Oversight of human genome editing fits within the overarching framework of oversight of gene therapy. That framework is embedded within the larger context of international conventions and norms for protection of human rights and, more specifically, for research involving human subjects and clinical care. From these international instruments, one can derive principles for governance of genome editing that have general application within the United States and across the globe, and are reflected in the specific statutory and regulatory rules that are adopted by various nations.
This chapter begins by describing the overarching principles for human genome editing adopted by the committee for this study, which are informed by those international instruments and national rules, and which in turn inform the conclusions and recommendations presented in this report. It then provides an in-depth look at U.S. governance of gene transfer research and therapy, and a brief review of alternative governance approaches used in other countries (some of which are explored in greater depth in Appendix B). Conclusions regarding the adequacy of U.S. oversight systems to deal with the specific technical and ethical issues raised by genome editing appear in Chapters 3 through 6.
Louis Pasteur once said: “La science n’a pas de patrie, parce que le savoir est le patrimoine de l’humanité” (Science has no homeland, because knowledge is the heritage of humanity). But while science is global, it proceeds within a variety of political systems and cultural norms. It is important to identify principles that can transcend these differences and divisions while accommodating cultural diversity. This is no easy task. Achieving consensus around overarching ethical principles to undergird specific recommendations for action can be difficult, whether because no one theory of ethics has been accepted by philosophers and theologians or because no one algorithm for deriving principles from those theories has been found. Utilitarians may agree on the need to evaluate overall beneficial consequences, but may disagree on whether to evaluate the consequences of a rule or of a specific act. Deontologists not only will struggle to derive a defensible list of fundamental rules of behavior, but also will be confronted with specific cases in which adherence leads to results that are intuitively unacceptable or even destructive. Other theories suffer from similar complications.
Bioethics, as a form of applied ethics, has suffered from all these complexities. It has also been dogged by long-standing debates about whether the best approach is high theory, from which all principles and specific actions flow, or anti-theory, in which deductive reasoning from specific cases leads to generalizable principles. And when bioethics is incorporated into public policy making, as opposed to individual clinical ethics analyses, it is necessary to incorporate a wider range of concerns about multicultural civil society, theories of democracy, and just distribution of burdens and benefits.2
Regardless of whether reasoning begins with theories grounded in utilitarian consequentialism or deontology or virtue ethics, there has emerged over time what some deem “reflective equilibrium.” This concept encompasses the use of both inductive and deductive reasoning, incorporating both theory and case-based casuistry, and accepting the need for reasoning that is understandable to the public, regardless of individual spiritual or religious orientation (Arras, 2016). It has helped shape influential statements and guidance documents across the globe.
The Universal Declaration of Human Rights (UN, 1948), adopted shortly after World War II, became the foundational document for many of the more particularized declarations, conventions, and treaties that followed. In its preamble, it states that “recognition of the inherent dignity and of the equal and inalienable rights of all members of the human family is the foundation of freedom, justice and peace in the world,” and its very
first provision reads, “All human beings are born free and equal in dignity and rights” (Article 1). Other international documents build on this core principle. The Convention on Rights of the Child, for example, calls for providing conditions for optimal development, such as health care and sanitation (UNICEF, 1990). And the Convention on the Rights of Persons with Disabilities emphasizes “respect for inherent dignity”(Article 3(1)), “respect for difference and acceptance of persons with disabilities as part of human diversity and humanity” (Article 3(4)), and “respect for the evolving capacities of children with disabilities and respect for the right of children with disabilities to preserve their identities” (Article 3(8)) (UN, 2006). Not every convention is legally binding in whole or in part on every country, but even where not incorporated into domestic statutes or applied in domestic court cases, the principles underlying these conventions have become important elements of global norms and aspirations.
Other international activities are focused more closely on biomedical research. The Council for International Organizations of Medical Sciences (CIOMS) is an international, nongovernmental, nonprofit entity, established in 1949 jointly by the World Health Organization (WHO) and the United Nations Educational, Scientific and Cultural Organization (UNESCO), whose members include nearly 50 organizations—professional societies, national academies, research councils—from across the globe. Among other things, it issues international guidelines for health research3 based on such guidance documents as the World Medical Association’s Declaration of Helsinki (WMA, 2013) and UNESCO’s (2005) Universal Declaration on Bioethics and Human Rights. The 2016 version of the guidelines (van Delden and van der Graaf, 2016) stresses “the need for research having scientific and social value, by providing special guidelines for health-related research in low-resource settings, by detailing the provisions for involving vulnerable groups in research and for describing under what conditions biological samples and health-related data can be used for research” (CIOMS, 2017, Summary). Of particular relevance to genome-editing policy questions are Guideline 1, emphasizing the need to generate knowledge to protect and promote health, and its relationship to Guidelines 2, 3, and 4, which focus on fairness in the balance and distribution of risks and benefits to individuals and groups (including distribution among populations of high- and low-resource countries). Also of particular relevance is Guideline 7 on public engagement, needed not only to develop and legitimize good policy but also to help translate research into clinical benefit.
In the United States, the landmark 1979 Belmont Report of the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research (HHS, 1979) focused on avoiding infliction of harm,
accepting a duty of beneficence, and maintaining a commitment to justice. These pillars of research ethics have been interpreted, expanded, deepened, and applied over the years and incorporated into the U.S. system for governing research with human participants (21 CFR Part 50 and 45 CFR Part 46). In practice, they have resulted in a focus on ensuring a reasonable balance between risk and hoped-for benefits, to the individual and to society, and on ensuring that both risks and benefits are equitably shared. These principles also have come to incorporate particular attention to the need for respect for individual autonomy in the form of generally requiring informed and voluntary participation, and the need to provide special protection against coercion or abuse of those who are vulnerable because of incapacity or circumstances.
Because both the science and the applications of human genome editing will transcend national boundaries, the core principles for governance of these technologies detailed below build on the foundations of these international and national norms. Some of these principles are generally relevant to biomedical research and care, while others are of particular importance in the context of an emerging technology, but all are foundational for the governance of human genome editing.
In this context, the committee focused on principles that are aimed at protecting and promoting the health and well-being of individuals; approaching novel technologies with careful attention to constantly evolving information; respecting individual rights; guarding against unwanted societal effects; and equitably distributing information, burdens, and benefits. Differences in social and legal culture inevitably will lead to different domestic policies governing specific applications of genome editing. Nonetheless, some principles can be shared across national borders. Thus, while the overarching principles presented here are aimed primarily at the U.S. government, they and the responsibilities that underlie them are universal in nature. The principles are listed in Box 2-1 and elaborated below.
- Promoting well-being: The principle of promoting well-being supports providing benefit and preventing harm to those affected, often referred to in the bioethics literature as the principles of beneficence and nonmaleficence.
