Abstract
I. INTRODUCTION
In May 2015, the first baby created through an emerging ova technology called AUGMENT, was born in Canada. 1 Developed by OvaScience, AUGMENT essentially introduces mitochondria sourced from the genetic mother into her own ovum in order to revitalize the ovum. 2 This technology is controversial because OvaScience is a publicly traded company, and it is driven by short-term results, such as earnings; 3 and (2) OvaScience did not complete adequate clinical trials before offering AUGMENT to the public. 4 Moreover, in its 2014 annual report, OvaScience declared that it was intentionally offering its products in countries where clinical trials are not required. 5 The lack of adequate clinical trials is the primary reason underlying the Food and Drug Administration's (“FDA”) prohibition of the technology in the United States. 6 Finally, as of August 2018, OvaScience has shifted its research away from AUGMENT, and it only offers it through an “exclusive license to IVF Japan Group in Japan.” 7
The purpose of this paper is to argue that while some individuals have used OvaScience's technology to give birth, greater regulation and federal oversight of assisted reproductive technologies is necessary, including rigorous clinical testing, especially with the use of private and public companies before the private use of new assisted reproductive technologies (“ART”). This paper proceeds as follows: Part I will outline what OvaScience is and the four proposed technologies they seek to develop; Part II will examine the history of mitochondrial manipulation; Part III will examine the laws in countries that currently permit the practice and why the FDA has prohibited OvaScience from using AUGMENT in the United States; Part IV will examine the ethical concerns of these technologies; and Part V will discuss the ethical issues surrounding OvaScience as a publicly traded company.
II. PART I: OVASCIENCE'S TECHNOLOGIES
OvaScience has four different fertility technologies in development. All of these technologies are derivative of OvaScience's “proprietary technology platform” of ova precursor cells. 8 The four technologies are (1) Autologous Germline Mitochondrial Energy Transfer, (“AUGMENT”), (2) OvaPrime, (3) OvaTure, and (4) OvaXon. 9 In 2014, several international fertility clinics began to use AUGMENT 10 , the furthest developed technology and the first technology to be offered to patients. The most prominently reported results are from TCART Fertility Partners of Toronto 11 in Toronto, Canada, Fakih IVF in Dubai, United Arab Emirates (UAE), and IVF Japan in Japan. 12 However, reports indicate that IVF clinics in Panama, Spain, 13 Turkey and the UK have also offered AUGMENT. 14
The origin of AUGMENT was the belief that “poor egg quality occurs when the mitochondria in an egg cell break down” and therefore the ovum does not have the necessary energy needed to create an embryo and maintain a pregnancy. 15 Poor ova quality is one the leading causes of infertility in older women. 16
There are several steps to incorporating AUGMENT as an IVF technique. Initially, a candidate will have her ova precursor cells isolated from a woman's ovarian biopsy. OvaScience has coined their precursor cells EggPC cells.
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EggPC cells are non-developed ova stored in a woman's ovarian cortical tissue.
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These cells contain mitochondria, which OvaScience claims assist in the rejuvenation and health of a woman's ovum.
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Like a woman undergoing traditional IVF, the candidate will undergo ovarian stimulation to retrieve ova through aspiration.
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Once the EggPC cells' mitochondria are isolated, they combine the mitochondria with either donor or partner sperm and then inject it into the candidate's ovum through Intracytoplasmic Sperm Injection (“ICSI”)
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to fertilize the ovum.
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One observational cohort reports a successful pregnancy rate of 35 percent,
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while another claims a success rate between 25 percent and 53 percent.
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In small controlled groups, TCART experienced a three-fold increased success rate in clinical pregnancies, while Fakih IVF experienced a six-fold increase.
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Additionally, TCART experienced an eleven-fold increase in ongoing clinical pregnancies, while Fakih IVF experienced an eighteen-fold increase.
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As of June 2015, in addition to the successful live birth in Canada, there were eight other “ongoing clinical pregnancies,” as a result of treatment at TCART
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and eleven at Fakih IVF in Dubai.
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These results, however, were merely observational.
