Mutant mitochondrial DNA (mtDNA) gives rise to a broad range of heritable clinical syndromes (1). A cure for those affected remains out of reach (1). However, recently developed mitochondrial replacement therapy (MRT) has raised the prospect of disease-free progeny for women carriers (2–4). Moreover, the feasibility of replacing mutant oocytic or zygotic mtDNA with a donated wild-type counterpart in humans has now been firmly established (2–4). In the United Kingdom, legislation regulating the clinical application of MRT, now 10 years in the making, has recently been approved by the House of Commons (5) and the House of Lords (6). The regulatory vetting of MRT in the United States, under way for a year, remains a work in progress (7). Here, we compare and contrast the regulatory history of MRT in the United Kingdom and the United States and examine potential lessons learned.
THE UK REGULATORY EXPERIENCE. In the United Kingdom, matters relating to reproductive technologies are wholly governed by the Human Fertilisation and Embryology Authority (HFEA), an independent regulatory agency established by Parliament through the Human Fertilisation and Embryology Act of 1990 (HFE Act). Among its responsibilities, the HFEA licenses and monitors human embryo research. In 2005, the HFEA issued a research license to the Newcastle Centre for Mitochondrial Research to “investigate the feasibility of using IVF-based techniques to prevent transmission of mitochondrial disease” (8, 9). At that time, the conduct of clinical trials of MRT was prohibited by the HFE Act. However, in 2008, Parliament amended the law to empower the HFEA to license and monitor clinical trials of MRT subject to subsequent parliamentary approval.
In 2011, the HFEA convened an expert panel to review the “effectiveness and safety of mitochondrial transfer” (10). The panel concluded that the “evidence currently available does not suggest that the techniques are unsafe” (10). Updated reports issued in 2013 and 2014 reached similar conclusions. In 2012, the HFEA launched a public consultation process on the social and ethical implications of MRT, the outcome of which revealed “general support for permitting mitochondria replacement in the UK, so long as it is safe…and is done so within a regulatory framework” (11). The Nuffield Council on Bioethics and the Ethics Committee of the British Medical Association reached similar conclusions. On 3 February 2015, the House of Commons voted to approve the conduct of MRT under the auspices of the HFEA (5). The House of Lords followed suit on 24 February. Clinical trials could commence as early as 29 October 2015.
Ethical questions discussed in the United Kingdom revolved around the safety of the procedure for newborns, the matter of parenthood, and the notion that MRT represents germline modification and thus crosses a “red line.” Although a full review of the ethical discussions in the United Kingdom is outside the purview of this policy piece, we would point out that several members of Parliament noted that MRT is more about changing a “battery pack” than it is about genetic modification (5). Although the term “three-parent” reproduction has been used in the public debate, as per the recent parliamentary vote, mitochondrial donors have not been accorded legal parental status. It follows that the identities of prospective donors are not to be disclosed to “mitochondrial donor-conceived persons” (5).
On the matter of germline modification, during the House of Commons and House of Lords debates, some MRT opponents suggested that the legislative action under consideration would violate the European Union Directive on clinical trials that states that “[n]o gene therapy trials may be carried out which result in modifications to the subject's germ line genetic identity.” Proponents who won the day argued that HFEA approval of MRT would not violate this directive and/or that the directive did not apply to MRT, but their view is thus far untested in court (5).
THE U.S. REGULATORY EXPERIENCE. The United States, unlike the United Kingdom, lacks a specific governmental entity whose sole charge it is to regulate reproductive technologies. In the case of MRT, jurisdiction has been asserted by the Food and Drug Administration (FDA) Office of Cellular, Tissue, and Gene Therapies of the Center for Biologics Evaluation and Research, whose task it is to oversee “human cells used in therapy involving the transfer of genetic material by means other than the union of gamete nuclei” (12). Under FDA's existing regulations, approval of the therapeutic use of MRT will require the conduct of phased clinical trials pursuant to an Investigational New Drug application (IND) (12).
The FDA has never officially considered or approved early-phase clinical trials of MRT. In fact, its 2 July 2013 draft guidance for industry for the “design of early-phase clinical trials of cellular and gene therapy products” (published for public comment) makes no mention of MRT (13). The first tremor in this status quo was felt early in 2014 when the FDA convened the Cellular, Tissue, and Gene Therapies Advisory Committee to discuss “oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease” (7). Although there was no official conclusion, Reuters quoted the chairman of the committee as summarizing the session in the following way: “Several panelists felt ‘there was probably not enough data in animals … to move on to human trials without answering a few additional questions’” (14).
The FDA has since commissioned an ad hoc committee of the Institute of Medicine (IOM) to weigh in on the “Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases” (15). Two of the planned committee sessions will be open to the public. No further FDA action is expected until the IOM report has been released, which is estimated to be 19 months after the start date of September 2014. In the interim, any relevant INDs submitted would remain on hold.
The recent debate over MRT in the House of Commons and elsewhere went well beyond safety considerations to explore ethical arguments and matters of conscience. In the United States, some of these same issues have been discussed in the popular press, but a full consideration of the ethics and not just the science of MRT in the United States has yet to occur.
TRANSATLANTIC LESSONS. The regulatory paths of the United States and the United Kingdom toward MRT have diverged considerably, with the United Kingdom clearly further along in the decision-making process, having approved the clinical use of MRT. Why is there such a transatlantic difference? This is not an academic question, because MRT represents but one of a growing complement of novel reproductive technologies, many of which will require expert regulatory adjudication.
