- Email: [email protected]
The Evolution of Gene Transfer, Gene Therapy, and the RAC: IOM Recommendations to the NIH Director
© The American Society of Gene & Cell Therapy
editorial
doi:10.1038/mt.2014.37
The Evolution of Gene Transfer, Gene Therapy, and the RAC: IOM Recommendations to the NIH Director
N
early 40 years ago, the National Institutes of Health (NIH) Recombinant Advisory Committee (RAC) was chartered to address public and ethical concerns surrounding the development of recombinant DNA (rDNA) molecules for transfer across organisms. As the use of rDNA evolved toward first-in-human clinical trials, the RAC reoriented its mission toward review of human subject risks. With the reconfigured scope, the RAC had authority to review all NIH-funded rDNA studies, including approval of clinical trials separate from the US Food and Drug Administration (FDA). As the field of gene transfer/gene therapy matured, the RAC limited full-committee reviews to those trials with new safety concerns or inordinate risk, in part because of the establishment of various independent regulatory bodies. Despite the good intentions, the authority of the various regulatory bodies—institutional biosafety committees (IBCs), institutional review boards (IRBs), and the FDA and the RAC—began to overlap, especially as the gene transfer–gene therapy expertise within the various regulatory bodies increased. With greater redundancy, potential contradictory recommendations, and lengthy review processes, investigators, sponsors, and patients and patient-support groups began to question the existing regulatory pathway. The NIH recently sought an independent review of the practices of the RAC by the National Academies’ Institute of Medicine (IOM). An IOM committee, composed of experts in gene and cell therapies as well as genetics and bioethics (including both of the authors of this editorial), was charged with examining whether gene transfer research continued to raise issues of broad societal and ethical concerns that warranted exceptional oversight beyond that for other complex, potentially risky therapies. The committee received extensive input by way of a workshop and invited presentations from experts and stakeholders as well as by direct correspondences from the public, advocacy groups, and the scientific and clinical communities. Molecular Therapy vol. 22 no. 4 april 2014
The value of the RAC was widely recognized—most notably, its transparent public process, as well as the establishment of the Genetic Modification Clinical Research Information System (GeMCRIS) and the Gene Transfer Safety Advisory Board, with data and safety monitoring activities within and across gene transfer/gene therapy trials jointly conducted with the FDA. The committee concluded that many of the principal concerns that led to the creation of the RAC had been alleviated and that the current scope of the RAC was no longer appropriate. The members therefore recommended that individual gene transfer/gene therapy protocols should no longer be reviewed in general. Emerging technologies in gene transfer/gene therapy and other areas (e.g., nanotechnology and stem cell therapeutics) will probably require public discourse not unlike that provided by the early RAC. With this in mind, the committee made two broad recommendations1 to the NIH director, described below. The first recommendation is to restrict individual gene transfer protocol reviews to exceptional cases. All gene transfer protocols should also be registered with the NIH Office of the Director in order to monitor and evaluate adverse events in GeMCRIS as well as identify the exceptional cases that require broad review. Public review should occur only if protocol review cannot be adequately performed by other regulatory and oversight processes (in particular, IRBs, IBCs, and the FDA) and one or more of the following criteria are met: (i) the protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk; (ii) the protocol relies on preclinical safety data obtained using a new preclinical model system of unknown and unconfirmed value; and (iii) the proposed vector, gene construct, or method of delivery is associated with possible toxicities. Judging by the types of applications submitted to the RAC today, few studies would meet such criteria for review. 685
© The American Society of Gene & Cell Therapy
editorial The other recommendation is to consider integrating oversight of other emerging, potentially high-risk technologies in addition to novel gene transfer/gene therapy protocols. To this end, the IOM committee said that the NIH director should convene an ad hoc working group to consider whether additional oversight and a venue for public deliberation are warranted for other emerging technologies and, if so, to explore procedural options. As for emerging gene transfer/gene therapy studies, public review should be focused on studies that are associated with uncertain risk(s), pose harm to individuals or the public’s health, or could not otherwise be assessed by existing regulatory and oversight processes because of an insufficient knowledge base. The committee noted that a future process should include public forums for the review and discussion of emerging areas of science; the potential for a partnership to consult, inform, and educate IRBs and IBCs; a venue to foster scientific and public awareness of emerging science to address concerns about clinical investigation and possible societal implications; the capacity to surveil, aggregate, and analyze adverse events across related trials of emerging technologies; and the ability to conduct an additional level of review of individual protocols identified by the NIH director, in consultation with one
686
or more IRBs and IBCs, on the basis of exceptional issues raised as articulated in the committee’s gene transfer protocol criteria. In the near term, the RAC must continue its important functions. However, it is anticipated that a new construct will emerge that will cover all emerging technologies that have real or perceived risks. As with the RAC’s creation some four decades ago, such a forum will inevitably advance the science, inform the regulatory bodies, address broader ethical and social questions of public interest, and, hopefully, minimize the risks to individual subjects who participate in trials with these new technologies.