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There was not a completed trial with published results of AUGMENT until July 2018. Performed by Spain's IVF clinic, this study evidenced that “energizing eggs to improve their quality in assisted reproduction has been shown in an experimental randomized trial to offer
AUGMENT is not the only technology OvaScience is introducing to international markets. According to OvaScience, OvaPrime, a technology meant to increase a woman's ova reserve, was “to be introduced to patients in at least one international region by the end of 2015.” 32 In June 2017, OvaScience completed enrolling patients for an OvaPrime clinical study. 33 According to OvaScience, OvaPrime involves taking EggPC cells and implanting them into the “patient's ovaries where they may mature into fertilizable eggs during the IVF process.” 34
Similarly, OvaScience, also developed OvaTure, a treatment currently in preclinical development. 35 OvaTure “is a potential next-generation IVF treatment that could help a woman produce healthy, young, fertilizable eggs without hormone injections.” 36 OvaScience claims that OvaTure will mature EggPC cells into ova in the lab for women who have “compromised eggs, who are unable to make eggs, or who may be unwilling or unable to undergo hormone hyper-stimulation.” 37 OvaScience has even partnered with Intrexon Corporation - a synthetic biology company, to expedite OvaTure. 38 The two companies created a joint venture called OvaXon to “create [a] new application for improving human and animal health,” 39 by “prevent[ing] the transmission of inherited diseases by gene-correcting” EggPC cells. 40
III. PART II: HISTORY OF MITOCHONDRIAL MANIPULATION
It is important to note that mitochondrial manipulation is not new technology. In the late 1990's and early 2000's, 58 children were born through a technique that injected mitochondria in cytoplasm from “a young woman's eggs into the eggs of older women, effectively creating babies with genetic material from three people.” 41 Many of the children born from this technique have not been tracked. But, out of those that are known, one has not presented genetic material from the cytoplasmic donor and two have. 42 In 2001, the FDA “informed [IVF] clinics that using a third person's cytoplasm – and the mtDNA [mitochondrial DNA] therein – would require an Investigational New Drug [IND] application.” 43 The technology was under the FDA's jurisdiction, but the subsequent application was never approved. 44 One reason for the lack of approval was the presence of “genetic abnormalities such as a missing X chromosome in a fetus created with the technique.” 45
Recently, the issue of whether mitochondrial transfer qualifies as genetic manipulation resurfaced with the recent legalization of the three-parent embryo in the United Kingdom. 46 Creating the three-parent embryo involves removing unhealthy mtDNA from the intended mother's ovum and replacing it with mtDNA from a donor who has healthy mitochondria. 47 This new mtDNA will become a part of the child's genetic material, resulting in the child having three genetic parents. 48 Because this is a germline modification, it will have genetic implications for any future generations. 49 AUGMENT is similar to the techniques used in the late 1990's and early 2000's, as the mitochondria injected contain, but do not replace, mtDNA. 50
IV. PART III: INTERNATIONAL LAW AND THE FOOD AND DRUG ADMINISTRATION
In its 2014 annual report, OvaScience explicitly stated they were implementing their technologies in countries that “do not require pre-review and approval of applications for marketing authorization by the relevant regulatory authorities.” 51 The company claims they will occasionally reevaluate whether they are abiding by relevant laws and guidelines. 52 A central question to determining compliance with the law is whether a country's regulations consider AUGMENT a genetic modification. Some believe that because no genes are intentionally altered, these technologies do not constitute genetic modifications. 53 This section will identify the relevant laws in Canada, the United Arab Emirates and in Japan “permitting” AUGMENT and identify why the FDA rejected AUGMENT without clinical trials.
A. Canada
Dr. Robert Casper, the former medical director of TCART, claimed that OvaScience could partner with fertility clinics in Canada to use AUGMENT because the technology “falls under Health Canada's guidelines for ‘cell therapy.’” 54 This section will argue that AUGMENT directly falls under and violates Canada's Assisted Human Reproduction Act (“AHRA”) and the Canadian Panel on Research Ethics. In order to understand the arguments made below it is important to note that because mitochondria contain mtDNA and physicians use these mitochondria with their mtDNA to create an embryo during AUGMENT, that AUGMENT could foreseeably genetically alter an embryo.
AUGMENT does not qualify as a cell therapy for two reasons. First, OvaScience refuses to conduct clinical trials of AUGMENT, a pre-requisite for Health Canada to classify a product as a cell therapy. 55 Second, AUGMENT does not fall under Health Canada's definition of “cell therapy.” Health Canada defines “cell therapy products” as “human cells of somatic (fetal, neonatal and adult) or embryonic origin … this includes both cells derived from the individual undergoing treatment (autologous) as well as from donated tissues (allogeneic) and encompasses induced pluripotent stem cells or other cells in which the differentiation potential has been altered or enhanced.” 56 Generally, cells “from embryonic origin” are embryonic stem cells. 57 Notably, Health Canada's guidelines have two exclusions: (1) “gene therapy products, including cells that have been genetically manipulated, such that the therapeutic function of the product is afforded by the introduced gene(s)” and (2) “cells and tissues used for human assisted reproduction purposes.” 58
AUGMENT involves the manipulation of gametes, not somatic cells.
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In addition, even if AUGMENT could fall under “cells of embryonic origin,” AUGMENT is specifically excluded from Health Canada's cell therapy guidelines because (a) the injection of mitochondria introduces genes into the cell and (b) AUGMENT's sole purpose is to create cells for “human assisted reproduction purposes.”
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Thus, Ubaka Ogbogu, a professor of law and pharmacy, states “[t]o regard [AUGMENT] as a treatment procedure is dishonest.”
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AUGMENT does not fall under Health Canada's cell therapy guidance. Instead, it is governed by the AHRA and research ethics guidelines. The Canadian Legislature passed the AHRA in 2004 to act “as federal oversight to the fertility industry.”
