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In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop (2023)

Chapter: 6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States

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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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6

Imagining a Potential Clinic Research Pathway for Human IVG in the United States

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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This chapter summarizes perspectives on the elements that could be part of a potential clinical research pathway for IVG in humans and the existing regulatory barriers. These presentations and discussions were held during a panel and a breakout group. Both the panel and group were moderated by Jeffrey Kahn of John Hopkins University. Kahn challenged the panelists and participants to focus on the unique aspects of IVG, particularly its potential to create a human life in a way never performed before, and how that impacts the path forward.

U.S. POLICY AND LEGAL APPROACHES TO ART

Alta Charo of the University of Wisconsin Law School provided a brief history of the changing U.S. legal and ethical oversight of ARTs. She also discussed how funding policy and political restrictions could affect both basic and clinical research on IVG. Before sharing her perspective, Charo disclosed her role as a paid consultant to two companies working on the development of IVG technologies, Conception Bioscience and Gameto.

Historical Perspective on the Regulation of ART

Charo began by giving a historical perspective on how the United States tends to approach issues related to human reproduction and new ARTs.

Fetal Research Regulations in the 1970s

The modern era of regulation to protect human research subjects began in the 1970s after controversies involving allegedly unethical

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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research on fetuses and adults prompted a series of congressional hearings. Several states quickly passed laws aimed at regulating research on fetuses. However, by defining fetuses as the product of conception from fertilization onward, some of these laws also captured laboratory research involving embryos and inadvertently encompassed some aspects of what would become IVF research.

The congressional hearings and subsequent events culminated in creating the Ethics Advisory Board to offer an additional layer of required review for federally funded research that created, used, or destroyed embryos. After a change in administration, the board was deliberately left without members, even though its review was required as a condition of funding through the 1980s, so a de facto prohibition on federal support began in 1980.

FDA Authority in the 1990s

Regulating medicine is primarily a function of state law, but at the federal level, FDA regulates the products used in medical practice—such as drugs, devices, and biologics, such as blood and products derived from other types of human cells. Throughout the 1980s and the growth of IVF, advances in ART were regulated as the practice of medicine. However, in the 1990s, FDA began to expand its policies and enforcement powers over manipulated human tissue used as medical products.1 After the announcement of Dolly, the cloned sheep, FDA asserted in a congressional hearing that the manipulated cell lines needed to perform reproductive cloning would fall under its regulatory authority. FDA has also published guidance covering many aspects of ARTs, such as screening requirements for donors.

NIH Human Embryo Research Panel in the 1990s

From 1994 to 1995, the U.S. government expanded and then shrank its ability to support human embryo research. After the transition from the George H.W. Bush to the Clinton Administration, NIH established the Human Embryo Research Panel to reevaluate the de facto prohibition on federal funding, Charo said. The panel, on which Charo served, agreed that research using human embryos could be funded in certain

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1 Charo noted that, unlike the United Kingdom, no effort was made to create a federal regulatory body focused on ARTs, and such an authority would have been inconsistent with the primarily state-based regulation of medical practice in the United States. The United Kingdom established the Human Fertilization and Embryology Authority in 1990 to regulate and inspect clinics delivering ART services, including IVF, artificial insemination, and human gamete/embryo storage. The Human Fertilization and Embryology Authority also oversees human embryo research.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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circumstances, such as when other methods would not provide good alternatives for important research, and providing that human embryos would be used in the earliest stages of development and fewest numbers possible. Among these recommendations, the panel specified that on rare occasions, it may be necessary to create embryos for research purposes, including to study new forms of contraception. Charo said that this recommendation generated intense controversy and pushback. In response, Congress passed the Dickey-Wicker Amendment, still in place today.

U.S. Regulations on Basic and Clinical Research with Human Embryos

Dickey-Wicker Amendment

The Dickey-Wicker Amendment of 1995 limits federal funding for human embryo research. In short, it says that federal funding cannot be used to (1) create an embryo for research purposes or (2) perform research in which an embryo is destroyed, discarded, or knowingly subject to risk greater than the minimal risk that is allowed for research on fetuses.2 In the amendment, an embryo is defined by how it is made, including by fertilization, parthenogenesis, or cloning, rather than by its biological potential for normal development to term. Charo said that “this now is the background in terms of funding restrictions for the U.S.”

