Gene transfer research is a rapidly advancing field that draws from genetics, molecular biology, and clinical medicine. It has fascinated scientists and the public but, particularly in its early years, has also raised anxieties about its potential for harm to individuals and communities. These anxieties prompted the creation of special oversight procedures for gene transfer research.
CHARGE TO THE COMMITTEE
The Institute of Medicine (IOM), in collaboration with the National Research Council, convened an ad hoc committee to provide an independent review and assessment of the role of the Recombinant DNA Advisory Committee (RAC) in advising on clinical gene transfer protocols at the request of the Office of the Director of the National Institutes of Health (NIH). Specifically, NIH asked the committee to specify the scientific, safety, ethical, and other concerns that justify a special level of oversight for this and potentially other areas of clinical research. The committee was to consider the current regulatory context, which includes the U.S. Food and Drug Administration (FDA) and institutional bodies, and determine whether gene transfer research raises issues of concern today that warrant additional individual protocol review by the RAC. If the committee concludes that this particular function of the RAC should remain intact, it was asked to describe the criteria that the RAC should use to select protocols for review (see Box 1-1).
In response to a request from the Office of the Director of the National Institutes of Health (NIH), an ad hoc committee of the Institute of Medicine (IOM) will provide an independent review and assessment of selected activities of the NIH’s Recombinant DNA Advisory Committee (RAC). Specifically, the committee will determine if gene transfer research raises issues of concern that warrant extra oversight by the RAC of individual clinical trial protocols involving gene transfer techniques and will describe the criteria used in making this determination. If the committee determines that RAC oversight is still warranted, it will recommend criteria to guide when the RAC should review this research. In conducting the review and assessment, the committee will give due consideration to the current state of the science. It will also consider the current regulatory and policy context, including the roles of the U.S. Food and Drug Administration, institutional review boards, institutional biosafety committees, and other entities in overseeing gene transfer research and also the scientific, safety, ethical, and other concerns and objectives that would justify a special level of oversight for this area of research (and potentially others).
WHAT IS GENE TRANSFER RESEARCH?
The technique of gene transfer can be broadly understood as the introduction of genetic material, through a vector, into cells with the intent of altering gene expression (Kay, 2011). The NIH Office of Biotechnology Activities (OBA) currently defines clinical gene transfer research as
the deliberate transfer into human research participants of either 1) recombinant nucleic acid molecules, or deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) derived from recombinant nucleic acid molecules, or 2) synthetic nucleic acid molecules,1 or DNA or RNA derived from synthetic nucleic acid molecules that either contain more than 100 nucleotides; or possess biological properties that enable integration into the genome; or have the potential to replicate in a cell; or can be translated or transcribed. (NIH, 2013, p. 17)
1Synthetic DNA, a more recent genetic engineering technology, differs from rDNA in that it does not require a preexisting DNA sequence template. Instead, it is possible to chemically synthesize nucleic acids to form a double-stranded DNA molecule de novo (Clark, 2005).
The committee worked with a more general and functional definition of gene transfer: the transfer of nucleic acids (or a nucleic acid–like molecule) into a cell using ex vivo or in vivo techniques, intending to produce a biological effect, which could include therapeutic or symptomatic effects in humans. This expanded definition of gene transfer accommodates newly emerging technologies that would test the limits of the standard used by OBA, such as mitochondrial DNA transfer or the techniques of gene transfer using pluripotent stem cells.
OVERSIGHT OF CLINICAL GENE TRANSFER TRIALS
Some observers argue that human gene transfer research2 is the most heavily regulated type of biomedical research (Kahn, 2009). Because clinical gene transfer trials involve both rDNA and human subjects, investigators must submit clinical gene transfer protocols to the RAC and FDA at the federal level and to institutional review boards (IRBs) and institutional biosafety committees (IBCs) at the local level before human subjects can be enrolled. The history and changes over time in gene transfer research oversight demonstrate the difficulties and advantages of oversight by more than one agency. For example, the partially overlapping functions of NIH and FDA have prompted much discussion about tension between transparency and protection of proprietary information, between preventing harm and encouraging scientific progress, and between creating standards and remaining responsive to an evolving area of science (Wolf et al., 2009).