Responsibilities that flow from adherence to this principle include (1) pursuing applications of human genome editing that promote the health and well-being of individuals, such as treating or preventing disease, while minimizing risk to individuals in early applications with a high degree of uncertainty; and (2) ensuring a reasonable balance of risk and benefit for any application of human genome editing.
- Transparency: The principle of transparency requires openness and sharing of information in ways that are accessible and understandable to stakeholders.
Responsibilities that flow from adherence to this principle include (1) a commitment to disclosure of information to the fullest extent possible and in a timely manner, and (2) meaningful public input into the policy-making process related to human genome editing, as well as other novel and disruptive technologies.
- Due care: The principle of due care for patients enrolled in research studies or receiving clinical care requires proceeding carefully and deliberately, and only when supported by sufficient and robust evidence.
Responsibilities that flow from adherence to this principle include proceeding cautiously and incrementally, under appropriate supervision and in ways that allow for frequent reassessment in light of future advances and cultural opinions.
- Responsible science: The principle of responsible science underpins adherence to the highest standards of research, from bench to bedside, in accordance with international and professional norms.
Responsibilities that flow from adherence to this principle include a commitment to (1) high-quality experimental design and analysis, (2) ap-
propriate review and evaluation of protocols and resulting data, (3) transparency, and (4) correction of false or misleading data or analysis.
- Respect for persons: The principle of respect for persons requires recognition of the personal dignity of all individuals, acknowledgment of the centrality of personal choice, and respect for individual decisions. All people have equal moral value, regardless of their genetic qualities.
Responsibilities that flow from adherence to this principle include (1) a commitment to the equal value of all individuals, (2) respect for and promotion of individual decision making, (3) a commitment to preventing recurrence of the abusive forms of eugenics practiced in the past, and (4) a commitment to destigmatizing disability.
- Fairness: The principle of fairness requires that like cases be treated alike, and that risks and benefits be equitably distributed (distributive justice).
Responsibilities that flow from adherence to this principle include (1) equitable distribution of the burdens and benefits of research and (2) broad and equitable access to the benefits of resulting clinical applications of human genome editing.
- Transnational cooperation: The principle of transnational cooperation supports a commitment to collaborative approaches to research and governance while respecting different cultural contexts.
Responsibilities that flow from adherence to this principle include (1) respect for differing national policies, (2) coordination of regulatory standards and procedures whenever possible, and (3) transnational collaboration and data sharing among different scientific communities and responsible regulatory authorities.
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.
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 may
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.4 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 (IOM, 2005) or the embryo research oversight committees (EMROs) recently proposed by 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 its use. This FDA oversight entails review under rules governing biologics and, in many cases, under rules governing drugs.
Once gene therapies have been introduced into clinical care, not only will the FDA maintain surveillance to detect safety concerns, but also formal studies of the labeled uses may be conducted to take a fresh look at
4 See https://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/index.html?redirect=/clia (accessed January 5, 2017).
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.
Table 2-1 provides a summary of the major steps in the anticipated regulatory pathway for the development of a new medical product created
|Step||Primary Regulatory Authorities (U.S. System)||Examples of Considerations|
|Laboratory research in cells and tissues (nonembryonic), including human induced pluripotent stem cells (iPSCs)||
||Laboratory worker safety Tissue donor safety, privacy, and rights (human cells and tissue); adequacy of consent process|
|Step||Primary Regulatory Authorities (U.S. System)||Examples of Considerations|
|Laboratory research in human embryonic stem cells or embryos||
||Special ethical concerns and regulations (federal and state) associated with research using human embryo and hESC lines|
|Preclinical animal studies||
||Humane care, study design, and pain minimization|
|Clinical trials (Investigational New Drug [IND] application)||
||Balance of anticipated risks and benefits to human subjects
Appropriate protocol design and informed consent
|New medical product application (Biologic Licensing Application)||
||Evaluation of safety and efficacy data|
|Licensed medical product (postmarket measures)||
||Long-term patient safety|
using genome editing. The individual steps and considerations listed in this table are discussed in greater detail in the remainder of the chapter.
Oversight of Laboratory-Based Research
Rules governing research with human cells and tissues, including somatic cells, gametes, embryos, and fetal tissue tend to focus on several key issues. For most cells and tissues, an initial question is whether the donor can receive any kind of payment, in cash or kind. This has been a particularly sensitive issue with respect to gametes used in research, with debate being focused less on the ethics of research using gametes and more on the ethics of how they are obtained and whether it involves anything that resembles undue inducement. For embryos and fetal tissue, rules are influenced by broader legal regimes governing human reproduction and products of conception, to the extent such regimes exist in a given country. And for all tissues, attention is given to whether the tissue is obtained with required permissions from the donor and whether its use poses any risk to the donor’s privacy. These rules can change, of course, when tissue is obtained from cadavers rather than live donors.
In the United States, human tissue is donated for research in various ways. Rules governing that donation depend on several factors, the most important of which are whether the tissue is left over from a clinical procedure or is being obtained through a new intervention specifically for research, and whether the resulting tissue specimen has information attached to it that makes the donor’s identity readily ascertainable. When tissue is collected through a physical intervention (such as a blood draw) specifically for research, the donor is a human subject, and an IRB oversees the recruitment of donors, the procedures used for collection, and the information provided to obtain consent.5 However, as discussed below, merely giving consent to use of already excised tissue does not render the donor a human subject, unless the tissue has information that makes the donor’s identity readily ascertainable.
Once the tissue has been obtained, it is available for laboratory research, subject to the usual rules for oversight of recombinant DNA research by IBCs. This pattern of regulation is the same regardless of whether genome editing will be carried out on the tissues.
5 Donating embryos or fetal tissue remaining after miscarriage or abortion does not render the donor a human subject unless identifying information about the donor is retained and insufficiently obscured.
Recombinant DNA Research and Institutional Biosafety Committees
Research with human tissues and cells that takes place entirely within a laboratory and does not involve either preclinical testing on nonhuman animals or clinical testing on humans is subject to regulations and requirements, many focused primarily on ensuring the safety of the laboratory environment for workers. For experiments subject to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines), there is a requirement that the research be reviewed and approved by an IBC. The NIH Guidelines are applicable to all research that is conducted at or sponsored by an institution that receives NIH funding for such research; however, many institutions follow requirements of the NIH Guidelines even when they are not required. IBCs review nearly all forms of research utilizing recombinant (or synthetic) nucleic acid molecules at the local institutional level (e.g., university or research center). The IBCs ensure research is conducted in conformity with the biosafety provisions of the NIH Guidelines and assess the research for potential risks to human health and the environment. This biosafety review is accomplished by assessing the appropriate physical and biological containment for the research and ensuring the researchers are adequately trained to conduct the work they are proposing safely.