Embryonic Stem Cell Lines

Although the Dickey-Wicker Amendment clearly prohibits using federal funds to derive new ESC lines, as it would destroy embryos, different interpretations allow for federal funding for research on existing ESC lines. Harriett Rabb, the Counsel for the Department of Health and Human Services during the Clinton Administration, distinguished between creating ESCs and work involving previously derived lines; those were not embryos, she argued, and did not have the potential to go to term. When President George W. Bush took office in 2001, he limited federal funding to lines that were derived before that moment, aiming to disincentivize using private money to “destroy new embryos” to create federally fundable ESC lines. Despite this, Charo said that nonfederal funding began to support developing ESC lines. The Obama Administration lifted Bush restrictions on which cell lines can be used with federal funds. With the Dickey-Wicker Amendment still in place, researchers today cannot use federal money to

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2 Charo noted that the level of risk allowed for fetuses is very minimal unless the researcher is attempting to heal the fetus to bring it to term.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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destroy an embryo to make ESC lines but can use these funds to work on lines generated with support from other funders, which includes both private entities and state funds.

Clarifications Needed

Charo said that the impact of the Dickey-Wicker Amendment on funding of embryoid3 research remains an open question. The amendment’s definition of embryo, which relies on how it is produced rather than its biological potential, leaves the kinds of research prohibited open to interpretation. Embryoid models that use existing ESC lines and iPSC lines could be allowed, but Charo questioned what might happen if researchers “create something that looks a lot like an embryo,” even in the absence of biological potential. She said that in the current political climate, it might be politically and socially problematic to argue that the embryoid is not really an embryo and therefore eligible for federal money. Questions remain about what basic science research is permitted with federal funding, but IVG is likely ineligible, Charo concluded, by either law or politics.

Appropriations Rider

Next, Charo discussed a major barrier to IVG progressing to the clinical research stage: the FDA appropriations rider. It was initially written to prevent FDA from considering applications on nuclear genome germline heritable editing [and incidentally also prevents it from considering proposals for mitochondrial replacement therapy (MRT)]4 and serves as “an indirect ban on all clinical trials for reproductive uses of genetically modified embryos.” It reads as follows:

None of the funds made available by this Act [to FDA] 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 … in research in which a human embryo is intentionally created or modified to include a heritable genetic modification.

FDA cannot use its money or personnel time or acknowledge receipt of a request to start a trial that creates heritable genetic modifications.

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3 Embryoids are three-dimensional aggregates of pluripotent cells that can be induced to resemble the morphology of an early embryo.

4 Used when a prospective mother carries mitochondrial disease, MRT involves replacing her mitochondria with a third-party donor’s. MRT can also be used to generate a child with three genetic parents. It is approved for use in the United Kingdom. Other applications that do not involve heritable genetic modifications are under investigation in the United States.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Although the rider might seem to be a complete barrier to clinical trials on IVG, Charo noted that the inclusion of the word “intentionally” in the rider allows for different interpretations on what constitutes a genetic modification. Because IVG does not necessarily include purposefully creating genetic modifications, some interpretations may allow FDA to consider applications for its clinical use, Charo said.

State Law

Charo discussed how the U.S. regulatory landscape for embryonic research is made more complex by laws at the state level. About half of states have no laws that address embryonic or fetal research; 11 states limit either fetal research (for which close attention must be paid to whether fetuses are defined in a manner that might encompass embryos) or embryo research. These laws range from outright prohibitions (e.g., Louisiana and South Dakota) to restrictions on using state funds (i.e., Arkansas, Kentucky, Nebraska, and Oklahoma). For many of these states, basic IVG research involving human embryos would be illegal or ineligible for state funding.

Charo said that those performing IVG research in the United States must examine their jurisdiction’s laws closely to ensure they are in compliance. She said that new laws could be written as legislators learn about IVG. With several states controlled by a single party, legislative proposals can often “fly through the legislature,” Charo said, noting the breakneck pace at which abortion bans have passed through state legislatures. She concluded that these laws may be “a harbinger” of what is to come for new reproductive technologies.

AN INDUSTRY PERSPECTIVE ON A POTENTIAL PATH TO CLINICAL RESEARCH

Krisiloff offered an industry perspective, drawing on his experience as the CEO of Conception Bioscience, a for-profit company developing IVG. He focused his talk on safety requirements that would need to be assessed in preclinical contexts for IVG and potential regulatory frameworks. He disclosed that he was expressing his “own personal optimistic viewpoint” that it is plausible to test the safety of IVG for potential human use, noting that if it is deemed unsafe, then it should not move forward.

Progress in IVG Development

Krisiloff briefly outlined preliminary, unpublished data collected by Conception Bioscience in its pursuit to generate stem cell–derived human eggs capable of being fertilized. Krisiloff stated that the company

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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has developed a protocol to efficiently produce oogonia-like cells from PGCLCs, which could allow scientists to assess downstream procedures to further differentiate oogonia-like cells more effectively. Krisiloff said that some of the in vitro–derived oogonia express SYCP3, an important marker of meiosis, although images were not shown. He echoed Paula Cohen’s remarks that meiosis is a complex process that will need to be further validated. Conception Bioscience scientists also claim to have observed putative follicles forming with an in vitro–derived gamete at the center surrounded by granulosa cells. Krisiloff expressed excitement that these in vitro–derived follicles resemble in vivo follicles and seem to grow over time. The IVG field is moving toward generating the first proof-of-concept human gametes, he said.