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It governs gametes, fertility procedures and techniques, and cloning and embryonic research. AHRA
The Canadian Panel on Research Ethics created a guidance document discussing the ethical conduct required for research involving human gametes, embryos, and fetuses, in order to expound on the relationship between research ethics and the AHRA. 64 These conduct requirements give researchers significant discretion in research activities and only require that researchers have the informed consent of the patients whose gametes they obtain. 65 Overall, the guidelines permit embryonic research if (a) the embryo was not created for research purposes and (b) researchers obtained the gametes through informed consent; (c) the research does not genetically alter gametes or embryos; (d) the researchers will not transfer the embryos for pregnancy if the researchers manipulated them in ways not conducive to natural development; and (e) researchers cannot conduct any activity on embryos after 14 days of formation. 66 However, the guidelines prohibit research on gametes from cadavers, 67 gametes acquired through “commercial transactions,” 68 and the creation of chimeras. 69 Similarly, three-parent embryos, as well as the cytoplasmic transfers occurring in the United States in the late 1990's and early 2000's, are also prohibited. 70 Dr. Casper, however, does not believe that the addition of mitochondria is “changing the genome;” instead he states, “We're really providing a little extra energy.” 71
Dr. Casper, however, has disregarded the fact that a child from a three-parent embryo and cytoplasmic transfer can have a measured presence of donor mtDNA in the resulting child. This mtDNA is then passed down to any of that child's offspring. Notably, mtDNA typically remains unchanged through maternal bloodlines, which is presumably the reason Dr. Casper does not believe that the addition of mitochondria will change the child's genome. 72 Dr. Casper, however, does not take into consideration that (1) mtDNA can mutate 73 and (2) how the additional mtDNA from the mitochondria will interact with a particular ovum's DNA. Adding the genetic mother's mitochondria into her ovum may have varied responses, as each ovum has a different genetic sequence. 74
B. United Arab Emirates
In 2010, United Arab Emirates (“UAE”) passed Federal Law No. 11, which appears to have created the initial guidelines for ART. 75 Unlike Canada and the U.S., the law greatly restricts the types of ART offered and the individuals who can undergo these procedures. Originally, UAE law only permitted four types of ART: (1) Intra-Uterine Insemination (“IUI”); (2) In Vitro Fertilization (“IVF”); (3) Gamete Intra Fallopian Transfer (“GIFT”) and Zygote Intra Fallopian Transfer (“ZIFT”); and (4) “any internationally adopted insemination techniques.” 76 The law also only permitted government medical clinics to provide these ART. 77 As a result, private clinics were only able to provide hormonal medications and perform certain surgical procedures. 78 In 2009, the UAE changed its law to allow private medical clinics to offer ART under strict regulation. 79 After this change, Dubai became a destination for medical tourism; 80 for example, 90% of the patients at Fakih IVF in Dubai are international. 81
Arguably, AUGMENT is not permitted under UAE Federal Law No. 11 because it does not fall within the purview of the four permitted ART. Even if one wishes to argue that AUGMENT qualifies as a type of IVF, Article 14 of the Federal Law prohibits AUGMENT because it states, “[t]he Center or any other party of whatever capacity shall be prohibited from using non-fertilized or fertilized eggs, or sperm for commercial purposes, research, or for introducing genetic modifications to the genes of the embryos.” 82 As in Canadian law, adding mitochondria, with its additional mtDNA, could foreseeably have an impact on the genetic composition of an embryo and; therefore, is prohibited by federal law.
C. Japan
Historically, Japan does not have laws regarding ART. Instead, “it is self-regulated through various guidelines on reproductive medicine formulated and issued by [the Japan Society of Obstetrics and Gynecology].” 83 However in 1998, legislators created a committee to clarify permissible ART practices. 84 In 2003, the committee created the Report on Assisted Reproductive Technologies using Donor Sperm, Eggs and Embryos.” 85 This guidance document created six broad criteria to govern ART. The guidance document stated: (1) that those using ART were “legal couples” in which the female was below the age of 50; (2) using donor gametes is only permissible when couples would remain infertile without them; (3) only couples donating to other couples can participate in embryo donation; (4) “cytoplasm or nuclear substitution of donor eggs” is prohibited; (5) an absolute prohibition on surrogacy; and (6) those above the age of 15 can request disclosure regarding their genetic parentage. 86
Additionally, currently Japan prohibits the genetic editing of human embryos. 87 However, there have been reports of future changes regarding genetic editing. 88 Since there is no direct prohibition of the use of OvaScience's AUGMENT, it is unclear what guidance governs this form of ART. Notably, the committee prohibited cytoplasmic transfer from donor eggs. 89 This practice is not entirely different from autologous mitochondrial transfer, as it is the practice of using additional mitochondria to improve overall ovum quality. Moreover, adding additional mitochondria into an ovum does have the potential to alter its genes and an embryo's genes. It is unclear whether Japan would find this permissible.