An IBC is required to have at least five members with expertise in recombinant or synthetic nucleic acid molecule technology, at least two of whom are independent of the institution at which the research is being conducted. The NIH Guidelines encourage institutions to open IBC meetings to the public when possible and when consistent with the protection of privacy and proprietary interests (NIH, 2013c). The NIH Guidelines also require institutions to make IBC meeting minutes available to the public upon request.
Human Tissue Use and Institutional Review Boards
Laboratory-based research using human tissue may also trigger certain human subjects protections, even though all the work is done in vitro. Two situations trigger this additional level of regulation.
First, as noted above, if the tissue is being collected from a living individual, specifically for research, this interaction generally will be subject to oversight by an IRB. Although IRBs are designed primarily to protect the rights and welfare of research subjects in clinical investigations, the act of collecting tissue for research is considered to render the donor a research subject, even if subsequent work with the tissue will yield no information that could be traced to or in any way affect the donor.
The second situation may occur when tissue is collected without interaction with the person from whom it is derived, such as when surgical tissue that would otherwise be discarded is collected for use in research. If the tissue is sufficiently anonymized, the use of the tissue in research will not trigger IRB review. But if the donor’s identity can be readily ascertained, the donor is considered a research subject, and IRB review is triggered unless the work is eligible for exemption or waiver of some or all elements of informed consent.
The rules will change with respect to research using stored human specimens upon the effective date of the January 2017 revisions to the “Common Rule” that sets out the framework and requirements for human subjects research that is funded by most federal agencies and departments or is otherwise subject to its jurisdiction.6 Effective as of January 2018, the revised rule covering use of identifiable tissue
Allows the use of broad consent (i.e., seeking prospective consent to unspecified future research) from a subject for storage, maintenance, and secondary research use of identifiable private information and identifiable biospecimens. Broad consent will be an optional alternative that an investigator may choose instead of, for example, conducting the research on nonidentified information and nonidentified biospecimens, having an institutional review board (IRB) waive the requirement for informed consent, or obtaining consent for a specific study.
Establishes new exempt categories of research based on their risk profile. Under some of the new categories, exempt research would be required to undergo limited IRB review to ensure that there are adequate privacy safeguards for identifiable private information and identifiable biospecimens.7
6 The FDA has its own set of regulations governing human subjects research, which can differ in some details (e.g., regarding waivers of consent in minimal-risk research). Those regulations can be found at 21 Code of Federal Regulations (CFR) Part 50. The Common Rule applies to research funded by the following departments and agencies: Agency for International Development, Environmental Protection Agency, National Aeronautics and Space Administration, National Science Foundation (NSF), Social Security Administration, U.S. Department of Agriculture, U.S. Department of Commerce, U.S. Department of Defense, U.S. Department of Education, U.S. Department of Energy (DOE), U.S. Department of Health and Human Services (HHS), U.S. Department of Homeland Security, U.S. Department of Housing and Urban Development, U.S. Department of Labor, U.S. Department of Transportation, and U.S. Department of Veterans Affairs. Historically, genetics research funding has come from NSF, DOE, and HHS, in particular (Rine and Fagen, 2015). The Common Rule also applies to research conducted at institutions that have voluntarily extended the rule’s application to research funded by sources other than those listed above.
7 Federal Policy for the Protection of Human Subjects; Final Rule Federal Register, Vol. 82, no. 12 (January 19, 2017), 7149-7274.
The rules governing use of anonymous, de-identified, or coded materials8 will allow for even broader use. Research will be exempted from all or most IRB oversight if it is for secondary research use9 of identifiable private information and identifiable biospecimens for which consent is not required, and when
- The identifiable private information or identifiable biospecimens are publicly available;
- The information is recorded by the investigator in such a way that the identity of subjects cannot readily be ascertained, and the investigator does not contact subjects or try to re-identify subjects;
- The secondary research activity is regulated under HIPAA [Health Insurance Portability and Accountability Act] or
- The secondary research activity is conducted by or on behalf of a federal entity and involves the use of federally generated nonresearch information provided that the original collection was subject to specific federal privacy protections and continues to be protected.
With IRB review comes a set of protections focused on ensuring that the risks (physical, psychological, and socioeconomic) and possible benefits to the research subject and society are in reasonable balance. Furthermore, except when eligible for waiver, informed and voluntary consent is required from the research subject (in the present context, the person whose tissue is being used) or from a legally authorized representative.
Additional Rules Governing Laboratory Research on Human Gametes and Embryos
Basic science research on genome editing may entail experimentation on human gametes and embryos, with no intention of performing intrauterine transfer to establish a pregnancy in a woman (see Chapter 3). Indeed, such in vitro research on embryos has already proceeded in China (using nonviable embryos) and has been approved (with viable embryos) by the
8 Anonymous tissue is collected and stored without any personal identifiers at any time; de-identified tissue has earlier identifiers removed; and coded tissue has identifiers that are obscured by virtue of coding. Where the investigators lack easy access to a key with which to break the code, the tissue will no longer have a personal identity that is “readily ascertainable.”
9 “By “secondary research,” this exemption is referring to reusing identifiable information and identifiable biospecimens that are collected for some other “primary” or “initial” activity. The information or biospecimens covered by this exemption would generally be found by the investigator in some type of records (in the case of information) or some type of tissue repository (such as a hospital’s department for storing clinical pathology specimens). Federal Policy for the Protection of Human Subjects; Final Rule Federal Register, Vol. 82, no. 12 (January 19, 2017), 7149-7274 at 7191.
relevant regulatory bodies in Sweden and the United Kingdom. Work also is proceeding on understanding human germ cell development, research in which genome editing is one of many tools that can be used to explore the roles of specific genes (Irie et al., 2015).
This laboratory research might take a number of forms, each raising slightly different ethical and legal issues. First, it might involve editing somatic tissue in such a way that gametes would or might also be affected. Second, it might involve editing an existing gamete or gamete progenitor, such as a spermatogonial stem cell, in vitro or in vivo. Third, it might involve editing an egg in the process of fertilization (e.g., during intracytoplasmic sperm injection), or editing an already fertilized egg (zygote) or embryo.
As long as the work on gametes and embryos remains preclinical—that is, there is no transfer for gestation—the regulatory oversight and limits in the United States derive from state embryo research laws or limitations imposed by federal or other funders. Should there be a clinical trial involving efforts to gestate the edited reproductive materials, the research would come under FDA jurisdiction, and approval of an Investigational New Drug (IND) application would be required prior to beginning each such trial (see Chapter 5 for discussion of such potential future applications).
