Segmented Innovation in the Legalization of Mitochondrial Transfer: Lessons from Australia and the United Kingdom

Introduction

The United States is a leader in science and innovation. Recent data shows that the United States spends more on research and development than any other country in the world.^[1] Yet, the United States’ research spending lead has narrowed over the years.^[2] Currently while the U.S. is ranked first in research and development spending, China is second, the United Kingdom is seventh , and Australia is thirteenth.^[3]

The United States has been a leader in other areas of technological and medical innovation, but it lags the U.K, not only in insurance coverage of fertility treatments but also in terms of the pace of innovation.^[4] A few years ago, mitochondrial transfer—a technique that combines in vitro fertilization (IVF) with genetic substitution—was the subject of significant media attention, especially as the United Kingdom debated and ultimately legalized the use of the technique.^[5] As will be detailed in Part I, mitochondrial transfer could not only improve fertility outcomes but also prevent the transmission of harmful genetic diseases like Leigh Syndrome that have severe negative impacts on organs such as the brain, heart, and kidneys.^[6] Mitochondrial transfer continues to inhabit the scientific and popular spheres, as babies continue to be born as a result of the technique in Ukraine, Greece, and Mexico.^[7] This Article focuses on the experiences of the United Kingdom and Australia in the legalization of mitochondrial transfer.^[8] In doing so, the Article contributes to the assisted reproductive technology (“ART”), innovation, administrative law, and drug law literatures.^[9]

Mitochondrial transfer, a technique that combines IVF with genetic substitution, has been legalized for human clinical research and use in the United Kingdom while the technique remains effectively banned in the United States by both FDA and Congressional action.^[10] Regulatory progress has essentially stalled in the United States, and there is little hope for imminent change. On the topic of the progress (or lack thereof) of mitochondrial transfer in the U.S., Dr. Eli Adashi has noted “It was really an American idea…[w]hich makes it all the more unfortunate that it has been restricted here.”^[11]

While the U.S. regulatory system remains at a standstill with minimal inquiry into mitochondrial transfer, Australia has been engaged in a public inquiry since 2018. In 2021, after hearing the story of a 5-year-old girl named Maeve Hood who was diagnosed with Leigh Syndrome, a debilitating form of mitochondrial disease, a Victorian Parliament member introduced “Mitochondrial Donation Law Reform (Maeve’s Law) Bill 2021” in the Australian Senate, hereinafter referred to as “Maeve’s bill.”^[12] Maeve’s bill is based on the U.K.'s legislation legalizing mitochondrial transfer.^[13] The Australian Health Minister, Greg Hunt, supported the law, as did the International Society for Stem Cell Research (ISSCR).^[14] In December 2021, Maeve’s bill passed in the Australian House of Representatives and in March 2022, it passed in the Australian Senate.^[15] Maeve’s law commenced on October 1, 2022.^[16]

In previous articles, I have argued for the legalization of mitochondrial transfer in the United States.^[17] This Article continues that argument and focuses on ways to use public deliberation in furtherance of that legalization. As such, the Article identifies those tools of deliberative democracy that have been successful in other countries, as they may prove useful in response to American (and foreign) scientists’ continued calls for a public discourse related to genetic modification.^[18] If societal discourse will impact regulatory decisions such that the lack of a societal discourse or widespread acceptance will continue to lead to an effective ban on reproductive genetic innovation, then society will need to decide whether to have that discussion and how that discussion would even be structured if it did occur.^[19] The U.K. and Australian experiences could also be part of a piecemeal approach to the larger issue of reproductive genetic innovation in the United States and other countries.

Part I of the Article provides brief scientific and bioethical background on mitochondrial transfer. Part II provides regulatory background on assisted reproductive technology and mitochondrial transfer in the United States, United Kingdom, and Australia. Part III identifies and explains which of the regulatory and deliberative mechanisms used in the United Kingdom’s and Australia’s legalizations of mitochondrial transfer could be adapted for use in the United States. The Article then concludes.

I. Mitochondrial Transfer

Assisted reproductive technology is becoming increasingly prevalent in the U.S. and abroad and enjoys widespread support in the United States.^[20] Assisted reproduction, including IVF, is legal and widely available in the United States.^[21] There are also forms of assisted reproduction that involve deliberate genetic changes, what I call “reproductive genetic innovation”: cytoplasmic transfer, mitochondrial transfer, and germline genome editing. Cytoplasmic transfer was a technique used in the late 1990s to improve fertility outcomes, and germline (heritable) gene editing in human embryos could prevent the inheritance of disease-causing mutations.^[22] Reproductive genetic innovation techniques are largely classified as “experimental” by the regulatory system and many observers although some of the techniques have been used by U.S.-based physicians and continue to be researched and used abroad.^[23]

While germline genetic modification has been the subject of x “bombshell” news such as Dr. He Jiankui’s use of germline gene editing in embryos that led to the birth of three children, mitochondrial transfer does not receive as much media attention these days but remains significant.^[24] This Article will focus on the legalization of mitochondrial transfer although the implications of the Article’s arguments related to mitochondrial transfer could be applied to reproductive genetic innovation, including cytoplasmic transfer and germline gene editing, more broadly.^[25] Section A of this Part provides scientific background on mitochondrial transfer. Section B of this Part provides a brief overview of the ethical controversy that accompanies mitochondrial transfer.