The additional layer of review has been the source of discussion and frustration within the research and patient-advocacy communities. Gene transfer is not the only clinical research that receives additional oversight, however. Several forms of clinical research receive additional levels of scrutiny, including but not limited to certain forms of pediatric research, research with pregnant women and fetuses, and research involving prisoners (Wolf and Jones, 2011).
2Gene transfer is the introduction of a genetic sequence with any function into a cell for research or diagnostic purposes. The process of gene transfer may or may not have a therapeutic purpose or demonstrated therapeutic effect. Gene therapy is gene transfer, but with the intent to produce beneficial health consequences.
Establishment of the RAC
As scientists began to experiment with rDNA technologies in the early 1970s, ethicists, policy makers, and many scientists raised concerns about the potential hazards that genetic engineering posed to individuals, communities, and future generations. In the early days of gene transfer investigations, a critical argument was that the technology was so novel and its risks so little understood that it warranted special review (see, for example, Rainsbury , Wolf and colleagues , and Chapter 3 of this report).
From virtually the outset, the development of rDNA technology has raised concerns about its risks (see, for example, Berg and Mertz , Fredrickson , OTA , President’s Commission , and Rainsbury ). These concerns can be roughly divided into three categories. One category—the subject of most early discussion—focuses on biohazards that might harm investigators and laboratory staff or affect the wider community. The potential hazards cited at the time included the creation of new cancer risks from altered organisms and the emergence of novel, deadly pathogens.
A second category of concerns, which intensified as scientific investigations approached the phase of studies in humans, focuses on shortand long-term health risks to individual research participants. Related concerns include the extent to which preclinical studies would provide sufficient evidence that it was ethical to proceed with human investigation and the extent to which potential research participants (or their parents or guardians) could be adequately informed about risks and could provide informed consent. These issues were considered and debated in the broader context of evolving views on ethical principles for research involving humans and continuing efforts to apply more explicit and stringent protections through education, regulation, and other means (DHEW, 1971). A key product of this evolution was the creation, under federal guidelines, of IRBs to review and approve federally funded biomedical and social-behavioral research involving human subjects, including gene transfer research.
A third category of concerns involves risks to future generations. A primary focus here is rDNA investigations involving germ-line cells that could produce heritable changes in organisms; concern has also been expressed about somatic-cell studies that unintentionally do so (RAC, 1990).
The uncertainty that characterized the nascent gene transfer technology increased worries among scientists and eventually the broader public about the nature and magnitude of both short- and long-term risks (see, for example, Berg et al. ). This uncertainty led very early to organized efforts to better identify risks and develop safeguards.
Conferences and Deliberations
One of the first safeguards was the postponement of further research by individual investigators until risks were better understood. For example, in the early 1970s, pioneer researchers in the field voluntarily delayed further research on rDNA techniques after considering and discussing with their peers the uncertain dangers of these investigations (Fredrickson, 2001). These individual actions were followed by collective recommendations from investigators and expert groups for moratoria on certain kinds of research (see below).
Another early response to worries about the safety of rDNA research was the organizing of scientific conferences to discuss the technology and research approaches and to assess risks and uncertainties (see, for example, Berg  and Fredrickson ). A conference in 1973 on laboratory safety or containment issues and strategies (sometimes referred to as Asilomar I, for the conference site) considered evidence on the risk of cancer from genetically modified viruses and safety precautions that might be taken. Another conference later that year (the Gordon Conference) produced further discussions of safety issues. These discussions prompted the drafting of a letter from participants asking that the National Academy of Sciences (NAS) establish a committee to examine safety concerns and create guidelines for rDNA research.