In the United States, the public policy issues surrounding laboratory research with human embryos were debated extensively by the 1994 NIH Human Embryo Research Panel, which was convened to provide recommendations to the Advisory Committee to the NIH Director. Its conclusions reflect the view that embryos should be regarded as different from ordinary human tissue but nonetheless be used for some areas of research if in the service of important scientific knowledge that cannot be obtained with less controversial methods. In addition, the panel’s report called for the use of human embryos at the earliest stages and in the smallest numbers consistent with needs of the research. Except in very limited circumstances, the panel called for use of only those embryos that, although originally created in the course of a reproductive effort, now would otherwise be discarded. Donation to research would require the informed consent of those who had created the embryos for reproductive purposes (NIH, 1994). While technically the panel’s report addressed conditions for federal funding of research that uses human embryos (which was subsequently prohibited by congressional action10), its recommendations came to be recognized within
10 The Dickey-Wicker Amendment prohibits the use of most federal funds for research that involves creating or destroying embryos, and for research that puts embryos at risk of injury or destruction except when necessary to increase their chance for healthy development. The amendment has been attached to the annual appropriations bills for the Departments of Health and Human Services, Labor, and Education since 1996.
the scientific community as a more general evaluation of the ethics and acceptability of such research.
Regulatory protections for human research subjects do not apply to the ex vivo embryo.11 Nonetheless, many (if not most) institutions housing embryonic stem cell research have put voluntary oversight measures in place (Devereaux and Kalichman, 2013), and the International Society for Stem Cell Research recently adopted guidelines calling for expanding these oversight committees to almost all research involving human embryos, regardless of whether stem cells will be derived and regardless of funding source (ISSCR, 2016b).
Some preclinical research on germline genome editing would likely take advantage of embryos left over from reproductive attempts using in vitro fertilization (IVF). Although no official numbers are available, a conservative estimate indicates that more than one million embryos, most of them produced but ultimately not used for IVF, remain in storage across the United States (Lomax and Trounson, 2013), with many more being stored around the world. As noted earlier, U.S. federal funding for research on embryos generally is prohibited. The work can, however, be supported with funds from individual states and private sources, often with policies similar to those proposed by the 1994 embryo research panel. California, for example, has been funding embryo research and embryonic stem cell research for a decade using funds from a state bond issued during the years when federal funding was limited to a small number of older embryonic stem cell lines. Connecticut, Maryland, New Jersey, and New York also created funds for research that could not be federally funded (NIH, 2016c).
Genome-editing research that generates human gametes from pluripotent stem cells would not be governed by the laws or funding policies governing embryo research unless a fertilized egg would be made in order to test the gametes. A single-cell fertilized egg is treated as if it were an embryo for most relevant state and federal laws, and restrictions on the work or on the funding would apply. In addition, such a step would constitute making an embryo solely for research purposes (i.e., without any intent to gestate the embryo and bring a fetus to term), and this has remained the most controversial form of embryo research in the United States. Some of those opposed to making embryos in research argue that fertilization brings a new, morally significant human being into existence, and that making embryos for research purposes is inherently disrespectful of human life and potentially open to significant abuses (NIH, 1994, p. 42). In some cases, this reasoning is extended to encompass totipotent cells made with somatic cell nuclear transfer (“cloning”). Even those who do not accord full moral
On the other hand, the panel concluded that making embryos is justified when “the research by its very nature cannot otherwise be validly conducted” or when it is necessary for a study that is “potentially of outstanding scientific and therapeutic value” (NIH, 1994, p. 45). This would appear to include research on in vitro-derived gametes and on techniques for avoiding mitochondrial disease, neither of which were on the immediate horizon for human application at the time of the embryo research panel’s report. The genome-editing research necessary to test edited gametes would seem to fall within this exception, as would the introduction of genome-editing components along with sperm during IVF procedures such as intracytoplasmic sperm injection. Among those countries that permit research on human embryos, rules differ on whether this exception also would permit making embryos specifically for research (UNESCO, 2004b).
Oversight in Other Nations for Research Using Human Embryos
As noted earlier, in the United States, a handful of states have laws governing or forbidding research using human embryos (NCSL, 2016). At the federal level, there is no prohibition on such research, although there are limits on the use of federal funds to perform the research.
By contrast, much of what is permitted in the United States would be more tightly regulated in the United Kingdom, where research on human gametes and embryos is subject to review by the Human Fertilisation and Embryology Authority, and a license is required for each specific set of experiments. (See Chapter 5 for discussion of clinical use of germline editing.) In other countries, such as Chile,12 Germany (DRZE, 2016), Italy (Boggio, 2005), Lithuania,13 and Slovakia,14 the research would not be legal under any regulatory regime.
This variation in governance approaches reflects the fact that research with gametes, and in particular with embryos, has been controversial in many countries. Views on the legal and moral status of the human embryo range from treating it the same as any other human tissue, to considering
12 Chile, Congreso Nacional, Sobre la investigacion cientifica en el ser humano, su genoma, y prohibe la clonacion humana, September 22, 2006, no. 20.120, art. 1, Witherspoon Council staff translation, http://www.leychile.cl/Navegar?idNorma=253478 (accessed April 25, 2017) (Spanish).
13 Lithuania, Seimas, Law on Ethics of Biomedical Research, no. VIII-1679, May 11, 2000, last amended June 26, 2014, no. XII-981, art. 3, § 2, http://e-seimas.lrs.lt/rs/legalact/TAD/d7231dc0489411e4ba2fc5e712e90cd4 (accessed April 25, 2017).
it a tissue deserving of some extra degree of respect, to viewing it as tissue that should be accorded the same respect or even the same legal rights as a live-born child. These views vary both among and within countries and reflect both religious and secular influences. The result has been public policies ranging from permissive, to regulated, to prohibitionist.
While genome editing is a powerful new technology for making genetic modifications in cells, its use in the context of research on human embryos raises issues essentially the same as those discussed in the past: the moral status of the embryo, the acceptability of making embryos for research or using embryos that would otherwise be discarded, and the legal or voluntary limits that apply to the use of embryos in research (CIRM, 2015; ISSCR, 2016b; NIH, 1994, 2015b). This report does not address those ethical arguments, and accepts as given the current legal and regulatory policies that apply in each country. If any of those general policies were to change in the future, genome-editing research would be affected as well.
Research Using Nonhuman Animals
The 1966 Animal Welfare Act (7 U.S.C. § 2131), the federal law covering the use of animals in research, regulates testing and maintenance of a number of species, although notably not some of those which are most commonly used, such as rats and mice. It is enforced by the U.S. Department of Agriculture’s (USDA’s) Animal and Plant Health Inspection Service, and at the local level requires that research institutions establish an institutional animal care and use committee “to oversee and evaluate all aspects of the institution’s animal care and use program,” such as ensuring that the standards for physical containment and pain minimization are met.
If genome-editing research at any point were to require the creation of chimeric organisms, funding from NIH would come with rules limiting certain combinations (NIH, 2015a). NIH has recently requested public comment on proposed changes to provisions relevant to chimeras in its guidelines for human stem cell research, including work that involves chimeras (NIH, 2016b).