A. Scientific Background

Mitochondrial transfer (also referred to as “mitochondrial donation therapy” or “mitochondrial replacement therapy”) is a type of assisted reproductive technology involving the use of in vitro fertilization and the substitution of genetic material.^[26] Mitochondrial transfer targets the mitochondria of a cell, which are organelles found in the cytoplasm of the cell.^[27] Mitochondria have their own DNA which is generally believed to be inherited solely from the mother.^[28] Mitochondrial DNA is distinct from nuclear DNA.^[29] Mitochondria constitute approximately 0.1% of total DNA in the body.^[30] Mitochondria are responsible for providing energy to the cell, so mitochondrial mutations can result in symptoms in parts of the body that require high amounts of energy like “the brain, heart, kidneys and major muscle groups.”^[31] Mitochondrial transfer is largely praised for its ability to target disease-causing mutations.^[32] In mitochondrial transfer, doctors replace defective mitochondria with donor mitochondria.^[33]

Mitochondrial transfer could be used to improve fertility outcomes, but its greatest medical promise appears to lie in preventing or lessening the incidence of mitochondrial disease.^[34] Due to the complexities of mitochondrial inheritance, it is difficult to ascertain the incidence of mitochondrial disease. In the United States, 1 in 5,000 people are affected by genetic mitochondrial disease.^[35] In the United Kingdom, estimates show that 1 in 5,000 people are affected by changes, often referred to as “mutations in mitochondrial DNA…[which] … can affect many different tissues and, in its severest form, is fatal in childhood.”^[36] In Australia, approximately 1 in 200 women carry “genetic mutation[s] that could potentially lead to mitochondrial disease developing and 1 in 5,000 babies are born with a severely disabling form of mitochondrial disease that can cause death in infancy, childhood or adulthood.”^[37] In other words, in Australia, approximately 56 children per year are born with a “severe form of [Leigh syndrome or other mitochondrial disease].”^[38]

B. Bioethical Background and Definitional Debate

Mitochondrial transfer is accompanied by many ethical, social, and policy considerations which arise in discussions related to the legalization and the safety of the technique, regardless of jurisdiction.^[39] In fact, “[a]t the 2014 FDA Cellular, Tissue, and Gene Therapies Advisory Committee meeting, an FDA employee stated that ‘[t]he FDA recognizes [that there are] moral, ethical, and social policy issues related to genetic modification of eggs and embryos, and that these issues have the potential to affect regulatory decisions’”—although the employee did not explain exactly what the potential effect of these issues might be.^[40] Further, the agency did not convene a meeting to discuss these issues and specifically prohibited such a discussion.^[41]

Debates related to mitochondrial transfer are part of a broader controversy over ART.^[42] Beyond “traditional” ART like in vitro fertilization, there are conversations in multiple literatures related to how reproductive rights and possibly society may be impacted by gene modifying techniques.^[43] Issues in assisted reproductive technology and genetic innovation also implicate the literatures of equality, access, and disability rights.^[44]

There is also a larger bioethical debate related to whether children created using forms of assisted reproductive technology would have existed but for the technology and the proper role of parents in selecting traits for children via assisted reproductive technology.^[45] Bioethicists and sociologists have substantially analyzed the impacts of assisted reproductive technology and genetic modification on identity.^[46] Issues related to identity accompany advanced assisted reproductive technologies as bioethicists and the public ask whether these techniques impact the identity of the children conceived using these technologies. For many bioethicists, modifications of non-nuclear DNA are not viewed as modifying “identity.”^[47] Similarly, there are concerns about parents’ ability to impact not only their children, but future generations of children.^[48] This leads to arguments based on hubris, sometimes from religious perspectives, in which observers note that physicians are “playing God” and will lead society down a “slippery slope” through actions involving genetic modification which constitute a “step too far.”^[49] Others, including religious groups, note that mitochondrial transfer and techniques that can lead to the disposal of embryos “do not respect the human dignity of embryos.”^[50] In previous works, I have argued that in spite of these ethical objections, advanced assisted reproductive technologies (“AARTs”) and germline gene editing should be treated similarly to ART and thus regulated by states and not the federal government.^[51]

Concerns over genetic modification are often heightened when changes affect the “germline,” meaning that the changes are inheritable by subsequent offspring. For example, the fact that mitochondrial transfer made a change “at” the germline was the basis for mitochondrial transfer’s prior illegality in the United Kingdom.^[52] The use of techniques involving heritable genetic modifications in the United States are stymied by the recent recurring budget rider.^[53]

Some argue that all uses of mitochondrial transfer constitute a change to the human germline. whereasOthers argue that because mitochondria are maternally inherited, only the use of modified female embryos constitutes a human germline modification.^[54] Some note that techniques like mitochondrial transfer involve a germline modification but not in the same way as germline gene editing as those AARTs involve the modification of non-nuclear DNA, which differentiates them from germline gene editing.^[55] Others argue that mitochondrial DNA are insignificant and thus not part of a germline modification.^[56] Some even contest the idea that mitochondrial transfer is “genetic manipulation” at all.^[57]

An Institute of Medicine panel, convened to study mitochondrial replacement techniques at the FDA’s request, concluded that mitochondrial replacement is not heritable genetic modification.^[58] This conclusion partly rested on the widely-accepted belief that mitochondria are maternally transmitted; for this reason, the National Academies of Sciences recommended that only male embryos be initially selected if mitochondrial transfer was used in the United States.^[59] The ISSCR also maintains that there is a difference between mitochondrial replacement therapy (MRT) and heritable genome editing and that MRT research and clinical use should be permissible.^[60] The ISSCR’s position does not include a sex-based caveat or recommendation.^[61] The next Part details regulatory responses in the U.S., U.K., and Australia to the bioethical considerations that accompany MRT.