The NAS responded positively by creating the Committee on Recombinant DNA Molecules, which met once, in April 1974. The conclusions of the seven-member committee were disseminated through a press conference and a letter published in the Proceedings of the National Academy of Sciences of the United States of America in July 1974 (Berg et al., 1974). The committee proposed that
until the potential hazards of [rDNA] molecules have been better evaluated or until adequate methods are de-
veloped for preventing their spread, scientists throughout the world should voluntarily defer the following types of experiments:
TYPE I: Construction of new, autonomously replicating bacterial plasmids that might result in the introduction of genetic determinants for antibiotic resistance or bacterial toxin formation into bacterial strains that do not at present carry such determinants, or construction of new bacterial plasmids containing combinations of resistance to clinically useful antibiotics unless plasmids containing such combinations of antibiotic resistance determinants already exist in nature.
TYPE II: Linkage of segments of the DNAs from oncogenic or other animal viruses to autonomously replicating DNA elements such as bacterial plasmids or other viral DNAs. Such [rDNA] molecules might be more easily disseminated to bacterial populations in humans and other species, and thus possibly increase the incidence of cancer or other diseases. (Berg et al., 1974, p. 2593)
In addition, the committee recommended caution in the undertaking of certain other research, and it proposed another international conference to consider scientific developments and discuss strategies for dealing with safety concerns. It further recommended that the director of NIH consider promptly establishing a committee to
(i) [oversee] an experimental program to evaluate the potential biological and ecological hazards of the above types of [rDNA] molecules,
(ii) [develop] procedures which will minimize the spread of such molecules within human and other populations, and
(iii) [devise] guidelines to be followed by investigators working with potentially hazardous [rDNA] molecules. (Berg et al., 1974, p. 2593)
Formation of the Recombinant DNA Molecule Program Advisory Committee
Despite some apprehension in the scientific community about government interference, the establishment of federal oversight of some aspects of rDNA research, as recommended by the NAS committee, was another response to concerns about the risks of the technology. NIH acted in October 1974 to create the Recombinant DNA Molecule Program Advisory Committee (a name later shortened to its present form and abbreviated as RAC). Although the initial membership of the committee was restricted to experts with knowledge of rDNA technology, NIH soon expanded the panel to include not only people with a broader range of scientific expertise but also lay members. The first lay member was a professor of government; the second was a professor of ethics, who later served as chair of the committee (Fredrickson, 2001; RAC, 1993).
Donald Fredrickson, the director of NIH and the official who chartered the RAC, noted that establishing extra oversight for rDNA out of an overabundance of caution was necessary and appropriate: “Uncertainty of risk . . . is a compelling reason for caution. It will occur again in some areas of scientific research, and the initial response must be the same” (Fredrickson, 2001).
Debating the Continued Need for the RAC
Some observers have suggested that the early creation of special review procedures may have insulated gene transfer researchers from “shifting winds of public opinion and politics” (Wolf et al., 2009) as public concerns about the technology have periodically intensified and ebbed. Today, rDNA and human gene transfer research has progressed as a function of both scientific advancement and the changing regulatory context, with the RAC providing an avenue for broad public participation and mechanisms for accountability as a key feature of oversight. However, at present in the United States, all gene transfer products remain investigational; none has received a New Drug Application (NDA)/ Biologic License Application (BLA) for an approved product or biological licensing by FDA thus far.
The 1990s saw increasing debate about the continued need for the additional RAC review. Support for gene transfer protocol review was reinforced, in particular, by the controversy created by the tragic death of
a participant in a gene transfer trial in 1999. The death of 18-year-old Jesse Gelsinger, who suffered from the rare metabolic disorder ornithine transcarbamylase deficiency (OTD), attracted widespread attention and public scrutiny of the trial protocol and its implementation, the investigators, and the infrastructure and process of human research protections in the United States (Deakin et al., 2009). Investigations launched by FDA, the University of Pennsylvania, and the Office of Human Research Protections at the U.S. Department of Health and Human Services (HHS) exposed a number of shortcomings in the OTD gene transfer trial and significant gaps in oversight. However, at the time that the RAC approved the OTD protocol, the RAC was unaware of study aspects that were not in compliance with the rules and regulations imposed on clinical gene transfer trials; therefore, these violations occurred despite RAC review. A general assessment of the state of gene transfer research in the aftermath of the death of this research subject was that this was a technology in which investigators were overestimating potential benefits, the media was hyping its curative potential, and oversight mechanisms were struggling to stay ahead of the technology (Kahn, 2009).