Based on the pace of progress in the field at large, Krisiloff speculated that the first in vitro–derived human gametes could be achieved within the next few years, but these would require years more research and refinement before any potential human clinical trials. Rigorous preclinical research is necessary and would need to encompass in vitro optimization of gamete derivation, quality control development, animal models to test the ability of mammalian in vitro–derived gametes to support successful pregnancies that result in healthy offspring, and safety testing. It is time to think concretely about how to measure benchmarks for preclinical safety, Krisiloff concluded, with the understanding that if these benchmarks are not met, then human trials would not be appropriate.

Potential Regulatory Framework: Biologic Cell Therapies

Krisiloff proposed that FDA’s regulatory framework for biologic cell therapies could serve as a potential framework for its regulatory oversight of IVG.5 If deemed appropriate, IVG could enter clinical trials under an investigational new drug application under this framework.6 IVG is reminiscent of other cell therapies, which involve taking cells from an individual, differentiating them into a specific cell type in vitro, and then placing them back into the body. Despite issues specific to generating gametes, much can be learned from the 19 FDA-approved cell therapies, he said. Like other cell therapies and biological products, preclinical research needs to set minimum baseline measurements for iden-

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5 Krisiloff specifically noted 21 CFR 600 for biologics regulation and 21 CFR 312 for drug regulation.

6 Krisiloff expressed his strong belief that government and scientific oversight is instrumental for safely advancing IVG and rejected performing it clinically without regulatory purview, which was mentioned earlier. He identified FDA, Institutional Review Boards, and Stem Cell Research Oversight Committees as important regulatory bodies.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

tity, purity, and potency of gametes produced by IVG. General steps for using iPSCs in the clinic have already been defined, although IVG may require increased examination of the starting cell type for mutation loads. Steps for verifying that autologous cell therapies meet certain standards before being given to a patient have also been set. Therefore, Krisiloff proposed that cell therapies can serve as a road map for IVG toward potential future clinical trials.

IVG also has considerations that are unique and specifically complex. Krisiloff suggested that some aspects of IVG may make quality control and safety a more accessible problem. Unlike other cell therapies, a select number of eggs and embryos are needed, rather than millions and millions of cells. Therefore, individual eggs or embryos can be highly scrutinized to select the highest-quality cell. Furthermore, embryos generated with an in vitro–derived gamete can be cultured for several days before implantation to ensure that development is proceeding authentically.

Preclinical Characterization of In Vitro–Derived Gametes

Screening individual eggs and embryos allows for rigorous preclinical characterization in vitro using powerful tools, such as genetic sequencing, RNA sequencing, epigenetic profiling, and morphologic analyses, Krisiloff said. Critically, in vitro–derived gametes and the resulting embryos can be compared to in vivo eggs and embryos generated via IVF, which are typically cultured for 5–6 days. These preclinical analyses will allow for creating specific benchmarks for epigenetic resetting, meiosis, and mitochondrial function, among other criteria.

Animal models are another key component of preclinical research. Krisiloff noted the importance of more in-depth experiments in mice and nonhuman primate data to live birth and beyond. Conversations need to be had to discuss whether other types of animal models would be useful for assessing IVG, he said.

Potential Endpoints for Clinical Trials

Before IVG ever reaches potential clinical trials, it is important to consider what mechanisms would be used to assess safety. Many reproductive therapies use miscarriage and live births as the main study endpoints. However, Krisiloff said that these endpoints would not be sufficient for this new therapy. Long-term follow-up of children born via IVG would be critical, he said, noting that it must be considered what is appropriate, ethical, and feasible.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

Legal Barriers

Krisiloff addressed the potential legal barriers outlined by Charo, noting that he does not believe these preclude IVG from moving forward. Conception Bioscience is based in California, where human embryo research is permitted. Research in both academia and industry relies on private funding to avoid issues related to the Dickey-Wicker Amendment. Last, his view is that IVG does not require genetic modifications to cells and therefore does not contravene the FDA appropriations rider.

Potential Impact on Patient Community

Krisiloff closed by centering the profound benefits IVG could have for those experiencing infertility. Conception Bioscience receives two or three e-mails each week from people with a strong desire to have genetic offspring: young cancer survivors, women going through IVF without success, same-sex couples, and more. As he reflected on this demonstrated interest, Krisiloff noted that the workshop would have been enriched by more opportunities to hear from prospective users directly.7 He shared his dream of creating genetically related children with the help of IVG as part of a same-sex couple; this personal investment, he continued, intensifies his commitment to ensuring safety.