II. Regulation of ART and Mitochondrial Transfer in the United States, United Kingdom, and Australia

The similarities between the U.S., U.K., and Australia render the potential lessons from those countries applicable to the United States. First, as alluded to in the Article’s title, all three are classified as “common law countries.”^[62] Second, while the U.K. and Australia are most similar, all three countries’ governments contain federal structures.^[63] Third, in vitro fertilization is legal in all three counties, albeit under differing regulatory regimes.^[64] Fourth, each country was an early user of in vitro fertilization; the first babies born in the United Kingdom (and the world), Australia, and the United States as a result of IVF, were born in 1978, 1980, and 1981, respectively.^[65]

In the American legal literature, analysis of assisted reproductive technology tends to focus on the lack of regulation of assisted reproductive technology in the U.S. and how this lack of regulation stands in stark contrast to the U.K.'s robust system for ART regulation through the Human Fertilisation & Embryology Authority.^[66] Similarly, accounts in multiple literatures focus on the first child born as a result of in vitro fertilization, Louise Brown, in July 1978 in the United Kingdom, along with the publication of the results of the Warnock Committee’s report.^[67] The Warnock Committee Report shows that public consideration of the moral, ethical, and social issues have existed since the early days of IVF in the U.K.^[68] Yet, these accounts often leave out innovations in Australia. For example, Australia funded IVF research “and by 1984, the team at Monash University in Melbourne had overtaken the UK as the world-leader with a series of other firsts, including twins, triplets, babies born from donor eggs and frozen embryos.”^[69] Today, the U.K. has arguably regained its position as the world leader in ART with its legalization of mitochondrial transfer. Australia is following as it lays the groundwork for the potential clinical use of mitochondrial transfer, while the United States remains in a regulatory standstill, despite the progress made in the U.S. related to the underlying science of mitochondrial transfer.^[70]

A. United States

Although the practice of medicine is mostly regulated by the states, the FDA has blocked the use of mitochondrial transfer and other related techniques by asserting jurisdiction over them.^[71] Over the past 20 years, the federal legal system discouraged the use of mitochondrial transfer in the United States as evidenced by the issuance of Untitled Letters to physician-researchers engaged in both mitochondrial transfer and techniques similar to mitochondrial transfer.^[72] These FDA-issued Untitled Letters and “advisories” fall short of official enforcement actions but nonetheless discourage physicians and scientists from using and researching techniques involving reproductive genetic innovation and also human reproductive cloning, an idea that generated an extensive uproar in the 1990s and early 2000s.^[73]

The FDA has posted an advisory online, listing the techniques that it proclaims require an investigational new drug (IND) application even though these techniques involve the practice of medicine, which is regulated by states and not the federal government.^[74] The FDA’s online advisory applies to a number of techniques, including mitochondrial transfer, germline gene editing, and cytoplasmic transfer.^[75]

In 2015, approximately five years into the FDA’s subterranean regulation of techniques involving reproductive genetic innovation, Congress added an appropriations rider to the 2016 budget to prevent the FDA from using funds on the aforementioned IND applications involving heritable genetic modification.^[76] The rider, which was accompanied by little substantive discussion in Congress, reads:

None of the funds made available by this Act may be used to notify a sponsor or otherwise acknowledge receipt of a submission for an exemption for investigational use of a drug or biological product under section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) or section 351(a)(3) of the Public Health Service Act (42 U.S.C. 262(a)(3)) in research in which a human embryo is intentionally created or modified to include a heritable genetic modification. Any such submission shall be deemed to have not been received by the Secretary, and the exemption may not go into effect.^[77]

That rider has been renewed every subsequent year.^[78] Thus, even though both the FDA’s informal regulation and Congress’ recent recurring budget rider have both been unaccompanied by substantial legal explanation, it is likely that public deliberation will be necessary to change the regulatory treatment of mitochondrial transfer.

This regulatory treatment has not prevented some U.S.-based physicians from traveling abroad to provide the technique to patients in countries with more favorable regulatory climates.^[79] For example, the U.S.-based physician, Dr. John Zhang traveled to Mexico to provide the technique to a couple who wanted to avoid transmitting Leigh’s syndrome to their children.^[80] Providing the technique in Mexico allowed Dr. Zhang, his team, and the intended parents to avoid the limitations of the U.S. regulatory system.^[81] After providing mitochondrial transfer in Mexico and requesting a pre-IND meeting with the FDA, Dr. John Zhang was informed by letter that the FDA could not consider its application due to the congressional budget rider.^[82]

Dr. Shoukhrat Mitalipov of the Oregon Health Sciences University has achieved mitochondrial transfer in rhesus macaques; however, the use of this techniques in human pregnancies has not yet occurred.^[83] In 2015, Mitalipov confirmed that he had submitted two applications to the FDA for clinical trials related to mitochondrial transfer.^[84] While Dr. Mitalipov predicted a potential year-long delay by the FDA in order to consider ethical issues related to mitochondrial transfer, the recent trajectory of U.S. restrictions means that predicted year-long delay is continuing to grow.^[85] For example, as indicated by the FDA’s 2017 letter to Dr. John Zhang, in spite of objections by many scientists, the FDA has interpreted a recuring Congressional budget rider preventing the agency from using funds on applications involving “heritable genetic modification” to encompass mitochondrial transfer, thus stymying innovation related to mitochondrial transfer in the U.S.^[86] Moral views have shaped legislation and regulatory decisions and will continue to do so.^[87] Currently, concerns about embryo destruction, “playing God,” possibly harming future children using germline gene editing, the possibility of using enhancement for gene editing, and the idea of changing the gene pool have been proffered as possible rationales underlying the current budget rider prohibiting FDA-consideration of IND applications involving heritable genetic modification in the United States.^[88]