D. United States and the FDA
In order to avoid the previously mentioned IND application, OvaScience told its American investors that AUGMENT “qualified as a human cellular and tissue-based product (“HCT/Ps”) exempt from regulation under section 361 of the governing statute (“361 HCT/P designation”).” 90 The requirements for a product to qualify for an exemption under section 361 are:
“(1) it is minimally manipulated; (2) it is intended for homologous use as determined by labeling and advertising; (3) its manufacture does not involve combination with another article, with limited exceptions; (4) either (a) the HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function, or (b) the HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function and (i) is for autologous use, (ii) is for allogenic use in a first or second degree blood relative, or (iii) is for reproductive use.” 91
OvaScience claimed AUGMENT fell within the exception because the mitochondria taken from the EggPC cells “(1) are minimally manipulated, (2) are intended for homologous use only, (3) do not involve the combination of cells or tissue with another article, and (4) are for reproductive use and dependent upon the metabolic activity of living cells for their primary function.” 92 As a result, OvaScience began a clinical trial in late 2012 without filing an IND application with the FDA. 93 Nevertheless, in two letters, dated April 9, 2013 and September 6, 2013, the FDA informed OvaScience that they did not consider AUGMENT as minimal manipulation. 94 Additionally, the FDA prohibited AUGMENT without an IND, and deemed it a form of genetic therapy. 95 Subsequently, OvaScience ceased use of AUGMENT in the United States. 96
Significantly, Canada, the UAE, Japan, and the U.S. all take a different approach to genetic manipulation. Canada and the UAE have an outright ban. Japan does not clearly identify genetic manipulation, nor does it legislate in favor or in opposition to the practice. However, the U.S. has a preclearance approach, which permits many different medical advances as long as there is appropriate regulation. The FDA's purpose is to “protect[] the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, and medical devices ….” 97 This is aligned with American values regarding freedom but also counsels caution when using new technologies.
V. PART IV: ETHICAL CONCERNS OF USING AUGMENT WITH IVF
The concept of mitochondrial transfer in fertility treatments is highly controversial. As a result, there are several bioethical concerns and numerous ethical arguments in opposition to ART. 98 Critics argue that ART (1) negatively impacts the parent-child relationship; (2) impermissibly and unethically tampers with nature; (3) allows fertility specialists to “play God” by creating human beings outside of natural conception; (4) causes social problems by allowing women to delay childbearing; (5) may be eugenic; and (6) creates an unethical socio-economic divide between the wealthy and poor. While all of these arguments can be applied to IVF, this paper will argue that regardless of IVF's permissibility, AUGMENT itself is ethically impermissible because (a) it is impossible to acquire appropriate informed consent, and (b) it is unethical to provide fertility treatments without an adequate completed clinical trial. Most of the arguments in this section are based on the precautionary principle. Under this principle, “health hazards should be anticipated and forestalled before the reali[z]ation of damage even if [the] scientific understanding of the risks is inadequate.” 99
A. Informed Consent
Gaining informed consent for any medical procedure is difficult. It is also tenuous whether the patient fully understands the act to which they are consenting. However, obtaining appropriate informed consent from patients receiving fertility treatments can be especially difficult. Generally, individuals struggle with receiving a diagnosis of infertility. Thus, when presented with the option of using ART, many will agree to fulfill their desire to have children. 100 This is not to suggest that those utilizing ART cannot consent. However, the promise of having a child, especially a child that is genetically related to the intended parent(s), can impair an intended parent's ability to make an informed decision. 101 As such, there are two questions that need to be addressed: (i) whether it is ethical to allow individuals to consent to IVF with AUGMENT and (ii) whether it is ethical for individuals to consent to creating embryos through AUGMENT, when that embryo is a separate entity.
Whether individuals should be able to consent to IVF with AUGMENT is centered on two concerns: (1) should individuals be able to consent to non-medically necessary procedures and (2) are there medical procedures that individuals should be prohibited from consenting to. Before addressing whether intended parents should be able to consent to AUGMENT, one has to understand the medical risks associated with the procedure.