Clinical Trials of Human Genome Editing—The Role of IRBs
Clinical genome-editing trials—that is, studies involving human subjects—cannot commence without permission from the FDA, the details of which are discussed below. Along with FDA review, three other bodies—IRBs, IBCs, and the RAC—have clinical trial oversight responsibilities for genome editing.
IRB review and approval focuses on the risks and benefits of a clinical study and on the manner in which people are recruited for the study. It is
required for any research involving human subjects that is supported by the U.S. Department of Health and Human Services (HHS) or regulated by the FDA. It is also required for research conducted or supported by any of the other federal agencies subscribing to the Common Rule, for research on products regulated by the FDA, and for research conducted by investigators at any institution that has voluntarily extended these protections to research that is otherwise not subject to these rules. The Common Rule addresses research with living individuals, and some federal funding agencies have adopted additional rules specifically with respect to research with fetuses. Research on embryos, as noted earlier, is regulated separately by some states and through federal funding restrictions.
IRBs have the authority to approve or deny approval for research protocols, human subject recruitment plans, and informed consent documents. They also may require modifications to a protocol as a condition of approval. IRBs also oversee amendments to ongoing studies and can suspend studies proving to be problematic—for example, due to the rate or severity of adverse events. In this task, IRBs may be assisted by data and safety monitoring boards, designed to track interim data while a study is ongoing. They provide additional expert and independent review to help ensure that a study continues to meet the standard for a reasonable balance of risks and potential benefits and that the information provided during initial recruitment of subjects remains a fair reflection of their risks and benefits as additional information is obtained during the study.
Federal regulations do not specify whether an IRB must hold open meetings or make its minutes and other documents available to the public; these are matters for individual institutional policies or state law. But an IRB, in addition to including experts with appropriate technical training, must include at least one member whose primary concern is in a nonscientific area and one lay member who is not otherwise affiliated with the institution. In addition, an IRB has the discretion to invite individuals with competence in special areas to assist in the review of complex issues.
Federal regulations require an IRB to determine that risks to research subjects are minimized and are reasonable in relation to the potential benefits to the subjects and the importance of the knowledge that may be expected to result from the research. They are also required to ensure that selection of subjects is equitable and that subjects are freely volunteering for the research with sufficient information. In pediatric protocols, risk tolerance is lower. If benefit to the child is possible, the research may proceed with the consent of one parent and risk tolerance will be geared to the potential benefits. But if the research offers no prospect of medical benefit, the child may not be exposed to more than a “minor increment over minimal risk” absent special intervention by the secretary of HHS.
When research is done on fetuses, certain federal funders insist on
special provisions related to the degree of risk that is permitted and to how (and from whom) consent must be sought (Subpart B 45 CFR 46); while not required, these same provisions may be adopted by investigators who use other funds. These provisions state that risk to the fetus is tolerated when it has been minimized to the extent possible and when it is balanced by the prospect of direct benefit for the pregnant woman or the fetus. If there is no such prospect of benefit, the risk to the fetus may not be greater than minimal, and the purpose of the research must be the development of important biomedical knowledge that cannot be obtained by any other means. Consent by the pregnant woman is sufficient when the research holds the prospect of benefit to her as well as the fetus. If the research holds the prospect of benefit only to the fetus and not to the pregnant woman herself, then paternal consent is also required, if feasible.
Requiring voluntary and informed consent is one of the key protections for human subjects. The elements, as listed in HHS regulations, include among other items
- an explanation of the purposes of the research, the procedures that will be used, and whether any procedures are experimental;
- a description of any reasonably foreseeable risks or benefits to the subject or to others;
- a disclosure of appropriate alternative procedures;
- a statement describing the extent, if any, to which confidentiality will be maintained;
- for research involving more than minimal risk, an explanation as to whether any compensation and medical treatments are available in case of injury; and
- a statement that participation is voluntary, refusal to participate will involve no penalty, and that the subject may discontinue participation at any time.15
First-in-human trials make compliance with these provisions difficult, given that by definition, it is very difficult to assess the degree of uncertainty that pertains when research is moving from preclinical models to human interventions. Nonetheless, such trials must take place, and IRBs work to ensure that subjects not only understand what is known from preclinical work but also appreciate the existence of knowledge gaps that will affect the extent to which the outcome of the trials can be predicted.
The federal rules include a provision stating that an “IRB should not consider possible long-range effects of applying knowledge gained in the
15 Federal Policy for the Protection of Human Subjects; Final Rule Federal Register, Vol. 82, no. 12 (January 19, 2017), 7149-7274 at 7266.
research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility” (21 CFR 56.111(a)(2)). This provision therefore excludes from IRBs the power to withhold approval of a study solely because the knowledge it produces or the policies it affects may be socially controversial or because of fears that the study will represent the beginning of a slippery slope to future applications that are controversial. The provision does, however, allow IRBs to withhold approval of a study because it may cause physical, psychological, or emotional harm to the subjects.
Clinical Trials of Human Genome Editing: The Role of the Recombinant DNA Advisory Committee
The late 1960s and early 1970s saw the rapid progression of the concepts and technology that led to the first intentional creation of recombinant DNA molecules (Berg and Mertz, 2010). The RAC was established by then–NIH Director Donald Frederickson in 1974 in response to scientific, public, and political concerns about the potential use and misuse of recombinant DNA technologies, as well as the associated known and unknown risks. The proposed RAC membership included requirements designed to ensure broader public perspective, such as a diverse membership that included scientists, clinicians, ethicists, biosafety experts, theologians, and public representatives, among others. Over time, the RAC’s membership and responsibilities have evolved in response to scientific developments and shifting public concerns.
Early actions by the RAC included requiring that every research institution create a biohazard review committee (later renamed an IBC) to review risks and certify the presence of adequate safety measures. The major initial task of the RAC was the drafting of guidelines for recombinant DNA research discussed that, while lacking the legal force of regulations, have had an enormous influence on practices for preventing the unintended release of or human exposure to genetically modified organisms and material (Rainsbury, 2000). The NIH Guidelines are a term and condition of NIH funding, and are applicable to all recombinant DNA research that is conducted or sponsored by a public or private institution that receives NIH funding for any such research (NIH, 2013a). Many other U.S. government agencies and private institutions require that their funded research be conducted in accordance with the NIH Guidelines (Corrigan-Curay, 2013).
Initially, the RAC reviewed and approved all proposals for gene-transfer research protocols to be performed at institutions receiving NIH funds for recombinant DNA research and advised the NIH director on the issuing of official approvals, as technically, official approvals came from the NIH director, based on the RAC’s decision (Freidmann et al., 2001). Over time,
the interplay between RAC review and FDA review has evolved. The RAC’s initial focus on safety broadened over time to include providing a venue for discussion of social and ethical issues. And in the mid-1990s, the FDA assumed sole authority to approve gene transfer research protocols, with some protocols selected for in-depth review and public discussion after an initial review by RAC members. Provision was also made for a compassionate use exemption process (Rainsbury, 2000; Wolf et al., 2009).