POTENTIAL U.S. REGULATORY FRAMEWORKS FOR IVG

Peter Marks offered his perspective as the director of FDA’s Center for Biologics Evaluation and Research (CBER). He outlined potential regulatory frameworks, roadblocks to consideration, and important preclinical information.

Regulatory Framework for Biologics

Marks gave a brief overview of what authorizes FDA to have jurisdiction of autologous cell therapies, including IVG if it ever progressed to human use. The Commerce Clause of the U.S. Constitution gives Congress the power to regulate interstate commerce.8 Because at least one component of any manufactured biologic or other medical product will have crossed state lines, FDA has authority to regulate them under the

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7 For further discussion of potential user perspectives and public engagement, please see Chapter 8.

8 https://constitution.congress.gov/browse/essay/artI-S8-C3-1/ALDE_00013403/ (accessed August 8, 2023).

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

Federal Food, Drug, and Cosmetic Act.9 Licensed biologics also adhere to Sections 351 and 361 of the Public Health Service Act. Section 351 allows FDA to require licenses for biologics, perform inspections, and revoke those licenses, and Section 361 is a provision to prevent communicable disease transmission. In practice, FDA oversees biologics through rules and regulations derived from these laws, which are interpreted through agency-issued guidance.

Appropriations Rider

As Charo outlined, the appropriations rider dictates that FDA cannot accept applications for treatments that intentionally create heritable genetic modifications. Marks said that recent attempts to remove this rider were met with resistance, and it was left in place.10 The rider poses difficulties for considering new technologies, such as IVG, that deal with the germline. Marks said that FDA attorneys feel uncomfortable whenever a technology could result in a heritable genetic modification, even if it is not by active intent but by accident.

Whether FDA could accept an application for IVG with the existing rider is an open question, Marks said. A strict reading might allow for IVG because the intention is not to make heritable genetic modifications. However, IVG would likely be disallowed by interpreting the rider more broadly as including technology that could enable or result in such modifications, even unintentionally. Marks raised concerns that if FDA considered any IVG applications, it might start a “game of cat and mouse” in which the rider is expanded to restrict more potential technologies.

Preclinical Research

FDA does not regulate nonclinical work, including the current laboratory and animal research on IVG. However, Marks noted that the conduct and outcomes of preclinical research are relevant for any FDA application for a clinical trial approval. Under typical circumstances, FDA and researchers engage in robust discussions about the preclinical research needed to build a strong application. However, IVG technology is in a

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9 Marks referenced United States v. Regenerative Sciences, LLC, which reinforced FDA’s authority over autologous cell therapies. Regenerative Sciences argued that its therapy was part of the practice of medicine rather than a biologic and involved no interstate commerce. The court ruled that it met the definition of a drug or biologic under the Food, Drug, and Cosmetic Act and was subject to the Commerce Clause, as components had crossed state lines.

10 Marks noted during the discussion panel that he was consulted about removing the rider. He felt it was “appropriate to do,” especially given advances in MRT in the United Kingdom.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

“strange situation” in which FDA cannot accept applications, but nonclinical work can proceed. Whether FDA and researchers can converse about this nonclinical development is open to interpretation, Marks said.

Marks said that FDA would be most interested in understanding how IVG affects the integrity and stability of the genome. Assessing the former may be easier for researchers due to the availability of sequencing technologies. However, genome stability over generations will require more work and necessitate discussions about how many generations is enough, Marks said. Testing stability in different animal models, both rodents and nonhuman primates, will likely be necessary. Nonhuman primates are the most closely related to humans, but studying multiple generations is very difficult. Conversely, mice are more distantly related to humans, but studying 10–20 generations is more reasonable. Ultimately, preclinical research is critical for FDA to make choices about whether a product is safe and effective as part of its pursuit to protect people, Marks concluded.

Looking Forward

Marks stated that FDA wants to enhance progress and not stand in the way. Its rules and regulations ensure that fields are not set back by errors that compromise human safety. Failing to adhere to FDA oversight and the ensuing issues can have a chilling effect on research advances, Marks explained.11 Rigorous preclinical research that establishes safety and efficacy would be key if FDA were ever to consider an IVG application for human use. Marks closed by saying that FDA is interested in understanding IVG and helping it move forward “within the confines of what we are allowed to do by Congress, some of which is interpreted by our attorneys.”