Objectively, IVF and AUGMENT subject individuals, especially women, to unnecessary medical risks. Due to advances in research, the known medical risks of IVF have increased over time. 102 This portion of this paper will discuss known IVF medical risks and highlight potential medical risks with AUGMENT, as AUGMENT requires the use of IVF. The American Society for Reproductive Medicine (“ASRM”) states that IVF medications can cause side effects, such as bruising, nausea, allergic reactions, breast tenderness, vaginal discharge, mood swings and ovarian hyperstimulation syndrome (“OHSS”). 103 In addition, there have been other reports that IVF drugs can cause blood clots 104 and increase certain cancers. 105 Notably, OHSS can cause “renal impairment, liver dysfunction, thromboembolic phenomena, shock, and even death.” 106 The risks of ova retrieval include abdominal pain, injury to organs near the ovaries, bladder, bowels, and blood vessels. 107 It can also cause pelvic infections that can be severe enough to warrant the removal of the ovaries, fallopian tubes, and/or uterus. 108 Damaging the ureter is another concern because the ureter often runs alongside the ovary, which has to be punctured in order to retrieve the ova. 109 Lastly, a longer-term risk of IVF, is ovarian torsion, in which the ovary twists and cuts off blood supply to itself. 110 Moreover, women undergoing ova retrieval are required to undergo anesthesia, which poses its own unique set of risks separate from the aspiration process. 111
Furthermore, AUGMENT, requires women to undergo an additional procedure prior to the ova retrieval so that physicians can harvest EggPC cells from the ovarian tissue. The removal of ovarian tissue can cause infection, 112 “discomfort, pain, [and] bleeding from cicatrices.” 113 Similar to aspiration, the woman will also be under general anesthesia. A woman has already died from general anesthesia complications during an ovarian tissue retrieval. 114 For the most part, the retrieval of sperm is minimally invasive as the usual retrieval technique is masturbation resulting in ejaculation. 115 After an embryo(s) is created through IVF, there are also medical risks with implanting the embryo(s) into the intended mother. 116 Similar to the ova retrieval process, there is concern about “perforation of organs,” but there is also the concern about an embryo implanting outside of the uterus. This is because there appears to be an increased rate of ectopic pregnancies with IVF. 117
In addressing whether intended parents can consent or should be able to consent to AUGMENT, it is also imperative to discuss whether medical practitioners and OvaScience should be offering this technology. In regard to the intended parents, the freedom to make autonomous medical and reproductive decisions is engrained both in law and ethics. General ethical guidelines regarding medical informed consent require that (1) the individual understands the prognosis and diagnosis including risks, benefits, consequences and reasonable alternatives to a medical intervention; (2) the patient comprehends the information; (3) the patient has the capacity to make such a determination; and (4) the decision is made free from coercion or undue influence. 118 The argument prohibiting intended parents from consenting to IVF and AUGMENT is inherently paternalistic. Paternalism, however, is often ethically permissible, if the infringement upon freedom protects an individual or community. 119 AUGMENT is based upon balancing paternalistic views about safety and the intended parents' ability to choose how they address their infertility. While it is ethically permissible to allow intended parents to seek fertility options based upon respecting their autonomy, intended parents likely unaware of all of the risks. 120 Moreover, even if intended parents are aware the medical risks, there is the concern of whether they fully comprehend the medical information.
Considering that intended parents are likely to discount many of the inherent risks of AUGMENT, should medical practitioners or OvaScience offer the option to these patients with AUGMENT in the first place? Patients often place a lot of trust in their medical practitioners to provide them with the best advice to achieve the best results. However, in fertility clinics, there is a clear tension between providing the best medical advice and procuring the patient's desired result: having a child. As a result, the incentive for fertility specialists to provide procedures is problematic. Moreover, differentiating oneself in the fertility market is also fiscally advantageous to private fertility clinics. Additionally, it is unclear what protocols are in place to inform the patient that these procedures are (1) not robustly clinically substantiated and (2) abiding by the law. While many ART are not under the FDA's jurisdiction, the FDA should have jurisdiction over AUGMENT not only because there is the concern of genetic impacts, but also because the FDA's process determines whether certain risks are acceptable or unacceptable. If the FDA finds that a relevant procedure or product is safe, it permits medical practitioners to utilize it. If the FDA finds the procedure or product too risky, medical practitioners who provide these services are deemed irresponsible. If the FDA is finds that AUGMENT needs to be screened prior to implementation, OvaScience should not attempt to skirt the law by rolling out AUGMENT in foreign countries. Lastly, as will be discussed later in this paper, there is an undeniable conflict of interest with OvaScience's business model. As a result, OvaScience should be taking the time to medically substantiate their procedures. Considering that intended parents will have difficulty consenting to AUGMENT and the fact that both medical practitioners and OvaScience have significant conflicts of interest, OvaScience cannot ethically market AUGMENT at this time.
The second concern with AUGMENT and IVF surrounds the permissibility of allowing intended parents to consent to the creation of embryos in such a manner. Increasingly reports and data show that creating children through IVF results in a variety of medical risks to future children. In 2014, a report stated that children born through assisted conception were “significantly more likely” to be born with complications. 121 However, some of the epigenetic changes caused by IVF may not express themselves until the born child reaches “adulthood or middle or old age.” 122 These epigenetic changes have been identified in mice studies. 123 A study conducted in 2013 evidenced a “small but statistically significantly increased risk of mental retardation” in children who were conceived through IVF. It is hypothesized that these epigenetic changes may be the cause. 124 Additionally, 9 percent of children born through IVF have a birth defect, while only 4.2 percent of children “naturally conceived” have one. 125 Moreover, children who are conceived through IVF have a greater occurrence of multiple birth defects. 126 Arguably, manipulating fertilization by injecting mitochondria into the ovum will have some impact as well. AUGMENT compounded with IVF invariably will increase potential risks to future children.
Therefore, given the risk, the question posed is whether it is permissible for parents to create children that are statistically subjected to a higher risk, which risk may be even greater than the risk associated with traditional IVF. Intended parents have a distinct ethical obligation to embryos and to the creation of embryos. If embryos are given the same status as human beings, then AUGMENT is ethically impermissible because the embryo does not have the capacity to consent to the risk. If embryos are property or given “in-between” status, then intended parents have legal obligations and ethical obligations to prevent harm to their future child. Mitigating the risk is one aspect of harm prevention. There are many procedural and societal safeguards in place that prevent parents from subjecting their children to risks in medical and non-medical contexts. 127 The creation of embryos should not be an exception. Considering that there is little clinical data documenting the benefits and potential consequences of implanting additional mtDNA into an embryo, intended parents have an ethical obligation not use AUGMENT.
