DISCUSSION DOCUMENT

U.S. Public Policy and the Biotechnologies
That Touch the Beginnings of Human Life:
A Detailed Overview

CONTENTS

Introduction

I. Power to Initiate Human Life by Artificial Means

II. Power to Screen and Select for Genetic Conditions
and Traits

III. Power to Modify Traits and Characteristics

IV. Power to Observe and Manipulate Nascent Human
Life In Vitro for Purposes of Scientific Research

V. Commerce and Commodification

Summary and Conclusion

Footnotes

Endnotes

INTRODUCTION

It is by now commonplace that advances in biomedical science and technology are raising challenging and profound ethical issues—for individuals and families, for scientists and health care professionals, and for the broader society. Many important human goods are implicated, among them health and the relief of suffering, respect for life and the human person, human freedom, and human dignity. The flourishing field of modern bioethics, not yet forty years old, arose to explore these issues, and various bodies, including local research review boards, academic bioethics institutes, and several national commissions have been wrestling with them. Yet amid all this activity, it is far from clear whose business it is to monitor, oversee, and offer guidance where guidance is needed, in order to safeguard the myriad and often competing human goods at stake. Which institutions, public or private, are now responsible for which sort of oversight or regulatory activity, and in the name of what? We can readily name some—the Food and Drug Administration, for example—that are responsible for the efficacy and safety of new drugs or devices. But which permanent bodies, if any, are charged with effective authority to protect some of the other goods we care about? And how well are they doing their job?

At its very first meeting, the President’s Council on Bioethics signaled an interest in exploring how, if at all, the existing regulatory mechanisms in the United States address the ethical and moral issues that arise from advances in biomedical science and technology. Some members of the Council suggested that new regulatory institutions might need to be devised. Others were skeptical, especially before we knew how well the current arrangements worked or which principles should guide any such new institutions. In the Council’s 2002 report, Human Cloning and Human Dignity, a suggestion emerged for pursuing this interest regarding regulation in the context of a specific domain. Members observed that for the activities at the intersection of assisted reproduction, preimplantation genetic diagnosis, and human embryo research,

we lack comprehensive knowledge about what is being done, with what success, at what risk, under what ethical guidelines, respecting which moral boundaries, subject to what oversight and regulation, and with what sanctions for misconduct or abuse. If we are to have wise public policy regarding these scientifically and medically promising but morally challenging activities, we need careful study and sustained public moral discourse on this general subject, and not only on specific narrowly defined pieces of the field.¹

Three months following the release of the report, Council members agreed to undertake a thoroughgoing inquiry into the current regulation of those biotechnologies that touch the beginnings of human life. This discussion document is the first fruit of that inquiry. Its principal aim is to provide Council members with a detailed account of the institutions and authorities that presently govern the uses and applications of the biotechnologies and practices at the intersection of assisted reproduction, genetics, and human embryo research. The document explores precisely who currently provides oversight and guidance in this context, pursuant to what authority, according to what principles and values, and to what ultimate practical effect. It is strictly diagnostic and expository in nature. It is intentionally neutral regarding what changes, if any, might be necessary, desirable, or feasible if one should wish to improve upon the present arrangements.
The precise focus of this inquiry is the growing powers over the beginnings of human life, especially as exercised ex vivo, in the clinic and the laboratory. These powers emerge out of the confluence of work in reproductive biology, developmental biology, and genetics. The practices of assisted reproduction are today being augmented by techniques of genetic screening and selection of embryos; some day, the gametes or embryos employed may be modifiable by directed genetic manipulation. Our focus here is not assisted reproduction, as such, nor is it the human embryo or the evolving understanding of human genetics and the powers of genetic diagnosis and manipulation. Rather, we are concerned with the unique interactions among these elements, and the new possibilities they create for controlling and perhaps someday remaking the character of procreation and human life.