PANEL DISCUSSION

The Appropriations Rider

Several speakers noted that the FDA appropriations rider could serve as a major barrier to advancement of IVG. Whether IVG is covered by the

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11 Marks referenced a tragedy that set back the gene therapy field. Jesse Gelsinger joined a clinical trial for a metabolic disorder, ornithine transcarbamylase, to help infants born with more severe forms of the disease and died due to his participation. His death resulted in a lawsuit, government investigation, new regulatory processes for gene therapy trials, and the delay of several trials. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81135/ (accessed August 8, 2023).

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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rider is an open question. Panelists discussed its ambiguity, the context in which it was written, and how FDA could clarify its applicability to IVG.

Clarifying Perspectives

Suter asked the panelists to dive deeper into their perspectives on the applicability of the rider to IVG. Because it bars introducing heritable genetic modifications, Marks said that the preclinical data would have to strongly support that IVG does not do so. Rigorous research is necessary to ensure that FDA attorneys feel confident that they are on the “right side of the congressional appropriations rider.” Charo added that “the word ‘intentional’ is crucial [in the rider] because it allows for some slippage.” By this interpretation, the rider could allow for technology that results in unintentional heritable mutations, even if they could be anticipated. Krisiloff reiterated and clarified that the rider may not prohibit FDA from accepting applications on IVG. Unlike MRT, IVG does not require integrating or altering elements of the genome, he said, making its prohibition more questionable. Nonetheless, he recognized that the interpretation of the rider by FDA and its attorneys will determine the agency’s course of action.

A Product of Its Time

Both Marks and Charo agreed that if those writing the rider had known IVG were a possibility, they would likely have broadened the language to include it. However, the rider was a “product of its time,” Marks said, written to block potential clinical uses that would create heritable genetic modifications. A strict interpretation of it as written might enable an application to FDA for IVG, but “there is an excellent chance that at the state and at the federal level, somebody is going to catch on and pass something else that clarifies that this too is not allowed,” Charo concluded.

Legal Interpretations

Glenn Cohen asked Marks how FDA attorneys are interpreting the appropriations rider. Marks reiterated the concerns that FDA lawyers have about accepting an application for IVG with the appropriations rider in place; moving forward, its attorneys would likely seek clarification. Charo followed up with Marks by asking from whom FDA attorneys would consult about it. Charo and Marks both agreed that requesting clarification from Congress would be difficult, given the diverse points of view. Marks responded that the attorneys would likely consult the Office of General Counsel for Health and Human Services. He emphasized that

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

General Counsel needs to be willing to stick by whatever interpretation is made.

Developing a New Pathway

Greely expressed concerns about whether FDA would categorize a human embryo as a drug or biological product, especially given the recent expansion of embryonic rights. Assuming FDA has jurisdiction, he asked Marks whether it would regulate IVG as a standard biological product or solely a human cell, tissue, or cellular and tissue-based product. Marks responded that although it would be ideal to categorize in vitro–derived gametes and their embryos as the latter, they are more than minimally manipulated during production. Marks suggested that regulating either may require adapting an existing pathway or finding another pathway. An important goal of any pathway developed “in a humanistic way” would be to ensure that the children conceived by IVG did not feel like products, he continued. Greely cautioned that there is not “infinite time” and urged FDA to consider potential pathways for regulating human embryos resulting from technologies soon. Marks agreed, noting that since MRT is likely closer to clinical application in the United States than IVG, learning from its path could help “prepare the way” for IVG if it ever were considered for clinical research.

Preclinical Discussions on IVG with FDA

A participant asked Marks to discuss the extent to which FDA can engage with a company like Conception Biosciences, if any. Marks responded that the possibility for interaction is open to interpretation, which can shift from administration to administration. Although FDA is barred from accepting applications for therapies that can result in heritable genetic modifications, “application” is ill defined. It certainly includes an investigational new drug application, but it could be expanded to include company requests for meetings and discussions. Before joining the workshop, Marks cleared his participation and discussion points with the FDA General Counsel. By that token, discussions about preclinical requirements with companies may also be permitted. However, opening a file for a company that FDA has any hint of moving toward an investigational new drug application would be a challenge.

Marks asked Charo for her outside perspective on how FDA may best proceed, given the challenging waters to navigate. Charo said that discussing the specific preclinical steps and milestones with researchers may be the best way to start. These conversations could reveal which preclinical laboratory and animal studies to prioritize and where to place the

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

most resources. Charo concluded that these discussions may allow FDA to be “very helpful for quite a long time without having to bump against the stuff” that is concerning to its attorneys.

Intergenerational Consent

Marks discussed informed consent, a key part of any clinical trial that involves giving patients important information, including possible risks and benefits, to help them decide whether they want to take part. As part of follow-up for any first-in-human use of IVG, it would be particularly valuable to track the children conceived for certain medical data. Marks said that this setup would necessitate intergenerational consent; parents could consent for the child up to a certain point, but, ideally, the child would consent to continue in the study. Although Marks said that generations of nonhuman primate data would be needed before moving into humans, cross-generational human data would be ideal to have as well.