B. Inadequate Clinical Trials
Recently, with the legalization of three-parent embryos in the United Kingdom, the safety and efficacy of mitochondrial transfer has come into question. 128 Simply because a technique has had some success in animal studies does not necessarily warrant the jump to human subjects research. 129 There are two concerns with AUGMENT: (1) the lack of completed clinical trials prior to creating embryos, and (2) the lack of a concrete animal study data. Part of the concern with ART is that scientists and fertility specialists often create experimental technologies and start using them in the private market prior to conducting appropriate clinical trials. 130 Eventually, a regulatory agency may prohibit an activity if concerns about risks develop. This was evidenced in the FDA's reaction to the cytoplasmic transfers in the late 1990's and early 2000's as well as the requirement that OvaScience file an IND application for AUGMENT. 131 The fertility industry is different from other health related industries because, at least in the United States, there is little direct federal oversight.
The FDA has broad authority. It regulates food, drugs, biologics, medical devices, electronic products that emit radiation, cosmetics, veterinary products, and tobacco products. 132 However, most ART do not fall under FDA's jurisdiction, with the exception of fertility pharmaceuticals. Nevertheless, the FDA considers AUGMENT to be a biologic because biologics include gene therapy products. 133 Depending on the FDA classification, a product will have to fulfill different requirements. “In general, biological products that are used to treat or prevent diseases, like traditional drug products, have to be thoroughly tested and shown to be safe and effective in order to enter interstate commerce.” 134 As a result, all new products are generally required to submit an IND if they plan on using the product in humans. 135 Typically, the process involves initial laboratory testing and then clinical testing in humans. 136 If the product is safe and effective, the manufacturer then submits the information to the FDA for final approval. 137 Thus, OvaScience would have to submit an IND and provide adequate preclinical or animal data before implementing AUGMENT in a clinical trial. There are several different phases to clinical trials depending on an agency's role in relation to the clinical trial. The National Institutes of Health (“NIH”), which funds but does not regulate clinical trials, has a four-phase guideline. Phase I includes a small cohort with healthy volunteers determining how the human body may react to a drug. 138 Phase II is a larger trial with recruited participants in order to determine efficacy of the treatment or drug. 139 Phase III is an even larger study to “monitor side effects, compare it to commonly used drugs or treatments, and collect information that will allow the drug or treatment to be used safely.” 140 During Phase III, a placebo may be used in order to have a controlled study. 141 Finally in Phase IV, the long-term effects of the drug or treatment are determined. 142 Similarly, the FDA, which regulates clinical trials, has a four-phase trial system. The FDA has also disclosed the typical time frames for each phase. Phase I typically lasts several months, Phase II is several months up to two years, Phase III is one to four years, and Phase IV is ongoing. 143 As a result, it would take AUGMENT up to seven years to reach Phase IV.
There are many different trial models, including randomized controlled trials with or without a placebo, observational studies, 144 active control clinical trials, 145 and stepped-wedge trials. 146 The gold standard, however, is a randomized control trials with a placebo. 147 Due to the unknown medical consequences to both embryos and women who are gestating these altered embryos, OvaScience had an ethical obligation to conduct appropriate clinical trials of AUGMENT. Evidently, OvaScience does not agree. In a presentation at the European Society of Human Reproduction and Embryology (“ESHRE”), OvaScience stated that randomized placebo controlled clinical trials are “not feasible,” because of (1) difficulty in “select[ing] proper controls”; (2) “lack of agreement on criteria”; (3) ethical concerns about using a “placebo arm”; and (4) “enrollment challenges.” 148 While some of these concerns are valid, not creating a trial just because it is difficult does not mean that a trial should not be completed. Even if a randomized controlled trial with a placebo is not possible, another trial could be designed before AUGMENT is used in the private market. Evidently, it was possible to create an appropriate trial as shown by the results produced in July 2018, approximately six years after OvaScience began use of AUGMENT. 149 Moreover, OvaScience chose to roll out AUGMENT in countries that do not require strong quantified research and it is questionable whether they were appropriately abiding by the law.