Appendix M of the NIH Guidelines is a “Points to Consider” document that details the requirements for human gene-transfer protocol submission and reporting and review by the RAC (NIH, 2013c). The NIH Guidelines state that “NIH will not at present entertain proposals for germline alteration” (p. 100). With regard to in utero gene transfer, the NIH Guidelines state that NIH may be willing to consider such research, but only after significant additional preclinical and clinical studies satisfy criteria developed at a RAC conference. In April 2015, the NIH director issued a statement that “NIH will not fund any use of gene editing technologies in human embryos” (Collins, 2015).
Within the entire system of oversight for gene-transfer research, the RAC provides a forum for the in-depth review and public discussion of a protocol. The IRBs convene in private, although, as noted earlier, they do include nonscientists as members. The public nature of the RAC is due to its status as a public advisory committee under the Federal Advisory Committee Act (FACA) of 1972. To comply with FACA regulations, the RAC must hold open meetings, giving advance notice of the time and place; provide minutes; and allow for public participation (Steinbrook, 2004).
The RAC also sponsors public symposia on important scientific and policy issues related to recombinant DNA research (Friedmann et al., 2001), providing a public forum for scientific, clinical, ethics, and safety experts along with the public to discuss emerging issues in the field of gene transfer. Along with the RAC’s protocol review and mechanisms for informing institutional oversight bodies, this transparent system is intended to optimize the conduct of individual research protocols and to advance gene-transfer research generally (O’Reilly et al., 2012). In this way, the RAC serves as an important channel for scientific debate, informing institution-level oversight, increasing transparency, and promoting public trust and confidence in the field of gene transfer.
In April 2016, amendments to the NIH Guidelines (NIH, 2016a) went into effect. Under the revised guidelines, which reflected many of the recommendations of an earlier National Academies study (IOM, 2014), individual human gene-transfer trials are limited to cases in which NIH concurs with a request from an oversight body (such as an IRB or an IBC) that has determined that a protocol would significantly benefit from RAC review and has met one or more of the following criteria:
- The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk.
- The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.
- The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for oversight bodies involved to evaluate the protocol rigorously. (IOM, 2014, p. 4)
Human gene-transfer protocols may also be reviewed by the RAC if the NIH director determines that the research presents significant scientific, societal, or ethical concerns. The RAC has reviewed several protocols involving the three major genome-editing technologies, and certain human genome-editing protocols, at this early stage of development, would be expected to meet these criteria.
Public Engagement Under the Auspices of the Recombinant DNA Advisory Committee
Public review of protocols for gene-transfer research is intended (1) to disseminate information so that other scientists can incorporate new scientific findings and ethical considerations into their research, and (2) to enhance public awareness of and build public trust in such research, allowing for a public voice in the review of the research (Scharschmidt and Lo, 2006). According to NIH’s Office of Science Policy (OSP), protocol review by the RAC serves many functions (Corrigan-Curay, 2013), including
- optimizing clinical trial design and increasing safety for research subjects, and in some instances strengthening biosafety protections necessary for researchers, health care workers, and close contacts of research subjects;
- improving the efficiency of gene therapy research by allowing scientists to build on a common foundation of new knowledge emanating from a timely, transparent analytic process; and
- informing the deliberations of the FDA, the NIH Office of Human Research Protections (OHRP), IRBs, IBCs, and other oversight bodies whose approval is necessary for gene therapy research projects to be undertaken.
The current process aims to be highly transparent. The OSP website provides information about protocols and the public discussions at the
RAC meetings, and the protocols themselves are made available to members of the public upon request (OBA, 2013). All correspondence between the RAC and investigators also is part of the public record for the protocol and is available to the investigators, sponsor(s), IRB(s), IBC(s), the FDA, and OHRP (NIH, 2013a). For protocols selected for in-depth review and public discussion, the protocol registration process is defined as complete when, following the review, the investigator receives a letter based on the recommendations discussed at the RAC meeting. The letter is also sent to the relevant IRB(s) and IBC(s) (NIH, 2013b). Minutes and webcasts of the RAC meetings are made available on the RAC’s public website. Neither investigators nor IRBs or IBCs are required to follow any of the RAC’s recommendations. Rather, a protocol’s approval comes from a collection of other regulatory bodies. A protocol must be approved by the relevant IBC(s) and IRB(s) before research participants can be enrolled in a clinical trial. These bodies often rely on the RAC’s recommendations in making their decisions, but the RAC’s approval per se is not required for the research to move forward (Wolf et al., 2009). The FDA, the agency responsible for regulatory approval, also takes into account the views of the RAC when reviewing IND applications (Takefman, 2013).
U.S. Food and Drug Administration Review of Investigational New Drug Applications
Regardless of the funding source, the FDA is the agency ultimately responsible for the regulation and approval of genome-editing products. Most of these products will be viewed as biologic drugs rather than devices. Thus, before being used in human trials, they will need to have FDA review and approval of their IND application. INDs for gene therapy are regulated by the Office of Tissues and Advanced Therapies (previously the Office of Cellular, Tissue and Gene Therapies) within the Center for Biologics Evaluation and Research (CBER). The review follows a regulatory framework in which the FDA and the sponsor interact throughout the product’s life cycle, from pre-IND to postmarketing surveillance.
CBER regulates a range of biologics, including human gene therapy products, and certain devices related to gene transfer. The FDA defines gene therapy products as products that “mediat[e] their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome . . . and [that] are administered as nucleic acids, viruses, or genetically engineered microorganisms” (FDA, 2006, p. 4). The general types of gene therapy products reviewed by the FDA to date, pursuant to its authority under the Federal Food, Drug, and Cosmetic Act (Public Law 75-717) and the Public Health Service Act (Public Law 78-410) as amended, are nonviral vectors (plasmids), replication-deficient viral vectors (e.g.,
adenovirus, adeno-associated virus), replication-competent oncolytic vectors (e.g., measles, reovirus), replication-deficient retroviral and lentiviral vectors, cytolytic herpes viral vectors, genetically modified microorganisms (e.g., Listeria, Salmonella, E. coli), and ex vivo genetically modified cells.