B. United Kingdom

The United Kingdom has played an important role in the development of assisted reproductive technology. The first child in the world born as a result of in vitro fertilization, Louise Brown, was born in the U.K.^[89] The Human Fertilisation & Embryology Authority (HFEA) “is the UK’s independent regulator of treatment using eggs and sperm, and of treatment and research involving human embryos.”^[90] As such, the HFEA is responsible for a number of tasks including licensing individual fertility clinics and research centers and “…regulat[ing] the storage of gametes and embryos…”^[91] As of the HFEA’s last annual report, released in November 2021, 103 clinics were licensed by the HFEA to provide fertility treatment.^[92] Sixteen additional licenses permitted research involving human embryos and fourteen additional licenses provided for storage of gametes and embryos only.^[93] In addition to licensing, the HFEA also publishes guidelines for fertility providers.^[94]

After a lengthy legalization process that included multiple public consultations, multiple scientific reviews, and extensive scientific and bioethical support, the UK legalized mitochondrial transfer in 2015.^[95] In the United Kingdom, an HFEA-issued license to provide the technique is required and the technique is limited to disease causing mutations.^[96] Only two mitochondrial transfer techniques are permitted in the U.K.: maternal spindle transfer and pronuclear transfer.^[97] In addition to licensing, the HFEA also approves the individual patients who would receive mitochondrial donation therapy. ^[98] Currently, the Newcastle Fertility Centre at Life has the sole license for research and treatment of patients using approved mitochondrial donation techniques in the U.K.^[99] In 2018, the HFEA approved the Newcastle Fertility Centre’s use of mitochondrial donation for two women.^[100] So far, no live births have been reported.^[101]

C. Australia

In July 1978, when Robert Edwards and Patrick Steptoe announced the birth of Louise Brown, the first baby born as a result of using IVF, researchers in Melbourne were “devastated” to have not achieved this milestone first.^[102] Instead, the first baby born as a result of IVF in Australia was born in 1980.^[103] After much public discussion and Parliamentary action, Maeve’s law is now in effect in Australia.^[104]

After the law passed both houses of the Australian Parliament on March 31, 2022, the Australian National Health and Medical Research Council posted an announcement on April 10, 2022 for the 2022 Pilot Mitochondrial Donation Pilot Program Grant Opportunity, which aims to “support one Australian medical research and medical innovation project that conducts a pilot program, including a clinical trial, for the purposes of building the evidence base to determine the safety, efficacy and feasibility of implementing mitochondrial donation reproductive technology in clinical practice settings.”^[105]

Australia is a federal constitutional state.^[106] It is composed of nine jurisdictions including the Commonwealth of Australia, six states, and two territories.^[107] While Australia has a federal structure in which ART regulation comes from both federal and state sources, only four of the eight Australian states and territories have their own ART legislation.^[108] Other states rely on the NHMRC’s Ethical Guidelines on Assisted Reproductive Technology in Clinical Practice.^[109]

Similar to the United States, ART regulation in Australia has been described as “splintered.”^[110] In Australia, the national government creates regulatory schemes surrounding issues like embryo research, the creation of embryos (for research and reproduction), and the accreditation of reproductive clinics, while individual states and territories are “responsible for parentage and ART regulation.”^[111] The Australian Health Ethics Committee also publishes guidelines, which are being reviewed “specifically for mitochondrial donation.”^[112] Also, similar to the United States, doctors also engage in self-regulation through the participation in and adherence to guidelines promulgated by various societies.^[113]

Until this year, mitochondrial transfer was illegal under Australian law.^[114] Before Maeve’s Law, it would have violated the Prohibition of Human Cloning for Reproduction Act (PHCR) to develop an embryo containing the genetic material of more than 2 individuals.^[115] Similarly, it would have violated the PHCR to make any heritable changes to “the genome of a human embryo for reproductive purposes,” meaning that the Australian government interpreted “heritability” to include mitochondrial transfer, similar to the FDA’s current interpretation of the word.^[116] Like in the United States, mitochondrial transfer in Australia faces opposition from many directions, including Catholic religious figures.^[117] Others oppose the use of mitochondrial transfer based on “slippery slope” concerns that using mitochondrial donation could later lead to human reproductive cloning.^[118]

In 2018, the Australian Senate examined scientific, legal, and ethical issue related to mitochondrial transfer.^[119] After this examination, the Senate issued a report and recommended further consultation with multiple stakeholders and regulatory actors before the process was used in Australian clinical practice.^[120] In June 2021, a committee of members of Parliament released a report that recommended a public consultation in relation to proposed legislative changes within Australia to permit mitochondrial transfer.^[121] The committee charged with writing the Senate’s report concluded by noting that “[t]he committee makes no recommendations as this is a conscience matter.”^[122]