Further, even if a clinical trial cannot be conducted, there is not sufficient data from experiments to ethically permit this research in human beings. While OvaScience “has launched the first Global IVF Registry to collect patient experience data,” 150 they are doing so without having the pre-requisite standards in place. According to Dr. Robert Casper, the preclinical studies of mitochondrial transfer have only occurred in mice, cows, and pigs. 151 The only healthy live births have been reported in mice. 152 AUGMENT has not completed the same rigorous clinical research as the fertility specialists that are working on three-parent embryos. The fertility specialists have at least conducted trials in monkeys, a species closer to human beings than mice. 153 This is not to suggest that animal trials are always indicative of reactions in human beings. 154 However, considering that AUGMENT may have germline implications, significant research needs to be conducted prior to allowing fertility specialists to create embryos using this technique. 155
VI. PART V: ETHICAL CONCERNS OF FERTILITY TECHNOLOGIES BEING PUBLICLY TRADED
There has been a small but growing movement of fertility treatments becoming a part of publicly traded companies. In 2013, Virtus Health, an Australian company, was the first ART company to go public, and it made nearly half a billion dollars.” 156 Publicly traded fertility companies are in direct opposition to the traditional fertility clinic business model where fertility specialists offer treatment at independent clinics, clinic chains, or in conjunction with hospitals. The typical reason is that fertility techniques are meant to be medical procedures used to treat infertility. As a result, ART, including IVF procedures, are essentially the same between providers.
In 2011, OvaScience launched and revealed its plan to become a publicly traded company by August of 2012. 157 The initial funding was provided by a variety of well-heeled investors, including BBT Capital Management Advisors, Cycad Group, Hunt BioVentures, RA Capital and BioVentures. 158 However, since going public, OvaScience's stock price has fluctuated significantly. The initial significant drop in stock value occurred after the FDA sent OvaScience the letters that halted the use of AUGMENT in the US. 159 The next significant drop, a drop more than 50 percent, occurred in September 2015, when OvaScience announced it would not meet its earlier goal of performing 1,000 AUGMENT procedures in 2015. 160
Additionally, after the FDA banned AUGMENT in the U.S., shareholders brought a securities fraud class action against OvaScience. They claimed OvaScience made material misstatements and failed to disclose material information, which then caused “artificial inflation of stock prices.” 161 On September 28, 2015, a district court in Massachusetts dismissed the claim. In its order, the court stated that while some of OvaScience's statements were misleading, the Plaintiff's claim could not satisfy the scienter requirement. 162 For context, OvaScience in January 2015 was trading at $50 USD per share and as of August 2018, the stock was trading at $0.78 USD per share. 163
There are four distinct ways ART researchers seek funding: (a) by a private company; (b) by a public company; (c) by a non-profit organization; and (d) by the government. 164 Simply put, a privately held company is required to follow federal and state law applicable to private companies. The advantage of developing ART through private companies is that private companies can fund and develop research that is controversial or may have limited funding in other corporate sectors. The main ethical concern with private companies is that they will potentially feel pressured to inappropriately incentivize implementation of unsafe or ineffective treatments or products.
A publicly held company is required to follow federal and state law applicable to public companies. The major regulatory agencies that govern publicly held companies are the Securities Exchange Commission (“SEC”) 165 and the Consumer Finance Protection Bureau 166 . The advantage of ART development by publicly traded companies is that there is greater disclosure to the public about the company, its techniques, and products. This disclosure is a result of SEC requirements and the vast resources publicly traded companies have for research and development. The disadvantages of seeking development of ART through publicly traded companies are that these companies are profit driven, and they have responsibilities to their shareholders. In addition, shareholders can potentially pressure companies to inappropriately incentivize implementation of unsafe or ineffective treatments or products.
A non-profit organization is required to follow federal law, state law, and other special requirements. The advantages of seeking ART development through a non-profit organization is that non-profit organizations inherently lack profit driven motives and their research is often governed by an Institutional Review Board to safe-guard against unethical practices. The disadvantage of seeking ART development through non-profit organizations is that there is a lack of substantial resources. This can limit development.
Lastly, there is government funded and government conducted research. If an organization receives government funds or if the government conducts its own research, the entities are required to follow federal and state law. The advantages of government involvement are that (1) there is a high level of regulatory control over research to safe-guard against unethical practices, and (2) the government is generally willing to seek non-profitable ventures that benefit the public. However, because the government has limited funding for research, certain research, including ART development, is less of a priority.
In relation to OvaScience, the most ethically concerning aspect about allowing fertility companies (and for that matter all medical companies) to be publicly traded is that the company will be “looking to make a healthy profit, and if it is a publicly traded company, it has to show some kind of revenue growth from quarter to quarter to appease shareholders.” 167 As a result, such corporations' main intention is not to only provide fertility treatments to individuals, but to do so at a profit. This pressure might encourage corporations to cut corners and speed up implementation of potentially unsafe treatments and products. It is arguable that OvaScience rushed AUGMENT into the market to keep the company profitable, and it did not want to become delayed by clinical trials. OvaScience has created a myriad of success stories, such as the Canadian couple who gave birth to the first AUGMENT child 168 but, as it is evidenced by the Spanish study, AUGMENT does not improve pregnancy outcomes. 169
However, this is not to suggest that governments should outright ban publicly traded fertility companies. Publicly traded fertility companies can provide valuable research and development. For example, publicly traded pharmaceutical companies have significant resources available for research and development and use it to produce many beneficial treatments, vaccinations, and drugs. However, the significant difference between publicly traded pharmaceuticals companies and OvaScience is that publicly traded pharmaceuticals companies are highly regulated by the FDA while much of the ART industry remains unregulated. While this paper suggests the FDA should regulate products like AUGMENT, it is unlikely that the FDA would expand governance to ART. However, there are other potential solutions to governing ART in the United States. For example, the United States could follow Canada and the United Kingdom's governing model and create a committee to address new ART practices. While Canada's Royal Commission on New Reproductive Technologies is no longer active, 170 the United Kingdom's Human Fertilisation & Embryology Authority has been instrumental in more recent ART regulation, including the regulation three-parent embryos. 171
VII. CONCLUSION
While OvaScience is trying to create unique fertility treatments to rejuvenate ova and lengthen the period in which a woman can become pregnant, the evidence suggests that they provided a fertility product that has little to no medical efficacy. The inability to gain appropriate informed consent from all parties, the lack of appropriate clinical data, and the concerns regarding corporate structure highlight how governments need to reassess ART regulation. While there may not be a clear solution to address the lack of ART regulation, companies like OvaScience can be used as a case study to call attention to the need for both American and international ART regulation.