The FDA also maintains a federal advisory committee—the Cellular, Tissue and Gene Therapies Advisory Committee—that reviews and evaluates available data related to the safety, effectiveness, and appropriate use of human cells, human tissues, gene-transfer therapies, and xenotransplantation products that are intended for transplantation, implantation, infusion, and transfer in the treatment and prevention of a broad spectrum of human diseases and in the reconstruction, repair, or replacement of tissues for various conditions.16
The FDA process applies to all gene-therapy clinical research, regardless of funding source. During the FDA’s review of INDs and its subsequent review of major steps in the research process (e.g., movement from phase I to phase II studies), any RAC preliminary scientific and ethical review of human gene transfer, as well as its public discussion of novel applications, is taken into account (Takefman, 2013). Unlike RAC review, the FDA’s review process for granting an IND to begin a gene-therapy clinical trial is closed to the public. To go on the market, products must have received approval of their Biologic Licensing Application (BLA) (21 CFR 600-680), which focuses on manufacturing information, labeling, and preclinical and clinical studies. The process for approving the BLA may include some public participation. Many first-in-class products are taken to an advisory committee, which typically includes members with medical and scientific expertise, as well as ethicists, industry representatives, and patient representatives. These meetings often represent the FDA’s first public discussion of a new medical product, providing access to information for patients, physicians, and other stakeholders who observe the meeting, and to those who use the meeting transcripts made available on the agency website. Meetings are publicly announced in advance, and include public comment periods.
The FDA offers assistance to the research community in the form of “Points to Consider” documents that present the current thinking of FDA/CBER staff about important issues in gene transfer and gene therapy (FDA, 1991). These documents are intended to guide investigators in understanding FDA perspectives and requirements for development and testing as they prepare their IND applications. In 2015 the FDA released “Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products” (FDA, 2015b).
To ensure that all regulatory requirements are met, the FDA encourages a “pre-IND” meeting between investigators and agency officials early
16 51 Federal Register 23309 (1986).
in the protocol development process at which specific questions related to the planned clinical trial design are discussed. The meeting also provides an opportunity for the discussion of various scientific and regulatory aspects of the medical product as they relate to safety and/or potential clinical hold issues,17 such as plans for studying the gene-transfer product in pediatric populations (FDA, 2001). For the meeting, the investigator must submit an information package that describes the structure of the gene-transfer product, its proposed clinical indication, dosage, and administration; provides preclinical and clinical study descriptions and a data summary; includes chemistry, manufacturing, and controls (CMC) information; and specifies objectives expected from the meeting (FDA, 2000).
For certain types of protocols—including those involving gene-transfer products—it is sometimes necessary to discuss special issues regarding recombinant DNA proteins from cell-line sources, such as the adequacy of characterization of cells, potential contamination of cell lines, removal or inactivation of adventitious agents, or potential antigenicity of the product (FDA, 2015b). An investigator is expected to consider and address FDA guidance resulting from the pre-IND meeting before submitting an application for an IND.
As a general rule, when reviewing IND submissions, the FDA balances potential benefits and risks to participants in the clinical trials (Au et al., 2012; Takefman and Bryan, 2012). Once the investigator has submitted the IND, the FDA has 30 days either to allow it to proceed or to put it on clinical hold while more data are obtained from the sponsor. The application includes details on product manufacturing, safety and quality testing, and purity and potency, as well as preclinical, pharmacological, and toxicological testing. Safety testing required specifically of gene-therapy products includes (1) potential adverse immune responses to the ex vivo transduced cells, the vector, or the transgene; (2) vector and transgene toxicities, including distribution of the vector to germ cells in testicular and ovarian tissues; and (3) potential risks of the delivery procedure (FDA, 2012b).
The clinical protocol section of the application includes information about phase I, II, and/or III studies, including starting dose, dose escalation, route of administration, dosing schedules, definition of patient population (detailed entry and exclusion criteria), and safety monitoring plans. It also includes information regarding study design, including description of clinical procedures, laboratory tests, or other measures to be used to monitor the effects of the product. Because vectors and transgenes of gene-therapy
17 A clinical hold is an order to delay a proposed clinical investigation or suspend an ongoing investigation. Conditions for issuing a clinical hold include unreasonable risk to research subjects or discovery of information that undermines confidence in the investigators or the study protocol (Clinical Holds and Requests for Modification, 21 CFR, Sec. 312.42 [April 1, 2016]).
products may persist for the lifetime of the research subject, the FDA has issued guidance on observation of subjects for delayed adverse events (FDA, 2006).
Federal regulations require that information about many clinical trials be posted at ClinicalTrials.gov, the government’s database for information about a large proportion of clinical trials, or a similar site. This applies to many clinical trials of drug products (including biological products) and device products that are regulated by the FDA. Effective as of January 2017, there is an expanded registry with additional results data to help patients find trials.18 The goals are to enhance trial design, to prevent duplication of unsuccessful trials, to improve the evidence base and efficiency of drug and device development, and to build public trust.
In accordance with statutory mandates, however, there is little or no transparency in FDA reviews during the IND stage, including whether the agency is considering an IND for a specific product. But once the FDA has approved a license for a product, it may post the clinical, pharmacological, and other technical reviews of the product on its website (see, for example, information for Ducord, an umbilical cord–derived, stem cell product for use in certain transplantation procedures, as reported by Zhu and Rees ). Although proprietary information is redacted from these posted reviews, the clinical reviews provide considerable information about the trials.19 They may summarize early-stage discussions about trial design and assessments of whether sponsors conformed to certain ethical and good trial practice standards. When necessary, the FDA can engage its Cellular, Tissue and Gene Therapies Advisory Committee to receive public input on a pressing issue of broad applicability.
The FDA’s Sentinel Initiative—launched in 2008 to establish a national risk identification and analysis system using electronic health care data to monitor the safety of drugs, biologics, and devices after they have reached the market—complements the Adverse Event Reporting System. Through Sentinel, the FDA can access information from electronic health records, insurance claims data and registries, and other sources using a process that also maintains patient privacy. CBER has launched several projects within Sentinel aimed at improving postlicensure safety surveillance of vaccines and other biologics. In addition to monitoring, other postmarket quality control measures include registries, special patient information pamphlets, and requirements for formal phase IV studies. The European Union has its
18 81 Federal Register 64981-65157.
19 Section 916 of the Food and Drug Administration Amendments Act (2007) requires posting of certain information about a BLA approval on the FDA website. See SOPP8401.7 Action Package for Posting, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm211616.htm (accessed February 2, 2017).
own tools for postmarket monitoring and control, different in detail but similar in purpose (Borg et al., 2011).
Once the FDA has approved a drug, it may be prescribed for uses that differ from those for which it was approved and labeled. As noted earlier, such off-label prescribing is a legal and common practice of health care providers when they deem it medically appropriate. This may mean use of the product for a different medical condition from that for which it was approved (e.g., approved for one kind of cancer and used for another), or its administration at different doses, in different forms, or to different categories of patients. Off-label prescribing allows for physician discretion and the efficient use of information following a drug’s initial approval, while still maintaining postmarket surveillance for safety. In the United States, some areas of medicine, such as pediatrics (AAP, 2014) and cancer care (American Cancer Society, 2015), are known to have a high rate of off-label use.
