related The latter set of concerns is particularly central to debates trials of emerging technologiesâ (IOM, 2014b, p. 7). Max- regarding genome editing, as reflected in the National imizing rigor and data quality thus increases the value of Academies report on this issue (NASEM, 2017a). research and can help to minimize risks to patients and participants, linking this particular consideration to other considerations involving societal value and the protection Maximize Scientific Rigor and Data Quality of research participantsâ interests. Finally, the potential for increased data sharing further accentuates the need The value of scientific research is contingent on its for data quality and methodological rigor. effective design and execution. A central ethical commitment is thus adherence to high standards of research conduct and scientific practice. Flawed research designs can harm research participants, waste Engage Relevant Communities resources, fail to generate valuable data for patients National Academies reports have frequently called for a and society, and compromise public support for and commitment to community engagement in multiple forms. trust in the research enterprise. Well-designed research New technologies in health and medicine raise socially that is poorly executed poses similar threats. Potential challenging questions and genuine ethical dilemmas. threats to data quality in the process of studying a Democratic engagement with the public provides input new biotechnology thus deserve strong consideration and a range of perspectives on how best to meet these 4 This is not a new consideration; the 1980s, for example, saw a push social and ethical challenges. More generally, because for access to AIDS treatments in development that were only available innovations in biomedical technology have potentially to a limited number of research participants (IOM, 2007). 8
important impacts within society, the process of develop- patient population and needs to be specified in the con- ment, research, and implementation should be influenced text of a particular biotechnology. The report on MRTs, for by the public these innovations are intended to serve. example, highlights the value of transnational partner- Consideration of whether and what kind of community ship among countries and researchers as a guiding prin- engagement is most appropriate for the particular tech- ciple for MRT research and application (NASEM, 2016a). nology will be important. The report calls for the United States to pool data with other countries in order to assess the benefits and risks Multiple reasons for and forms of community engage- of MRTs. Similarly, the report on human genome editing ment have been described in National Academies reports recommends transnational cooperation as a principle related to innovative biomedical technologies. The report governing gene-editing research and clinical application. on human genome editing specifically recommended that Responsibilities that would flow from adherence to this public input precede any clinical trials in germline gene principle include the coordination of regulatory standards editing (NASEM, 2017a). The report notes that public where possible while respecting national contexts and engagement is bi-directional; it can serve as a means for policies. The principle also emphasizes an important role researchers to inform the public as well as for research- for collaboration and data sharing in order to responsibly ers to receive input and perspective from the public. In advance genome editing research, application, and over- addition, engaging the public in deliberating about policy sight (NASEM, 2017a). This commitment to broad and decisions may help to legitimize approaches to a morally context-sensitive understanding of community engage- challenging decision. Such full-spectrum engagement is ment is reflected in National Academies reports related emphasized as being particularly important prior to poten- to non-human uses of biotechnology (e.g., gene drives) tial clinical use of germline editing given the heritable as well (NASEM, 2016c). nature of the genetic changes and substantial heteroge- neity among the public regarding key moral questions in this domain (NASEM, 2017a). Ensure Oversight and Accountability Community engagement has also been recognized as The values of accountability and oversight are essen- serving the important functions of building trust within tial throughout the process of developing, studying, and a relevant community, demonstrating trustworthiness to implementing novel biomedical technologies. In a sense, a community, and fostering public engagement with sci- processes that ensure both accountability and oversight ence and research generally. An example of engagement are the âtoolsâ through which many of the other ethics for the purpose of building public trust in the research considerations described within this framework are real- community is the recommendation from the report on ized. Along with broad engagement, processes designed clinical gene transfer protocols that the National Institutes to ensure accountability and proper oversight can help to of Health (NIH) establish a public forum for review and demonstrate trustworthiness and provide transparency, discussion that would foster public awareness of emerg- both of which are essential when addressing social ques- ing science and provide an opportunity to address and tions and ethical concerns raised by emerging and inno- discuss public concerns about emerging and innovative vative technologies. This involves exploring the existing biomedical technologies (IOM, 2014b). The 2018 report accountability mechanisms and determining whether spe- Returning Individual Research Results to Participants: cial oversight of a new biomedical technology or research Guidance for a New Research Paradigm emphasized