Chain of Custody for In Vitro–Derived Gametes

IVG could potentially be misused to create embryos with genetic material obtained illicitly from individuals (e.g., hair or skin). Greely commented that laws would be needed to ensure that people cannot become genetic parents without their knowledge or consent “except maybe in rare, exceptional cases.” Given the importance of controls in this sphere, Greely asked Marks whether unwitting parenthood is an issue that would be regulated by FDA and, if so, how. Marks said that it could fall into the same category of regulation as chain of custody for other autologous cell therapies. “If you harvest white cells to make chimeric antigen receptor-T [CAR-T] cells, we get concerned about chain of custody to make sure it was truly yours going back to you,” he said. FDA would need to outline and approve protocols for gamete chain of custody.

Greely followed by asking whether a new pathway would be necessary to track in vitro–derived gamete chain of custody depending on whether it is done at ART clinics or through companies. FDA usually stays away from mix-ups at ART clinics when the wrong embryo is implanted, Marks noted. However, it can investigate clinics to assess adherence to policies and procedures and would be able to do so for IVG.

Potential Business Structure for Clinical IVG

Several questions for Krisiloff revolved around the potential business strategy for companies developing IVG. His answers revealed an industry perspective on cost and access if IVG were ever available clinically.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

Business Plan

Glenn Cohen asked Krisiloff to reflect on a potential business plan for IVG, including users and payment structures. If IVG overcomes the necessary hurdles for clinical use, Krisiloff envisions partnering with IVF doctors and clinicians. Modeling on IVF workflows, Conception Bioscience could receive tissue samples from doctors, perform IVG, and then send back either gametes or embryos to the clinic. He first expressed his hope for a more robust system for reimbursement around reproductive medical care. IVG will likely be very expensive at the outset, he said, due to the need for proper quality control, Good Manufacturing Practice standards, and the necessity for a team of experts to perform autologous cell therapies. Krisiloff said that he is optimistic that the price could come down.

Exclusive or Free Market

Cyranoski asked Krisiloff if the strategy at Conception Bioscience is to get an exclusive market on IVG, particularly in light of their patent applications. That might pose a barrier to access and make IVG more controversial, the participant suggested. Krisiloff responded that applying for patents is out of concern for the company’s freedom to operate given the number of other groups pursuing IVG development. The patent landscape is still uncharted territory for these types of cell therapies, he said. Furthermore, a certain cell type can be generated in more than one way; he noted that even within the IVG field, several protocols exist for generating PGCLCs. Krisiloff said his company is willing to collaborate with other researchers who have their own patents. Rather than the market, Krisiloff pointed to manufacturing processes, cost, and scale as the greatest barriers to access for IVG.

Concerns About Oversight

Participants asked about how IVG could advance in situations where researchers or clinics seek to evade regulatory bodies or move offshore. Panelists answered and uncovered shared concerns about the United States falling behind if regulatory restrictions are not relieved.

IVG as Clinical Innovation

Ogbogu asked Marks about whether FDA is anticipating clinicians claiming IVG is a clinical innovation and performing it outside of FDA oversight. Marks said that he does not think it is likely that clinicians in the United States would do so, because FDA can quickly shut them

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

down by asserting the need for an investigational new drug application. Clinicians attempting this would likely be offshore, he said, referencing previous experience with stem cell therapies. Krisiloff also expressed skepticism that rogue U.S. actors could perform IVG claiming clinical innovation. The resource scale needed for IVG with reasonable efficiency and safety will not be achievable by a few rogue clinicians, he said. Given the highly specialized skill sets and significant resources needed, Krisiloff shared his belief that human IVG will be developed by smaller groups of specific companies or university centers with awareness and oversight from regulatory bodies.

Offshore Advancements in IVG

Marks and Charo both expressed concerns about researchers moving offshore to advance IVG without proper oversight. Charo discussed opportunities for researchers to “elude regulatory regimes” for the initial stages. She specifically mentioned a city in Honduras, Prospera, that is marketing itself as a place where companies can go to create their own city-states and operate free from oversight (Clarke, 2023). Already home to biohacking companies, Prospera and cities like it could serve as sites for those who would prefer to evade FDA oversight, she said.