ADDENDUM
Since An Ethical and Legal Analysis of OvaScience – A Publicly Traded Fertility Company and it's Lead Product AUGMENT was accepted for publication in the American Journal of Law and Medicine there has been a development that is worth noting as it has a significant impact on this paper. As of September 26, 2018, OvaScience “entered into an all-stock reverse merger agreement” with Millendo Therapeutics Inc. 172 The result of this appears to be that OvaScience will no longer be developing AUGMENT; however, it remains unclear whether AUGMENT will continue to be offered in Japan by IVF Japan Group. According to the Registration Statement on Form S-4 in connection with the merger filed with the Securities and Exchange Commission on September 26, 2018, OvaScience and IVF Japan Group executed a collaborative access agreement on October 25, 2017, with the initial term lasting one year, unless extended. The filing notes OvaScience and IVF Japan Group are currently in discussions regarding the future of the collaborative access agreement. It also appears based on the filing that OvaScience may continue to pursue some activities related to OvaPrime, OvaTure and OvaXon.
While OvaScience may not be continuing development of AUGMENT, this paper can be utilized as a case-study to examine issues with the public trading of fertility companies. The ethical and legal issues highlighted in this paper not only address concerns regarding funding of fertility companies, but this paper also addresses the significant lack of regulation surrounding fertility practices. While OvaScience may no longer be developing AUGMENT, this paper calls into question the requirements and regulation needed prior to emerging technologies being offered to the public.
Footnotes
1
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2
Id.
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4
Eur. Soc'y of Human Reprod. & Embryology, Energizing Eggs with a Patient's Own Mitochondria Offers No Benefit in Assisted Reproduction, E] (OvaScience halted clinical trials.).
5
OvaScience, Inc., Annual Report (Form 10-K), at 17 (Mar. 16, 2015).
6
Id.
7
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8
See Press Release, OvaScience, Improved Pregnancy Rates and Healthy Births with OvaScience's AUGMENT Fertility Treatment to be Published in Peer-Review Journal (Aug. 10, 2015, 4:15 PM), https://www.businesswire.com/news/home/20150810006135/en/Improved-Pregnancy-Rates-Healthy-Births-OvaScience%E2%80%99s-AUGMENT [].
9
See OvaScience, Inc., Annual Report (Form 10-K) (Mar. 2, 2017).
10
See O
11
See Press Release, OvaScience, Publication of OvaScience's AUGMENT Fertility Treatment Shows Statistically Significant Improvements in Embryo Selection and Transfer Compared to Standard IVF (Aug. 26, 2015, 10:44 AM), https://www.businesswire.com/news/home/20150826005800/en/Publication-OvaScience%E2%80%99s-AUGMENT-Fertility-Treatment-Shows-Statistically [https://perma.cc/YZG7-AA5T]. TCART no longer exists independently. In 2015 LifeQuest Centre for Reproductive Medicine and TCART Fertility Partners merged. Our Medical Team, TRIO, http://triofertility.com/our-medical-team/ [] (“TRIO was established in 2015 when the experienced teams of fertility specialists from LifeQuest Centre for Reproductive Medicine and TCART Fertility Partners merged to form the new clinical practice TRIO Fertility.”).
12
Michael H. Fakih et al., The AUGMENTSM Treatment: Physician Reported Outcomes of the Initial Global Patient Experience, J. F].
13
A clinical trial was commenced in Spain; however, was not completed. See Press Release, OvaScience, OvaScience Announces Business Update, (Dec. 21, 2016, 4:04 PM), https://www.businesswire.com/news/home/20161221005882/en/OvaScience-Announces-Business-Update [] (“The Company is reassessing the ongoing IVI-sponsored clinical study in Spain ….”).
14
Alison Motluk, IVF Booster Offered in Canada but Not US, 187 C
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28
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The most controversial ART are IUI, IVF, and surrogacy. Hormonal treatments and reparative techniques do not pose the same ethical quandaries.
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165
15 U.S.C. § 78d (2012).
166
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168
CBC N
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170
S
171
See Human Fertilisation & Embryology Act 2008, c. 22, § 26 (Eng.); See also About Us, H].