The first transatlantic distinction of note concerns the regulatory agency charged with overseeing extant and leading-edge reproductive technologies. In the United Kingdom, the regulatory adjudication of MRT has been relegated to the HFEA. Absent a comparable U.S. agency, the task of regulating MRT has fallen to the FDA, the mandate of which encompasses all therapeutics. Even the FDA Office of Cellular, Tissue, and Gene Therapies—the designated proximate overseer of MRT—is entrusted with a diverse portfolio of cellular, tissue, and gene therapeutics. It follows that UK regulators, unlike their U.S. counterparts, view MRT as a circumscribed outgrowth of related and highly familiar technologies (e.g., in vitro fertilization) rather than as a therapeutic (5). In contrast, U.S. regulators are proceeding on the premise that MRT constitutes a drug and/or a biological product. We posit that the narrow framing of MRT by the HFEA is partially responsible for the expert nature of the UK regulatory paradigm.
The second transatlantic dissimilarity harkens back to the prevailing national values and mores regarding reproduction and especially research involving the derivation and destruction of a human embryo. In the United States, scientific research with human embryos has long been controversial, and federal funding in this area has been constrained. This is in part due to the fact that, in the United States, such research has been tangled in electoral and religious contestation over abortion. No such impediments cloud the regulatory adjudication of MRT in the United Kingdom, where public funding for human embryo–derived stem cell generation and human embryo research through day 14 of development has been legalized.
The third material transatlantic difference concerns the relative weight assigned to public consultation on regulatory issues of substance. The UK public consultation process was an extensive outsourced multimethod (e.g., surveys and workshops) effort on a national scale lasting 6 months. The U.S. regulatory approach has thus far been largely limited to a conversation among experts, with relatively brief sessions open to the public (7).
A fourth transatlantic variance revolves around the framing of MRT as a beacon of national scientific prowess. For better or worse, the parliamentary debate has proceeded with an air of national pride. Even those opposed to MRT noted their admiration for the worldclass work of the Newcastle group (2, 5). We believe that this national sense of pride may have swayed some votes in support of MRT. No such sentiment has been sweeping the United States, even though U.S. scientists have made equally vital contributions to this field of inquiry (3, 4).
CONCLUSIONS. This examination of the different approaches taken to the regulation of MRT in the United Kingdom and the United States leads us to reexamine the wisdom of burdening the FDA with the regulatory adjudication of MRT, as opposed to adopting an HFEA-like paradigm (16). In the eyes of some, the regulatory oversight of reproductive technologies in the United States leaves much to be desired. Yet others are content with the status quo, in which reproductive technologies are not directly licensed (as in the United Kingdom) but instead are left to what can be characterized as self-regulation by the medical profession and its representative associations. However, with the MRT challenge looming and others not too far behind, it may be time to renew the national conversation as to the rules that should govern this terrain. Understandably, the outcome of such conversation is far from certain. Because some forms of MRT involve embryo destruction, approval in the United States will be embroiled in the prolife/prochoice divide (17–19). It remains an open question whether an initiative to reform the regulatory oversight of reproductive technologies in the United States can be realized without capsizing under its own weight and the force of the political winds.
References and Notes
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↵ www.parliament.uk, Parliamentary business; Publications & records; Human Fertilisation and Embryology, 3 February 2015; http://www.publications.parliament.uk/pa/cm201415/cmhansrd/cm150203/debtext/150203-0002.htm#15020348000001
↵ G. Vogel , Mitochondrial gene therapy passes final U.K. vote, Science, ScienceInsider, 24 February 2015,; http://news.sciencemag.org/biology/2015/02/mitochondrial-gene-therapy-passes-final-u-k-vote
↵ U.S. Food and Drug Administration, Advisory Committees, 2014 Meeting Materials, Cellular, Tissue and Gene Therapies Advisory Committee, 25–26 February 2014; www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/CellularTissueandGeneTherapiesAdvisoryCommittee/ucm380047.htm
↵ Human Fertilisation and Embryology Authority, HFEA grants licence to Newcastle Centre at LIFE for Mitochondrial Research, 8 September 2005; www.hfea.gov.uk/671.html
↵ Human Fertilisation and Embryology Authority, Newcastle Fertility Centre at Life, R0152: Pluripotency, reprogramming and mitochondrial biology during early human development, 24 September 2014; www.hfea.gov.uk/1564.html
↵ Human Fertilisation Embryology Authority, Scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception (2011); www.hfea.gov.uk/docs/2011-04-18_Mitochondria_review_-_final_report.PDF
↵ Human Fertilisation and Embryology Authority, Mitochondria replacement consultation: Advice to Government, March 2013.
↵ U.S. Food and Drug Administration, Vaccines, Blood, and Biologics. Letter to Sponsors/Researchers, Human cells used in therapy involving the transfer of genetic material by means other than the union of gamete nuclei, 6 July 2001; www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm105852.htm
↵ Department of Health and Human Services, Food and Drug Administration, Fed. Regist. 78, 39736 (2013); www.gpo.gov/fdsys/pkg/FR-2013-07-02/pdf/2013-15797.pdf
↵ S. Begley , U.S. FDA weighs evidence on producing ‘three-parent’ embryos, Reuters, 25 February 2014; http://uk.reuters.com/article/2014/02/25/us-usa-health-ivf-idUKBREA1O1WL20140225
↵ The National Academies, Current Projects System, Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases (2014); www8.nationalacademies.org/cp/project.
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