Several panelists also discussed how barriers on FDA oversight of IVG could limit U.S. leadership in discussions around its advancement and governance. Marks said, “One of the things that we have tried to explain to our legislature is that it is a little bit like atomic energy. You are not putting the genie back in the bottle.” IVG will progress, whether the research is based in the United States or somewhere else. He expressed concerns that by not allowing for movement in this field, the United States could put itself in a position where it cannot take leadership to ensure that progress is ethical and safe. Kahn agreed, noting that the United States might also want to lead from a competitive perspective. Charo added that she thinks the United Kingdom “may very well get ahead of us on this” and be the first site for responsible in-human use of IVG. The Human Fertilisation Embryology Authority (HFEA) has advanced MRT to initial clinical trials, and the U.K. political backdrop seems more comfortable with reproductive innovations. Marks added that if researchers have solid science to support IVG and make it clear that they are moving offshore because it cannot proceed in the United States, that may serve as a wake-up call for legislators.

BREAKOUT GROUP DISCUSSION

A breakout group moderated by Kahn focused on the topic of “Translating IVF from Laboratory to Market.” Given that many emerging tech-

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

nologies require extensive testing and approvals before human use, participants discussed pathways that IVG could take from the laboratory to potential clinical testing, including regulatory considerations and what enabling scientific information would be needed. This discussion focused on the U.S. regulatory system and included participants familiar with FDA. Key points from participants in the breakout group discussion were reported to workshop attendees by the rapporteurs, Kahn and Emily Packard Dawson.

Potential Regulatable Products for IVG

Several participants proposed that the gamete resulting from IVG would be the regulatable product. An industry representative expressed an alternative view that the embryo generated using the in vitro–derived gamete could be considered the product. However, if IVG were combined with a technology such as genome editing of the resulting embryo, then the embryo would also become subject to FDA regulatory authority, many suggested.

During the report-out, Glenn Cohen questioned whether regulating the gamete as the product would impact the current interpretation of the appropriations rider. Marks and Deborah Hursh both agreed that if the in vitro–derived gamete were used to intentionally create an embryo, the implications of the rider would not be avoided.

Potential Regulatory Frameworks for IVG

A few participants suggested that FDA’s regulatory framework for CAR-T cells12 could be useful when considering a potential regulatory framework for IVG. Both would be autologous13 products created in a laboratory and sent to a clinician to administer to a patient. As with CAR-T cells, each patient’s gametes would be a new lot that must be assessed for identity, purity, and potency before release. However, one participant noted that in vitro–derived gametes would be unlike any other regulated cell therapy, breaking ground by being used to create a new person and suggested renaming a first-in-human trial to either “first-to-human” or “first-with-human” to capture this distinction. Several participants felt

___________________

12 In CAR-T cell therapy, a patient’s T cells are altered using a genetic construct. The CAR-T cells are infused back into the patient, where they will recognize and kill a specific target, often cancer cells. FDA regulates CAR-T cells as an Advanced Therapy Medicinal Product. CBER issued a suite of regenerative medicine guidance documents, including on CAR-T cells, in 2017 (Marks, 2019).

13 “Autologous” means that the cells were taken from a person and then put back into the same person.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

that a new regulatory approach informed by those of other autologous cell therapies would be needed.

Scientific Information and Testing

Several participants noted that before considering IVG for any initial clinical trial aimed at establishing a pregnancy, extensive laboratory testing and analysis would be needed to generate sufficient evidence of safety and efficacy. Such analyses could include characterization of in vitro–derived gametes, potential to create embryos, and molecular and development characterization of the embryos in the laboratory. Several participants said that in vitro–derived human gametes would need to be successfully generated and analyzed via a battery of tests, including human genome sequencing for mutation load and epigenetic analyses to ensure correct epigenetic resetting.

The embryos would also need to be cultured and analyzed extensively in the laboratory as part of preclinical testing, several participants said. However, participants deliberated over how long to culture, with some suggesting as long as allowed by ISSCR guidelines, currently 14 days. IVF laboratories have generated lots of information about embryos cultured through 7 days, but those cultured past this point remain less well characterized. The utility of culturing past 7 days remains an area of debate.

Finally, successful proof-of-concept experiments in nonhuman primate models14 would also be needed to indicate that IVG is possible and safely produces offspring before trials in humans, some participants suggested. Such studies may also need to include transgenerational studies of progeny created via IVG tracked for one or two generations to monitor for any late negative effects.

Animal Models in Preclinical Research

Although standard safety studies could be performed in rodents,15 several participants noted that the proof of concept that IVG creates functional gametes and healthy offspring would need to be shown in a nonhuman primate model. The proof-of-concept model is important for demonstrating feasibility and establishing safety for the resulting baby and

___________________

14 Such a system would involve using a nonhuman primate in vitro–derived gamete to create an embryo and then implanting that embryo into a nonhuman primate of the same species.