Howard J Federoff
Georgetown University Medical Center, Washington, DC, USA
John E Wagner
Center for Translational Management, University of Minnesota, Minneapolis, Minnesota, USA
REFERENCE
1. Institute of Medicine (2014). Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. National Academies Press, Washington, DC.
www.moleculartherapy.org vol. 22 no. 4 april 2014
editorial
doi:10.1038/mt.2014.37
The Evolution of Gene Transfer, Gene Therapy, and the RAC: IOM Recommendations to the NIH Director
N
early 40 years ago, the National Institutes of Health (NIH) Recombinant Advisory Committee (RAC) was chartered to address public and ethical concerns surrounding the development of recombinant DNA (rDNA) molecules for transfer across organisms. As the use of rDNA evolved toward first-in-human clinical trials, the RAC reoriented its mission toward review of human subject risks. With the reconfigured scope, the RAC had authority to review all NIH-funded rDNA studies, including approval of clinical trials separate from the US Food and Drug Administration (FDA). As the field of gene transfer/gene therapy matured, the RAC limited full-committee reviews to those trials with new safety concerns or inordinate risk, in part because of the establishment of various independent regulatory bodies. Despite the good intentions, the authority of the various regulatory bodies—institutional biosafety committees (IBCs), institutional review boards (IRBs), and the FDA and the RAC—began to overlap, especially as the gene transfer–gene therapy expertise within the various regulatory bodies increased. With greater redundancy, potential contradictory recommendations, and lengthy review processes, investigators, sponsors, and patients and patient-support groups began to question the existing regulatory pathway. The NIH recently sought an independent review of the practices of the RAC by the National Academies’ Institute of Medicine (IOM). An IOM committee, composed of experts in gene and cell therapies as well as genetics and bioethics (including both of the authors of this editorial), was charged with examining whether gene transfer research continued to raise issues of broad societal and ethical concerns that warranted exceptional oversight beyond that for other complex, potentially risky therapies. The committee received extensive input by way of a workshop and invited presentations from experts and stakeholders as well as by direct correspondences from the public, advocacy groups, and the scientific and clinical communities. Molecular Therapy vol. 22 no. 4 april 2014
The value of the RAC was widely recognized—most notably, its transparent public process, as well as the establishment of the Genetic Modification Clinical Research Information System (GeMCRIS) and the Gene Transfer Safety Advisory Board, with data and safety monitoring activities within and across gene transfer/gene therapy trials jointly conducted with the FDA. The committee concluded that many of the principal concerns that led to the creation of the RAC had been alleviated and that the current scope of the RAC was no longer appropriate. The members therefore recommended that individual gene transfer/gene therapy protocols should no longer be reviewed in general. Emerging technologies in gene transfer/gene therapy and other areas (e.g., nanotechnology and stem cell therapeutics) will probably require public discourse not unlike that provided by the early RAC. With this in mind, the committee made two broad recommendations1 to the NIH director, described below. The first recommendation is to restrict individual gene transfer protocol reviews to exceptional cases. All gene transfer protocols should also be registered with the NIH Office of the Director in order to monitor and evaluate adverse events in GeMCRIS as well as identify the exceptional cases that require broad review. Public review should occur only if protocol review cannot be adequately performed by other regulatory and oversight processes (in particular, IRBs, IBCs, and the FDA) and one or more of the following criteria are met: (i) the protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk; (ii) the protocol relies on preclinical safety data obtained using a new preclinical model system of unknown and unconfirmed value; and (iii) the proposed vector, gene construct, or method of delivery is associated with possible toxicities. Judging by the types of applications submitted to the RAC today, few studies would meet such criteria for review. 685
© The American Society of Gene & Cell Therapy
editorial The other recommendation is to consider integrating oversight of other emerging, potentially high-risk technologies in addition to novel gene transfer/gene therapy protocols. To this end, the IOM committee said that the NIH director should convene an ad hoc working group to consider whether additional oversight and a venue for public deliberation are warranted for other emerging technologies and, if so, to explore procedural options. As for emerging gene transfer/gene therapy studies, public review should be focused on studies that are associated with uncertain risk(s), pose harm to individuals or the public’s health, or could not otherwise be assessed by existing regulatory and oversight processes because of an insufficient knowledge base. The committee noted that a future process should include public forums for the review and discussion of emerging areas of science; the potential for a partnership to consult, inform, and educate IRBs and IBCs; a venue to foster scientific and public awareness of emerging science to address concerns about clinical investigation and possible societal implications; the capacity to surveil, aggregate, and analyze adverse events across related trials of emerging technologies; and the ability to conduct an additional level of review of individual protocols identified by the NIH director, in consultation with one
686
or more IRBs and IBCs, on the basis of exceptional issues raised as articulated in the committee’s gene transfer protocol criteria. In the near term, the RAC must continue its important functions. However, it is anticipated that a new construct will emerge that will cover all emerging technologies that have real or perceived risks. As with the RAC’s creation some four decades ago, such a forum will inevitably advance the science, inform the regulatory bodies, address broader ethical and social questions of public interest, and, hopefully, minimize the risks to individual subjects who participate in trials with these new technologies.
Howard J Federoff
Georgetown University Medical Center, Washington, DC, USA
John E Wagner
Center for Translational Management, University of Minnesota, Minneapolis, Minnesota, USA
REFERENCE
1. Institute of Medicine (2014). Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. National Academies Press, Washington, DC.
www.moleculartherapy.org vol. 22 no. 4 april 2014