Australia’s Minister for Health and Aged Care, the Honorable Greg Hunt MP, introduced Maeve’s Bill, his proposal to legalize mitochondrial transfer.^[123] Under that proposal, the regulatory framework would focus on the issuance of licenses for mitochondrial transfer being administered by the National Health and Medical Research Council (NHMRC).^[124] Currently, the NMHRC maintains that some research could be conducted under current licensing; however, no human clinical use of mitochondrial transfer is permissible at this time.^[125] Licenses would be available in 5 stages, which is arguably similar to the FDA’s multi-stage drug approval process.^[126] The stages of the Australian licenses include research and training licenses, which one might expect would not be required in the U.S. depending on the type of research.^[127] In Australia, only 2 mitochondrial transfer techniques would be permitted: maternal spindle transfer and pronuclear transfer.^[128] On December 1, 2021, the Australian House of Representatives passed Maeve’s bill by a vote of 92 to 29.^[129] The bill passed in the Australian Senate in March 2022 .^[130]

D. “Comparator” Differences

Before addressing the lessons that the United States might learn from Australia and the U.K., I acknowledge that some would dismiss a comparative approach or emphasize the differences amongst the three countries. There are, admittedly, some differences. One noteworthy difference involves the amount of religious influence on regulation varies across the countries. Within the U.K., there are state-sponsored churches, yet many observers view the United States as more religious than the United Kingdom or Australia.^[131] In its Supplementary Submission related to Maeve’s bill, the Mito Foundation stated that the United States was not an “appropriate comparator” when assessing whether mitochondrial transfer should go forward in Australia because “there are a number of religious and other elements at work in the United States that impact access to women’s health, including IVF, birth control, and abortion.”^[132] While this assessment of the comparative differences between the U.S. and Australia is certainly accurate, the differences between the U.K. and Australia on the one hand and the United States on the other hand, do not hinder the Article’s overall aims, which are to foster discourse and to ascertain how one might structure a “piecemeal” or “segmented” approach to the legalization of mitochondrial transfer in the U.S.

Australia has legislation and substantive regulations related to ART, whereas the United States is notable for the lack of clearly applicable federal substantive law related to forms of ART involving genetic innovation.^[133] Individuals and governmental actors in the U.S., U.K., and Australia have different views on whether mitochondrial transfer is genetic modification and the significance of that genetic modification.^[134] For example, the U.K. Department of Health concluded that mitochondrial transfer was not genetic modification whereas currently, the FDA’s interpretation of the Congressional budget rider prohibiting “heritable genetic modification” includes mitochondrial transfer.^[135]

The three countries analyzed in this Article also have varying views on entitlements to donor information and the significance of genetic donors. In the U.K., mitochondria are generally not seen as significant to identity which, at least in bioethics discourse, tends to focus on nuclear DNA.^[136] In the U.K., children conceived as a result of mitochondrial donation would not be entitled to information related to their mitochondrial donor.^[137] In the U.S., children created using IVF are not entitled to information related to their donor, whereas Maeve’s law will permit children born as a result of mitochondrial transfer to “apply for identifying information about their donor when they turn 18.”^[138] Similar to the treatment of parentage in the U.S., mitochondrial egg donors in Australia would not be legal parents of the children conceived using mitochondrial transfer, an issue that is resolved by state law in the U.S. as opposed to federal law.^[139] Australians have taken a markedly different direction on the issue of sex selection than many Americans. For example, the National Academies of Sciences recommended that only male embryos be implanted in order to avoid issues related to the “heritability” of mitochondrial changes, whereas the Australian legislation leaves the issue of sex selection to the parents.^[140]

In Australia, parents who would use mitochondrial transfer would also be subject to counselling requirements, an approach that seems unlikely in the United States, although issues related to follow-up would likely arise.^[141] For example, across the world, follow-up studies are often difficult in ART as happy parents no longer want to continue visiting fertility providers and subjecting children to the requirements of follow-up studies such as tissue samples.^[142] Whether parents should be able to decide whether to include their children in future follow-up studies is an ethical issues that arises in discussions of mitochondrial transfer.^[143] The U.K.'s mitochondrial donation treatments are accompanied by expected follow-up appointments for children conceived using mitochondrial transfer at eighteen months and five years old.^[144] Additionally, while much attention is paid to the issue of physical follow-up, others in Australia have testified to the need for a registry that focuses not only on scientific issues but psychosocial implications.^[145] As has arisen in debates regarding ART and all forms of ART involving genetic modification or substitution, observers note that the risks of the techniques to the child and subsequent generations are unknown, however that is the case with many FDA-approved products.^[146] Follow-up studies have been recommended a part of recent FDA gene therapy approvals.^[147] In light of the concern for future generations (a concern that generally does not limit natural reproduction), it is possible that, like in Australia, where some have suggested writing follow-up studies into the legislation, the U.S. may, if mitochondrial transfer is approved through FDA regulatory pathways, consider including follow-up studies in future approvals.^[148]

Even though the U.K. takes a markedly more restrictive approach to access to donor information in the context of ART, lack of donor information thus far has not precluded IVF’s legality in the U.S. and is likely an insignificant factor in regulation.^[149] In other words, while some object to mitochondrial transfer as “three-parent IVF,” those individuals tend to give little emphasis to the identity or information about that “third parent”.^[150]

The U.S. is known for its “unregulated” or “minimally regulated” approach to assisted reproductive technology, where only one federal statute, the Federal Clinic Success Rate Act, directly addresses assisted reproductive technology.^[151] The U.S. has used budget riders and generally unreviewable agency action to regulate mitochondrial transfer.^[152] Those choices have led to a regulatory standstill. Yet, by targeting forms of ART involving genetic modification for the FDA’s investigational new drug requirement, the agency has arguably laid the groundwork for a more HFEA-like regime, like in the U.K. where a government agency is responsible for determining matters such as which ART techniques are available and the conditions under which individuals can access those techniques. Ultimately, differing constitutional structures, varied national- and state-level decisions on matters like donor information, and differing allocations of legal issues to federal and state jurisdiction do not preclude a comparative analysis or the use of solutions based on the Australian or U.K. experiences with mitochondrial transfer. The next Part of the Article identifies useful aspects of the U.K. and Australian approaches to the legalization of mitochondrial transfer in order to make structural suggestions for the U.S. going forward.