15 Some discussion was held over whether rabbits should replace rodents for such studies, considering that their germ cell development seems to match that of humans more closely. However, other participants felt that for these types of studies, rodents would still be appropriate and more cost effective.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

gestational carrier. Participants debated over which nonhuman primate model could be most useful: for example, marmosets have shorter generation time but are phylogenetically more distant from humans, whereas Rhesus macaques are phylogenetically closer but have longer generation times and are more difficult to manage.

Several participants suggested that transgenerational studies would be critical to evaluate epigenetic resetting. Rodent systems could be used to evaluate epigenetics in germ cells for several generations, but many felt that nonhuman primates may also need to be used and be tracked for at least one or two generations. Concerns were raised about the feasibility of such multigenerational studies in either model system.

Ultimately, one participant noted that laboratory characterization of human IVG and studies in other species, although vital, will not perfectly predict its safety and efficacy for human clinical use and that a decision on whether the evidence was sufficient to permit progress toward human clinical trials would need to be made.

Technology Needed for Assessing In Vitro–Derived Gametes

If scientists and clinicians can select healthy in vitro–derived gametes, it would be less necessary to generate several embryos to screen before establishing a pregnancy. However, current diagnostics for gamete health are limited to morphological analyses. Other tests require destroying the gamete. Several participants called for better diagnostic markers to understand the health of the gamete. With the goal of limiting embryos created via IVG, a few participants suggested that regulations could require developing a nondestructive diagnostic screening of the gamete before it is used to create embryos.

Although analyses are available to assess certain epigenetic markers (i.e., bisulfite sequencing for methylation), current testing options cannot capture the full breadth of the epigenetic landscape. Given concerns about ensuring correct epigenetic resetting, a few participants expressed interest in developing tools that could allow deeper analysis of the epigenome.

Criteria for a First-to-Human Candidate

Participants suggested that such a person would be a competent adult who cannot have genetically related children in any other way. A few participants said that FDA might prefer a candidate whose inability to have children was clearly due to a medical issue and suggested a cancer survivor. The candidate would need to properly consent and be educated on all risks and uncertainties. Many participants said that the embryo ought to be conceived using one in vitro–derived and one in vivo–derived

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×

gamete. Several participants also suggested that it ought to be implanted into one of the prospective parents, so that a gestational carrier would not be involved in the earliest trials.

Fair participant selection was raised as a concern given how small any initial cohort would be for a first trial, potentially just one person at a time. During the report-out, Glenn Cohen pointed out issues of justice related to having such specific medical inclusion criteria.

If FDA were to approve a clinical trial for IVG, several participants felt that it ought to be held in the United States and not abroad. Medical care also ought to be covered for the duration of pregnancy and for a period after the baby was born to ensure ongoing health and safety and adequate follow-up, they said.

Considerations for Follow-Up

Outcomes of IVF are only followed to the point of live birth. Several participants said that long-term follow-up of infants conceived using an in vitro–derived gamete would be needed as part of a clinical trial. The consenting process for the trial would require identifying the need for longer follow-up as part of enrollment, but participants could ultimately withdraw at any time. The U.K. trial for MRT under the HFEA could be used as an example for how to manage long-term follow-up, one participant suggested.

If IVG were tested in clinical trials, very few babies would be born in the initial cohorts. Therefore, combining the results from clinical trials across the world could be key to demonstrating safety and success, a few participants suggested. Given the potential for different IVG protocols, a participant expressed concern that one protocol might yield concerning data that set the field back prematurely. Participants debated the value of harmonizing protocols to enable results to be combined more effectively.

Embryo Research Funding in the United States

Development of human IVG is likely to involve creating embryos for research purposes, which precludes NIH funding due to the Dickey-Wicker Amendment. Several participants called for NIH to resume such funding, which would necessitate removing the amendment. In the absence of NIH funding and associated standards and oversight, many participants expressed concern that the human embryo research landscape has become a “Wild West.” Appropriate oversight and regulation, many noted, would be critical for the ethical advancement of IVG and other reproductive technologies.

Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
×
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Suggested Citation:"6 Imagining a Potential Clinic Research Pathway for Human IVG in the United States." National Academies of Sciences, Engineering, and Medicine. 2023. In Vitro–Derived Human Gametes as a Reproductive Technology: Scientific, Ethical, and Regulatory Implications: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/27259.
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Current assisted reproductive technologies such as in vitro fertilization (IVF) do not enable all prospective parents to have genetically related children. The National Academies Board on Health Sciences Policy hosted a workshop in April 2023 to explore the development of in vitro-derived human eggs and sperm from pluripotent stem cells through a process known as in vitro gametogenesis (IVG). Speakers emphasized the impacts of the potential biotechnology on research and reproductive medicine should clinical IVG ever be approved, along with the many social, ethical, legal, and technical considerations its development raises. This proceedings document summarizes workshop discussions.

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