STUDY ORIGIN AND STRATEGY
The decades have also seen the creation of overlapping and arguably redundant oversight roles for the RAC, FDA, and institutional bodies. With the accumulation of safety data and experience with gene transfer research, its associated risks are becoming better understood, as are the strengths and weaknesses of federal and institutional oversight mechanisms. Hundreds of clinical gene transfer trials—predominantly phase I trials designed to screen for safety—have been initiated and completed (Ginn et al., 2013). In addition to fears and anxieties surrounding gene transfer research, positive public perceptions can also be cited, notably the promise of more effective treatments or even cures or preventive interventions for devastating and debilitating diseases (see, for example, Seymour and Thrasher ). Although all gene transfer protocols must still be submitted to the RAC, over the years, fewer have been selected for additional public review. In the past year, only 20 percent of all submitted protocols were selected by the RAC for additional review. Nevertheless, even with the decline over the years in the number of protocols reviewed, gene transfer research continues to engage the public imagination. Therefore, it is reasonable to consider whether the concerns
articulated in the early days of gene transfer research are still relevant and continue to warrant special oversight today. It is in this context that NIH approached the IOM for an examination of the role of the RAC.
Committee Approach to the Charge
To complete its task, the IOM formed a committee of experts from a range of disciplines to conduct an 8-month study. The committee was composed of members with expertise in clinical medicine; molecular biology; virology; molecular genetics; high-risk clinical trials; gene transfer technologies; biomedical ethics; law; public policy; and advocacy for research participants, patients, and families. The committee invited input from experts in the field of gene therapy and received many statements from stakeholders and members of the public. To conduct this expert assessment and evaluate the necessity for the extra oversight of individual gene therapy protocols by the RAC, the committee deliberated from June 2013 through October 2013. During this period, the committee held three 2-day meetings and two public information-gathering sessions on June 5, 2013, and August 6, 2013 (see Appendix A). Committee members also participated in multiple conference calls.
Given its charge, the committee first interpreted its goal as advising NIH on the individual protocol review role of the RAC rather than its other functions (for example, organizing scientific conferences). The committee understood that an essential element of the RAC review is the balancing of two critical values—the protection of human participants in research and the advancement of medical science to the benefit of society—and it recognized that inherent tensions exist between advancing science and ensuring the adequate protection of research participants. These tensions revolve around the burdens associated with assessing the ethics of research protocols, including whether the anticipated benefits (taking into account the quality of the research strategy) are in reasonable balance with potential harms. If the regulatory burden can be eased, however, without endangering research participants (and intended patient beneficiaries), then the committee’s stance was that regulatory burdens should be reduced. Another element of the committee’s approach was the consideration of the state of gene transfer science from its inception to modern developments. A third element of the approach was the determination of whether there remains a justification for continued individual protocol review by the RAC given the current regulatory and policy con-
text. If a justification for extra oversight remains, the final element of the task is to develop criteria for selecting protocols for the RAC public review.
Organization of This Report
The report is organized into three chapters following this introduction. Chapter 2, “Gene Transfer Research: The Evolution of the Clinical Science,” offers an assessment of the scientific progress made in gene transfer over the years and outlines risks and concerns that still exist today. Chapter 3, “Oversight of Gene Transfer Research,” provides policy and historical context regarding regulation and oversight of gene transfer research and describes the complex oversight mechanisms that exist today for human gene transfer trials. Chapter 4, “Evolution of Oversight of Emerging Clinical Research,” offers the committee’s findings, conclusions, and recommendations.
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