III. Segmented Innovation for the United States: Applying the Experiences of the U.K. and Australia to the American Regulation of Mitochondrial Transfer

Mitochondrial transfer is now legal in the U.K. and Maeve’s Law has paved the way for its potential clinical use in Australia. In a previous article, I analyzed the United Kingdom’s process of legalizing mitochondrial transfer in light of the American “democratic deficit” in the federal regulation of assisted reproductive technology.^[153] Regardless of the fate of Maeve’s Bill, the processes that Australia and the U.K. have used could provide useful insights to be implemented in the United States. In particular, key lessons include educating the public about the underlying science of these techniques, to minimize sensationalism, and multiple forms of public consultation that extend beyond gathering comments from the public like with notice-and-comment rulemaking.

A. Public Consultation Beyond Notice and Comment Rulemaking

Public deliberation or engagement is a broad term that encompasses a number of goals including transparency, education, and “bring[ing] an informed democratic process to decisions.”^[154] Many methods of deliberative democracy exist, including “public communication,” “public consultation,” “public involvement,” “public collaboration” like consensus conferences, and “public empowerment.”^[155] Public deliberation or engagement would be useful in the United States as it could serve to (1) educate the public, (2) connect groups that usually do not interface with each other, including federal agency employees and the general public, (3) satisfy scientists’ and bioethicists’ calls for public consultation in the area of reproductive genetic innovation, and (4) broaden the perspectives available to legislators and agency officials.^[156]

Public involvement in decision-making comprises a range of actions from passive (such as soliciting public input) to more active (like voting). Public opinion polls are one method of public engagement; however, they tend to be carried out by non-governmental entities, like the Pew Research Center or the now-defunct Genetics and Public Policy Center at Johns Hopkins University instead of administrative agencies.^[157] Public communication can include agency outreach and the providing of information; it is often a part of public consultation.^[158] Public involvement, which can be part of a public consultation, can also include deliberative opinion polls that assess the views of members of the public before and after expert deliberations.^[159] Public consultation, like that which has occurred in the United Kingdom and Australia involves soliciting public feedback and considering as part of the regulatory process.^[160] Public empowerment, such as the empowerment that occurs in the context of ballot initiatives in the United States, involves direct decision-making by the public, but is unlikely in the case of mitochondrial transfer at the federal level although it could be possible in an individual state in the future.^[161]

In countries that have legalized mitochondrial transfer, public consultation has been a part of the societal and legal conversations.^[162] Public consultations, which involve far more outreach than the United States’ notice and comment processes, agency-led public meetings, and lack of administrative agency discussion altogether, have been used in both the United Kingdom and Australia.^[163] Part of the U.K. and Australian experiences with mitochondrial transfer have included public outreach and a societal discourse. In the United Kingdom, the five-strand public consultation that preceded the legalization of mitochondrial transfer involved “…deliberative public workshops, …[a] public representative survey,…[an] open consultation questionnaire,…open consultation meetings…and patient focus groups.”^[164]

Citizens’ juries or citizens’ panels are another method of addressing a “democratic deficit” in regulation as they aim to increase public participation in government.^[165] At the same time, critics of citizens’ juries note that “[w]hile it is agreed that citizens should share in decision-making, there is no feeling that they should be involved in the process of governing more directly.”^[166] Citizens’ juries have been used to obtain public views on a number of matters related to health care in the United Kingdom and Australia.^[167] Citizens’ juries are also used in other such as Canada, European Union Member States, the United States, and India.^[168] Notably, Professor Ainsley Newson and colleagues convened a citizens’ jury on mitochondrial transfer in Australia and published the results.^[169]

In Australia, various governmental bodies acted to inform the public and solicit their views. In 2018, the Australian Senate Community Affairs Committee published, Science of mitochondrial donation and related matters.^[170] In 2019, the Committee released information related to mitochondrial donation and opened a submission portal so that members of the public could submit their views on mitochondrial transfer.^[171] In addition to the Citizens’ Jury convened by Professor Newson and colleagues in Australia, the NHMRC convened its own citizens’ panel which met over two weekends: once in October 2019 and once in November 2019.^[172] As part of the citizens’ panel, citizens attended presentations by scientific, medical, legal, and ethical experts. ^[173] The Citizens’ Panel published a statement after its convention.^[174] The NHMRC also conducted multiple webinars, posted videos, and used roundtables to solicit the views of experts in the field.^[175] In 2020, the NHMRC published the report of the Mitochondrial Donation Expert Working Committee.^[176] Later that year, the NHMRC released a report that summarized the agency’s findings.^[177]

In 2021, as part of the public outreach portion of the leadup to Maeve’s bill, the Australian government received 60 submissions in a public consultation.^[178] Some submissions were less than 2 pages long while others were much longer.^[179] Submissions by members of the public also included scientific background including benefits and risks or side effects of the techniques, recommendations for or against the techniques, and questions about aspects and implications of the bill.^[180] This effort went beyond the U.S. approach to mitochondrial transfer, which has involved no solicitation of public comment and no discussion through public hearings either. Later, the Article will draw on this combination of public input as combined with legislative hearings that include legislative consideration and expert testimony, as part of its recommendations for the United States.