Our point of departure will be the practice of assisted reproduction. We are well aware that assisted reproduction is not new—indeed, it has become firmly established within the practice of medicine, and is thus subject to the usual formal and informal mechanisms that govern medical practice. Our purpose here is not to second-guess how this novel and profoundly important practice grew and came to be governed in the way it has. However, three reasons, taken together, recommend this point of departure. First, all the other new powers of interest—preimplantation genetic diagnosis, germ line genetic modification, human embryo research—presuppose the existence of nascent life in vitro. The power to evaluate and perhaps eventually to engineer genetic traits in vitro depend on the prior power to initiate and sustain embryonic life in the laboratory. Thus, in vitro fertilization and related techniques are the starting point for all the others, both in practice and, hence, in our inquiry. Second, as a consequence, any oversight or regulation of the use of genetic technologies in the beginnings of human life will necessarily depend on the systems of oversight and regulation of assisted reproduction itself, what they are and how well they work. Third, the coming additions of genetic technologies to those of assisted reproduction make it clear—if it has not been clear before—that we are dealing here with a most unusual branch of medicine. Regarded as an ordinary branch of medical practice, the activities of assisted reproduction now come under an unusual amount of professional self-scrutiny and guidance. But there is ample reason for this extra scrutiny: in no other area of medicine does the treatment of an ailment—in this case, infertility—call for the creation of another human being. Here, the therapeutic intervention, addressing the needs and desires of the procreating adults, aims at and consists in the production of a new human life, who, although patient to the manipulations, has of course no say in the matter. It is this deep concern for the safety and well-being of children born with the aid of these new biotechnologies that suggests to us the need for special attention—especially now that genetic screening and selection are being added to the practices of assisted reproduction.

All regulatory institutions and practices operate, either explicitly or tacitly, in order to promote or protect one or more important human goods. Identifying those goods and the challenges they face is indispensable for any analysis and evaluation of how—and how well—regulatory activities are conducted. It is therefore useful, at the start of this document, to identify the major goods, values, and ethical concerns that the Council finds pertinent to the subject area, and hence to our assessment. First among these, as already indicated, is the health and well-being of the human subjects directly affected by the biotechnologies, not only the couple seeking their use but also and especially all children who may be born with their aid. At stake are not only the bodily health and safety of children-to-be, but also the attitudes with which they will be regarded and the expectations under which they will live, in an age in which more and more aspects of their genetic make-up could be the result of technical intervention and deliberate human decision.

Other human goods of great interest include: (1) The joys of overcoming infertility and the blessings of having children, as well as (2) relief from the sorrows and burdens of being or caring for children with serious genetic disease, and (3) the desire for new knowledge of human development and genetic function and new treatments for diseases and disabilities—the main goals of the associated genetic and reproductive technologies under consideration. (4) The sanctity of human life and the respect owed to its nascent stages. (5) Various aspects of human freedom: the freedom of parents to make their own reproductive decisions or to refuse genetic screening, of scientists to do research, of children to be protected from despotic attempts to shape their lives through control of their genetic make-up and the expectations that accompany this activity. (6) Various aspects of justice and equality: equitable access to the use and benefits of the new technologies, equal respect and opportunity in a world that places increased emphasis on genetic distinctions, and the dangers of discrimination and contempt for genetic “defectiveness” or “inferiority.” (7) Privacy of genetic information and reproductive practice. (8) Various aspects of human dignity: the dignity of human sexuality and procreation, of the human body and its parts, of human responsibility and self-understanding.