that is required. returning results to research participants is a means to broaden engagement with research participants. Greater In addition to the legal requirements for human-subjects engagement with participants and participant groups has research, further mechanisms of ensuring accountabil- been recognized as having potential additional benefits ity and oversight have been recommended in previous related to increasing the representation of traditionally reports. Some reports, such as the one on the over- underrepresented groups in research (NASEM, 2018). sight and review of clinical gene transfer protocols, have focused almost exclusively on assessing the adequacy The National Academies reports on innovative biomedical of oversight mechanisms (IOM, 2014b). Just as in other technologies have emphasized international collaboration domains, future work addressing novel technologies will and engagement in an era of growing connectedness. need to adapt to a changing landscape with increasing These reports thus reflect a broad notion of community access to large amounts of data. National Academies engagement that extends beyond the affected public or reports outside the scope of novel biomedical technolo- 9
gies can be highly informative. The 2007 IOM report Eth- recommends that the U.S. Food and Drug Administration ical Considerations for Research Involving Prisoners, for should regulate MRTs to ensure that they are used only in example, focuses heavily on oversight mechanisms when approved settings and that public consultation should take enrolling a highly vulnerable population (IOM, 2007); these place prior to any expansion of their use (NASEM, 2016a). concerns are germane to work involving novel therapies This recommendation for government regulation curtails such as germline gene editing and mitochondrial replace- individual reproductive liberty by placing MRTs under ment therapy, which also involve vulnerable individuals. governmental oversight, but in recommending that MRT research go forward, it also respects the value that many individuals place on having genetically related children. In each of these cases, committees have had to consider Recognize Appropriate Governmental and explicitly the role of regulation and governmental action Policy Roles in a context of substantial public moral disagreement. As described in the introduction to this framework, a cen- Recommendations to the government are pragmatic when tral function of policy-oriented bodies, such as National they fit within its regulatory rules and limits, which are Academies committees, is to make policy recommenda- constitutionally prescribed and often driven by underlying tions, often to governmental regulatory agencies. This ethical principles. role is distinct from the role of individual researchers and requires careful consideration of what the role of Prior work also illustrates the way in which proper govern- governmental action and policy should be in regulating mental roles evolve. As research advances, knowledge research and the applications of biomedical technologies. grows, and social views on the technologies change, the Recommendations aimed specifically at the U.S. govern- role of regulatory agencies may also change. In the report ment best take account of governmental roles when they Oversight and Review of Clinical Gene Transfer Protocols: reflect both the division of authority between federal and Assessing the Role of the Recombinant DNA Advisory state governments and between government and individ- Committee, the authoring committee determined that the uals; those directed toward the international community Recombinant DNA Advisory Committees (RAC), which over- reflect an awareness of the diversity of forms of govern- sees gene transfer research at NIH, could limit the public ment across the globe and the limits of international law. review of research protocols to those that meet a few spe- Policy-level approaches to ethical challenges need to be cific criteria (IOM, 2014b). The original need for a public conscious of individual liberties, the role of religious or review of research protocols arose because gene transfer conscience-based concerns, and the reasonable reach research was a new technology in clinical research that of the state. raised substantial public concerns and stoked the public imagination. As the science developed, the review and Scientific developments involving human embryos and regulatory process became more focused. This example embryonic stem cells, which have been the focus of demonstrates how oversight and regulation change in several National Academies reports, present important response to experience and, in particular, in response to challenges because of differing moral views in American changing public views about the acceptability of specific society concerning the ethical nature of these technolo- forms of research. gies. The report Guidelines for Human Embryonic Stem Cell Research explicitly recognized this pluralism of views Groups advising on policy decisions have a responsibil- regarding the moral status of embryos and reached the ity to consider their recommendations in the context of conclusion that the appropriate response is government real-world policy settings while remaining forward looking. oversight and regulation rather than a total ban on the This is reflected in an emphasis on the responsibility to research (NRC/IOM, 2005). The report on human genome perform evidence-based assessments of future impact editing recommends government oversight and regu- when possible, while at the same time confronting the lation of genome editing in several contexts, including real-world issues that make up the context in which novel research using human cells and tissues and development biomedical technologies will emerge. For example, policy of non-heritable (somatic) genome editing applications. makers may address barriers to accessing a new treat- It also emphasizes a need for a stringent oversight sys- ment as part of their recommendations. However, at the tem and further public engagement prior to initiating any same time, they need to be cognizant of the regulations clinical trials and applications of heritable, germline gene and inherent limitations of the health care system into editing (NASEM, 2017a). The report on MRTs similarly which a new treatment modality will be introduced. 10