The Australian Senate’s Community Affairs Legislation Committee held “Senate Inquiry Hearings” on August 6, 2021, which involved the testimony of scientists including the President of the ISSCR, George Daley, who is also the Dean of Harvard Medical School.^[181] Commenters had access to public submissions before the Senate Inquiry Hearings and several incorporated those submissions into their testimony.^[182] The ISSCR supports Maeve’s bill “because it would establish a rigorous, incremental approach to enable MRT to prevent the transmission of mitochondrial diseases that is consistent with the process described in the ISSCR guidelines….[and] provides a process for evaluating the safety and efficacy of MRT before making it available more broadly in clinical practice.”^[183] The ISSCR was also cited in the National Academies Mitochondrial Replacement Techniques report as having established guidelines for the ethical use of human embryos in research.^[184] Thus, in addition to examining the successful experiences of other countries, when considering the future of mitochondrial transfer in the U.S., governmental actors should consider that groups in the U.S. and abroad have already contributed to an expert consultation process.

In the United States, agencies have used some of the techniques of public involvement, but more can be done. The Department of Health and Human Services used public outreach methods such as “listening sessions” in the leadup toward establishing “essential health benefits” even though it was not required by the Administrative Procedure Act.^[185] Thus, although the FDA, an operating division of the U.S. Department of Health and Human Services is not known for taking such a public-facing approach on issues of moral, political, or social controversy, it could certainly do so.^[186] Increasing public interactions outside of the notice and comment process might have an “equalizing” impact on access, as many FDA employees speak at industry events (often with financial requirements for attendance) or interface with patients through FDA-established patient groups, but these interactions do not include the general public.^[187] Beyond that, there are many options for public engagement, as identified by a report issued by another operating division of the U. S. Department of Health and Human Services, the Agency for Healthcare Research and Quality.^[188] Even if the FDA did not lead efforts at public engagement and those efforts were left to other sponsors like individual state actors or private groups, there would still be some value to obtaining societal perspectives and fostering societal discourse on techniques involving reproductive genetic innovation. As legislators and interested parties continue to consider the legal framework that will accompany techniques involving genetic changes in the United States, it is worth framing those techniques in a manner that is accessible to the public and that minimizes the sensational views that accompany reproductive genetic innovation.

Constructing a public consultation related to mitochondrial transfer would exceed the space allotted in this Article, but this Article notes some of the areas that could be considered in that consultation.^[189] Such a consultation could be conducted at the federal level, by the U.S. Food and Drug Administration (because it is currently seen as the regulator of these techniques) or by other agencies within the U.S. Department of Health and Human Services, such as the National Institutes of Health, which is arguably more interested in the educational and bioethical aspects of medical innovations.^[190]

Part of that consideration should likely include the stories of individuals who have used the techniques. While many who are seeking to have pharmaceuticals approved by the FDA have been vocal (and successful) at having those pharmaceuticals approved, those interested in using reproductive genetic innovation have been less successful and visible. Part of an American public consultation, whether orchestrated by Congress, the FDA, or another administrative agency, should include stories from individuals who have suffered from mitochondrial disease and who might also want to avail themselves of these technologies.^[191] Furthermore, it might be useful to have the perspectives of those who have used or been conceived using cytoplasmic transfer as that is the most similar technique of reproductive genetic innovation that has been used in the U.S.^[192] Similarly, stakeholder perspectives, including those of individuals who have obtained mitochondrial transfer or who wish to do so, would likely need to be represented. For example, “the lobbying for universal [newborn] screening [in the U.S.] relied on dramatic testimonies of parents.”^[193] Patient perspectives have been included within FDA Advisory Committees for years. For example, in response to Executive direction, the FDA added voting patient representatives to FDA Advisory Committees tasked with addressing cancer-related issues.^[194] While there is a debate within the FDA literature on the appropriateness of patient perspectives in regulatory decisions (and the connection between those patient perspectives and drug approval), the FDA’s Patient Representative Program appoints individual patients and advocates as “Special Government Employees,” if they are not already “regular” government employees who are then able to provide “direct input to agency staff … on their experiences with various diseases, conditions, and devices while gaining access to confidential information.”^[195] FDA Patient Representatives also interface with other groups of experts who are affiliated with the FDA such as members of Advisory Committees.^[196] Currently, the FDA Patient Representative program encompasses a number of “recruitment areas” including naloxone use, obesity, HIV, and retinitis pigmentosa.^[197] This program, however, is not sufficient as a public consultation because it does not resolve transparency concerns but rather leads to a different kind of influence on agency decision-making that is still outside of public scrutiny.^[198]

There are disadvantages to public consultations. For example, the lack of a public consultation can permit an issue to remain unregulated and thus legal, like surrogacy in some states, or in vitro fertilization in general, which is viewed as unregulated.^[199] Yet, while there has been no public consultation related to mitochondrial transfer, the lack of a public consultation has also corresponded with concise but highly effective federal regulation. In the U.S., a future public consultation could include several issues including explanations of the science of mitochondrial transfer, the role of the FDA in product approval, the limitations of FDA approval, the impacts of state and federal actions on parental and reproductive autonomy, disability rights, and other ethical issues that accompany the use of mitochondrial transfer.^[200]