There are a number of mechanisms by which products may follow an accelerated regulatory pathway, including Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review (FDA, 2015a). The means used to accelerate the review range from earlier, more frequent, and more intensive consultations with FDA staff; to easing rules for the submission of materials; to changing the endpoints required in the study; to conducting the review before that of other products for which the applications were submitted earlier.
This provision for accelerated review was expanded to include regenerative medicine and other cell therapy products in the 21st Century Cures Act,20 signed into law in December 2016. The act allows for approval of a “regenerative-medicine therapy” based on surrogate endpoints reasonably expected to predict clinical outcomes and on evidence provided by a wider range of sources, including those outside the realm of controlled clinical trials. Postapproval measures can still include requirements for further trials, as well as surveillance, patient information brochures, registries, and other risk mitigation measures. This process resembles to some extent the “conditional approval” mechanism adopted in Japan for regenerative-medicine products, although it lacks any trigger that automatically withdraws approval if postmarket risk mitigation and clinical trial commitments are not fulfilled.
The therapies being developed with human genome editing were not excluded from this new expanded category, and some might be eligible for a variety of accelerating mechanisms if they meet the definition of
20 21st Century Cures Act, Public Law No. 114-255, HR 34, 114th Cong. (2015-2016) (https://www.congress.gov/bill/114th-congress/house-bill/34/text?format=txt). See also http://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm537670.htm (accessed January 30, 2017).
“regenerative-medicine therapy” (which “includes cell therapy, therapeutic tissue engineering products, human cell and tissue products”), as well as the criterion of having the potential to fulfill an unmet need for a “serious or life-threatening disease or condition.” Since passage of the new law, the FDA has been working on implementing these provisions and considering a number of issues, including the scope of the products that meet the definition of regenerative-medicine therapy as specified in the legislation. As written, though, the criterion of fulfilling an unmet need for a serious or life-threatening disease would seem to exclude intended uses for enhancement.21
The Interplay Between the FDA and the NIH RAC
Concern about the conduct of gene-transfer trials reached a new level of intensity after the 1999 death of Jesse Gelsinger, a participant in one such trial (Shalala, 2000; Steinbrook, 2002). In response, NIH took steps to coordinate reporting of adverse events and expand public access to information regarding human gene transfer trials, for example, through the creation of the Genetic Modification Clinical Research Information System (GeMCRIS) (NIH, 2004). This database, which became operational in 2004, includes summary information on human gene-transfer trials registered with NIH (2004). Included in the GeMCRIS summaries is information about the medical conditions under study, institutions where trials are being conducted, investigators carrying out these trials, gene products being used, and routes of gene product delivery, as well as summaries of study protocols.
Differences remain between the RAC’s and the FDA’s approach to oversight of gene-transfer research. The FDA, as the sole federal regulatory agency for biomedical products in the United States, focuses on safety and efficacy when evaluating gene-transfer products, from the first time they are used in humans through their commercial distribution (Kessler et al., 1993) and over the lifetime of their use. FDA regulation includes many steps that, by statutory provision, are confidential because of the presence of proprietary information (Wolf et al., 2009). In contrast, the RAC is able to address broader scientific, social, and ethical issues raised by gene-transfer and gene therapy research, and—unlike IRBs—the RAC is permitted to address these broader issues in its review of individual protocols as well (NIH, 2016b, Sec. IV-C-2-e). In addition, RAC review is conducted publicly by experts who are not employed by the government (Wolf et al., 2009).
21 21st Century Cures Act, Public Law No. 114-255, HR 34, 114th Cong. (2015-2016) (https://www.congress.gov/bill/114th-congress/house-bill/34/text?format=txt [accessed January 30, 2017]).
To encourage communication between the agencies, the RAC charter calls for a member of CBER to be one of the nonvoting federal representatives to the RAC (NIH, 2011). NIH and the FDA also have harmonized reporting of adverse events.
As noted by former FDA Commissioner Robert Califf, “[s]cientific advances do not adhere to national boundaries and therefore it is critical that we understand the evolving views of our international counterparts.” To that end, the FDA actively participates in the International Pharmaceutical Regulators’ Forum and its Gene Therapy working group for the purpose of exchanging technical information and identifying areas for regulatory coordination (Califf and Nalubola, 2017).
The regulatory pathways for gene therapy in other jurisdictions are similar to those in the United States in important ways (see Appendix B), particularly with respect to the centrality of premarket risk and benefit assessment. For example, gene therapy in South Korea has a pathway very similar to that in the United States except that it includes a system of conditional approval that allows for use with less robust evidentiary bases. The United Kingdom has rigorous premarket risk and benefit review, as in the United States, but singles out therapies involving gametes or embryos for more intensive regulation (see Box 2-2). The European Union has additional layers of quality control for “advanced therapy medicinal products,” which would include some gene therapy products, although as in the United States, off-label use would be permissible (George, 2011). Japan uses a system for gene therapy products that resembles the U.S. device regulations, in which new products are sorted prospectively by level of anticipated risk and regulated accordingly. Singapore also has adopted a risk-based approach, with such criteria as whether the manipulation is substantial or minimal; whether the intended use is homologous or nonhomologous;22 and whether it will be combined with a drug, a device, or another biologic. These criteria resemble many of those used by American authorities in determining whether tissues should be subject to rules governing transplant medicine or rules governing the marketing of cell-therapy products (Charo, 2016b). Box 2-2 illustrates the differences between the United States and other regulatory regimes by describing the example of the United Kingdom.
22 The FDA defines homologous use as the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with a human cell, tissue, or cellular or tissue-based product (HCT/P) that performs the same basic function or functions in the recipient as in the donor (21 CFR 1271.3(c)), including when such cells or tissues are for autologous use.
Genome editing holds great promise for preventing, ameliorating, or eliminating many human diseases and conditions. Along with this promise, however, comes the need for ethically responsible research and clinical use.
The existing U.S. regulatory structures discussed in this chapter provide a starting framework for governance of laboratory research, preclinical testing, clinical trials, and potential medical uses involving human genome editing in the United States, as well as for an understanding of differences between the U.S. system and the regulatory infrastructures of other nations.
There is considerable similarity in the structures for product regulation among different jurisdictions, with an emphasis on premarket balancing of risk and benefit. Some differences exist in the availability of conditional approval or other accelerated approval mechanisms for cell-therapy products, as well as in the management of embryos and gametes. In clinical care, off-label use is commonly permitted, again with the notable exception of the more comprehensive controls on therapies involving embryos and gametes in the United Kingdom.
Overall, while capable of improvement, the structure of the U.S. regulatory system is adequate for overseeing human genome-editing research and product approval. Specific areas in which additional effort might be made are identified in Chapters 3-7.
RECOMMENDATION 2-1. The following principles should undergird the oversight systems, the research on, and the clinical uses of human genome editing:
- Promoting well-being
- Due care
- Responsible science
- Respect for persons
- Transnational cooperation
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