DISCUSSION OF NEXT STEPS BOX 2 National Academies Reports Discussed This framework draws from multiple National Academies in the Framework reports and offers a set of ethics considerations that are broadly applicable in evaluating emerging and innovative â¢ Returning Individual Research Results to Par- biomedical technologies. The framework is not intended to ticipants: Guidance for a New Research Para- be constraining but is intended to be practical and action digm (2018) guiding in three key respects. â¢ Human Genome Editing: Science, Ethics, and Governance (2017) First, it provides a structure for systematically evaluating â¢ pportunities for Organ Donor Intervention O the ethical implications of emerging and innovative bio- Research: Saving Lives by Improving the Qual- medical technologies. In this way, it can help to identify ity and Quantity of Organs for Transplantation and clarify what is at stake in addressing a particular (2017) set of issues and to illustrate competing considerations. It does not, however, resolve difficult conflicts between â¢ itochondrial Replacement Techniques: M competing considerations. For example, the sections on Ethical, Social, and Policy Considerations advancing patient interests and protecting research par- (2016) ticipants explicitly draw out some of the ways in which a â¢ ene Drives on the Horizon: Advancing G personâs position as both a participant and as a patient Science, Navigating Uncertainty, and Aligning may suggest different interests. Similarly, individual Research with Public Values (2016) patient interests may need to be considered against the â¢ Sharing Clinical Trial Data: Maximizing Bene- potential for negative societal impacts. The presence of fits, Minimizing Risk (2015) these conflicts does not undermine the framework, and the framework is not an ethical checklist. Rather, the â¢ ealth Standards for Long Duration and H framework functions in many cases to clarify and charac- Exploration Spaceflight: Ethics Principles, terize conflicts. Policy efforts for emerging and innovative Responsibilities, and Decision Framework biomedical technologies often require âthe balancing of (2014) two critical valuesâthe protection of human participants â¢ versight and Review of Clinical Gene O in research and the advancement of medical science to Transfer Protocols: Assessing the Role of the benefit societyâ (IOM, 2014b, p. 17). When considering Recombinant DNA Advisory Committee (2014) policy recommendations for emerging and innovative bio- â¢ Final Report of the National Academiesâ Human medical technologies, policy makers and others working Embryonic Stem Cell Research Advisory Com- in this area can explain their rationale for balancing the mittee and 2010 Amendments to the National ethical considerations in the manner they did. The bodies Academiesâ Guidelines for Human Embryonic receiving the recommendations, often federal agencies, Stem Cell Research (2010) then have the opportunity to weigh similar evidence and recommendations when deciding how and whether to â¢ Ethical Considerations for Research Involving implement a reportâs recommendations. Prisoners (2007) â¢ Guidelines for Human Embryonic Stem Cell Second, and closely related, the framework of ethical con- Research (2005) siderations serves to identify a core set of values that â¢ Ethical Conduct of Clinical Research Involving characterize the National Academiesâ work in the domain Children (2004) of emerging biomedical technologies. In this respect, it is hoped that this framework will help to facilitate com- â¢ Responsible Research: A Systems Approach to parisons across efforts to address ethical dimensions of Protecting Research Participants (2003) science policy for emerging biotechnologies and, where â¢ cientific and Medical Aspects of Human S appropriate, lend a measure of consistency in approach Reproductive Cloning (2002) or language across these efforts. Third, this framework is aimed at promoting efficiency by minimizing the work needed to identify and articulate 11
general ethical principles or guidance at the outset of Finally, the framework is expected to evolve. New inno- the policy recommendation process. This work can thus vations may disrupt current thinking about the ethical be focused on unique areas of concern raised by the bio- dimensions of innovation and research and may demon- technology issues being studied. strate the need for new values or revisions to the current framework. Similarly, the application of this framework to While these properties are undoubtedly valuable, this the range of topics addressed by National Academies com- framework is limited in several ways. Specifically, it is mittees and their like will surely identify gaps and areas novel, has boundaries, and is focused on emerging bio- for further development. This is desirable and important. medical technologies as applied to improving human One of the key virtues of a framework such as this is its health and well-being. There is more work to be done. utility in structuring ongoing discussions about the ethi- It will be important to understand whether this frame- cal dimensions of emerging biomedical technologies. For work could be helpful more broadly beyond the domain committee members, policy makers, and advisers, this of emerging biomedical technology. The values set forth framework can provide a starting point for determining