B. Re-interpretation or Removal of the Recurring Federal Budget Rider

As noted in Part II, in 2015, a rider limiting FDA consideration of applications involving “heritable genetic modification” was added to the 2016 budget.^[201] This budget rider has been renewed each fiscal year since it was approved in 2015.^[202] In general, federal budget riders typically occur without much substantive discussion.^[203] There are drawbacks to any approach that involves the federal government: namely, that any such approach would strengthen a current trend of increasing federal regulation of the legality of assisted reproductive technology.^[204]

Although budget riders typically occur without much substantive discussion, the U.S. could have a much larger conversation surrounding the currently recurring budget rider.^[205] Part of that conversation could include the testimony of individuals who are affected by mitochondrial disease, as there has been a lack of that perspective in the limited conversations held in the U.S. This conversation could motivate the FDA to change its currently overbroad interpretation of heritable genetic modification as including mitochondrial transfer, or influence Congress to write a narrower budget rider (or none at all).^[206] At the same time, the budget rider could have been intended to not only preclude use of the technique in the United States, but also to discourage discussion of the technique at the administrative agency level all together.

C. Substantive Congressional Hearings

Moreover, while there have been conversations and testimony at the level of Congressional subcommittees, perhaps the U.S. should also consider substantive legislation on mitochondrial transfer. At the very least, Congress should convene hearings related to the technique in order to foster conversation similar to what occurred with organ transplantation decades ago, especially if political and social views will impact regulatory decision-making.^[207]

Congressional hearings could be useful not only as they related to the recurring budget rider but also in terms of a broader societal discourse. Mitochondrial replacement therapy does not appear to be a priority on any state or federal legislative agenda. Similarly, there seems not to be a “Maeve” in the United States who has influenced the writing of proposed legislation, but there could be. Personal stories and emotional pleas have also resulted in (and accompanied) legislative and policy changes in various health areas including newborn screening and research, treatment, funding, and advocacy for HIV/AIDS, abortion, and breast cancer.^[208] Moreover, public consultation could be employed in the U.S. in at least two ways. First, any reporting related to public workshops could be shared with legislators, similar to how evidence from the United Kingdom’s public workshops was synthesized in a report that was made available before Parliament changed the U.K. law on mitochondrial transfer.^[209] Second, educating legislators about mitochondrial transfer, similar to the education that individual U.K. participants in HFEA-sponsored deliberative workshops, could change regulatory perspectives, including the views of those who may be indifferent to mitochondrial transfers use in the United States.^[210]

A broader lesson from the Australian approach to the legalization of mitochondrial transfer is one in which the United States’ inquiry into the legalization of mitochondrial transfer occurs in an incremental manner. Australia pursued a “staged” approach to the potential legalization of mitochondrial transfer.^[211] A “cautious, staged” approach was mentioned by the National Academies of Sciences when they explained the type of trial design that would need to take place in clinical investigations related to mitochondrial transfer.^[212]

One issue that arises in the context of public consultations is what the impact of negative perspectives is on regulatory outcomes. One might ask: does opposition automatically veto mitochondrial transfer or similar reproductive genetic innovation techniques? In Australia, even though many opposed mitochondrial donation, the government continued to go forward.^[213] Similarly, in the U.K., negative views did not prohibit the legalization of mitochondrial transfer. One can expect that there will be negative views related to the legalization of mitochondrial transfer in the U.S., yet those negative views should not necessarily serve as a veto on the legalization of the technique. One can expect that any discourse in the U.S. would likely result in significant opposition from various groups including religious groups and those who are opposed to genetic innovation more broadly. Yet, such groups are opposed to several other techniques that continue to go forward in the U.S., such as stem cell research, abortion, in vitro fertilization and cryopreservation of eggs and embryos. While religious views have certainly precluded funding and led to substantial restrictions in access to techniques (including, especially abortion), thus far, they have not managed to completely ban the underlying techniques in the way that reproductive genetic innovation has been stymied in the U.S. Further, an emphasis on education may serve a particularly limited role in the United States, as illustrated by recent political opposition and public resistance to public health measures intended to reduce the spread of the COVID-19 pandemic although the U.K. has also experienced that resistance.^[214] Yet, if education fails to sway participants toward legalizing mitochondrial transfer, that education would still be useful in increasing knowledge and also would result in the maintenance of the status quo related to the legality of mitochondrial transfer in the U.S. Moreover, to the extent that religious, ethical, or moral views are prohibiting the use of reproductive genetic innovation in the U.S., public consultations and Congressional hearings can identify those views and facilitate a conversation as to exactly how influential these views should be.

Conclusion

A “staged” or incremental approach still does not eliminate or resolve many of the ethical debates and arguments that accompany ART and forms of ART involving genetic modification or substitution like embryo destruction, long-term effects, sex selection, and entitlement to donor information.^[215] It does, however, provide a structure for discussing those issues in a more transparent and publicly available manner than they are currently addressed in the U.S. It is possible that the United States needs more time with mitochondrial transfer than the United Kingdom and Australia before approving it. As that time unfolds, there are many scientific, ethical, and safety issues to discuss and several blueprints available on how to conduct those discussions.