if within the framework are not highly specific and could be an innovative biomedical technology raises new ethical the starting point for an articulation of values or ethics concerns and also for deliberating about the best ways to considerations across a broad range of issues in biomed- identify and act on the ethical commitments that should icine. For example, the use of big datasets for research undergird biomedical research. and what that means for individualsâ privacy and status as research participants could be examined through this framework. Similarly, it may be of use in or adapted to the evaluation of non-human and non-biomedical appli- cations of biotechnology, such as the genetic engineering of crops (NASEM, 2016b), or to evaluating innovations outside of biotechnology with potential implications for human health such as artificial intelligence; however, it has explicitly been developed with an emphasis on the biomedical applications of biotechnology. There is also more work to be done to explore both the underlying justifications and further specification of each of these considerations. The framework focuses on what may be most appropriately labeled middle-level consid- erations. They are middle level in the sense that they are not general theoretical or abstract ethical principles and they are not highly specified requirements. Rather, these considerations reflect widely shared values that have been embraced or reflected in the work of the National Acade- mies that may help to structure future deliberations and identify important ethical challenges. In addition, they can help to provide consistency in approaches across projects and facilitate the communication of efforts addressing similar or related topics. Further work on justifying the nature of each consideration from various philosophical or theoretical perspectives will be of value in understand- ing both the strength of each commitment and the more specific implications in real-world contexts. This is critical, especially for understanding the implications of these considerations in the context of new situations and those characterized by conflicting considerations. 12
REFERENCES Emanuel, E. J., D. Wendler, and C. Grady. 2000. What makes clinical research ethical? JAMA 283(20):2701â2711. HHS (U.S. Department of Health and Human Services). 2016. Ethical codes & research standards. https://www.hhs.gov/ohrp/ international/ethical-codes-and-research-standards/index.html (accessed February 26, 2019). IOM (Institute of Medicine). 2003. Responsible research: A systems approach to protecting research participants. Washington, DC: The National Academies Press. IOM. 2004. Ethical conduct of clinical research involving children. Washington, DC: The National Academies Press. IOM. 2007. Ethical considerations for research involving prisoners. Washington, DC: The National Academies Press. IOM. 2011. Chimpanzees in biomedical and behavioral research: Assessing the necessity. Washington, DC: The National Acade- mies Press. IOM. 2014a. Health standards for long duration and exploration spaceflight: Ethics principles, responsibilities, and decision frame- work. Washington, DC: The National Academies Press. IOM. 2014b. Oversight and review of clinical gene transfer protocols: Assessing the role of the Recombinant DNA Advisory Com- mittee. Washington, DC: The National Academies Press. IOM. 2015. Sharing clinical trial data: Maximizing benefits, minimizing risk. Washington, DC: The National Academies Press. NAS/IOM (National Academy of Sciences and Institute of Medicine). 1991. Science, medicine, and animals. Washington, DC: National Academy Press. NASEM (National Academies of Sciences, Engineering, and Medicine). 2016a. Mitochondrial replacement techniques: Ethical, social, and policy considerations. Washington, DC: The National Academies Press. NASEM. 2016b. Genetically engineered crops: Experiences and prospects. Washington, DC: The National Academies Press. NASEM. 2016c. Gene drives on the horizon: Advancing science, navigating uncertainty, and aligning research with public values. Washington, DC: The National Academies Press. NASEM. 2017a. Human genome editing: Science, ethics, and governance. Washington, DC: The National Academies Press. NASEM. 2017b. Opportunities for organ donor intervention research: Saving lives by improving the quality and quantity of organs for transplantation. Washington, DC: The National Academies Press. NASEM. 2018. Returning individual research results to participants: Guidance for a new research paradigm. Washington, DC: The National Academies Press. NRC (National Research Council). 1998. The psychological well-being of nonhuman primates. Washington, DC: National Academy Press. NRC. 2002. Scientific and medical aspects of human reproductive cloning. Washington, DC: National Academy Press. NRC. 2011. Guide for the care and use of laboratory animals. 8th ed. Washington, DC: The National Academies Press. NRC/IOM (National Research Council and Institute of Medicine). 2005. Guidelines for human embryonic stem cell research. Wash- ington, DC: The National Academies Press. NRC/IOM. 2010. Final report of the National Academiesâ Human Embryonic Stem Cell Research Advisory Committee and 2010 amendments to the National Academiesâ Guidelines for Human Embryonic Stem Cell Research. Washington, DC: The National Academies Press. Nuffield Council on Bioethics. 2019. What is an âemerging biotechnologyâ? http://nuffieldbioethics.org/report/chapter-downloads/ emerging-biotechnology (accessed March 26, 2019). U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. 1979. The Belmont Report: Ethical principles and guidelines for the protection of human subjects of research. Washington, DC: Department of Health, Educa- tion and Welfare, Office of the Secretary. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/index.html (accessed February 26, 2019). 13