Throughout our analysis we shall be mindful of how the various regulatory practices address a series of ethical concerns that are connected with those goods. Some concerns are raised by the practice of ART as such, others by the practices of genetic screening and selection or of genetic manipulation and engineering, and still others by research on human embryos. In addition, there are concerns raised by the commercialization of human reproductive services and the advent of commerce in eggs, sperm, and embryos. Beyond the obvious concerns with health and safety, a partial list of these broader ethical concerns includes the following: the import of making entrance into human life contingent on passing certain genetic tests; the consequences for the relations between parents and children of genetic selection; the boundary between disease-preventing and so-called “enhancement” uses of these technologies—how to define it and what to do about it; consequences of moving procreation more and more into the laboratory and turning it in the direction of manufacture; aggravation of current social inequalities or the creation of new grounds for inequality and discrimination; the use, cryopreservation, and destruction of nascent human life; the dangers of coercion in the advent of mandatory screening; the hazards of living with too much genetic knowledge; truthfulness in reporting technological successes and failures; consumer protection; the effects of commercialization on the dignity of human procreation; and the effects on human self-understanding and judgments of personal responsibility that arise from an account of human life that appears to teach the primacy of genetic causation. Not all of these concerns are equally susceptible to regulatory activity, and few of them are likely to be the subjects of anything so drastic as restrictive legislation. But most if not all of these concerns are sufficiently serious as to suggest the desirability of monitoring what is going on, with a view at the very least of informing patients and policy makers of how well we are handling any possible untoward consequences.

Before moving to the substantive analysis of the present regulatory landscape, it is worth briefly noticing some unique aspects of American law that create the backdrop against which the current regulatory mechanisms exist.

First, because practices touching reproduction and nascent human life raise questions closely linked to the central themes of the abortion debate, efforts at regulation are fraught with political difficulty. Any proposed regulatory efforts of assisted reproduction are viewed by many people through the prism of Roe v. Wade and its progeny, arousing suspicion and concern among individuals on both sides of the abortion conflict. Defenders of the right of privacy or reproductive freedom want no infringement of any of their prerogatives. Pro-life opponents of embryo destruction or in vitro fertilization oppose the public and official legitimization of these practices that a federal regulatory system might imply. This situation creates a powerful disincentive for any regulation of ART or related activities. More generally, there is deep disagreement in our society about the respect owed to in vitro embryonic human life and the weight it should carry in relation to other moral considerations, such as helping infertile couples to have children, helping couples to have healthy children, and advancing knowledge in the research context. This disagreement is one of the main reasons for the current relatively laissez-faire approach to regulation. While some observers complain that the standoff over the moral status of nascent human life has prevented meaningful and useful regulation of ART and related practices, others respond that resolution of this dispute is the sine qua non of any responsible approaches to regulation.

Second, the practice of medicine (now embracing ART) occupies a special place in the American legislative and legal system. The practice of medicine is principally regulated through state licensure and certification of physicians rather than by reference to specific legislative proscriptions or prescriptions of conduct. Legislatures defer to the profession not only because medicine is highly esteemed, but also because of lack of institutional competence. Most governmental authorities simply lack the expertise to provide meaningful oversight of professional activity, and medicine is a profession where crucial judgments must be made on a case-by-case basis by a practitioner familiar with the details and circumstances involved. The law tends to give physicians ample latitude to make such judgments.

Third, the U.S. Constitution has several features that bear on the present discussion. The American system of federalism has tended to vest principal authority for safeguarding the health, safety, and general welfare of citizens in their respective states. This broad mandate of the states creates a lack of uniformity across local jurisdictions, but also permits states to serve as “laboratories” for regulatory experimentation. Moreover, the enumeration of federal powers in the Constitution sets limits on what the national government may legislate. Only conduct that meets a specific jurisdictional threshold (for example, activities that implicate interstate commerce) is reachable by federal mechanisms of regulation. Additionally, the Constitution recognizes certain individual rights inhering in all citizens (or, depending on the right, in all persons), as well as liberties that may be vindicated against both state and federal governments. The assertion of such “fundamental” rights can be controversial if not clearly grounded in the constitutional text and especially when discerned first by judges rather than legislatures. One such controversial “fundamental” right is, of course, the right to privacy in intimate matters relating to procreation. The relevance of the right to privacy to the regulation of assisted reproduction is easily recognized, while its likely application in actual cases is difficult to predict.

A fourth principal concept in American law, directly relevant to the present inquiry, is that the public and private realms of conduct are legally and ethically distinct. The reach of law is in many ways driven by this distinction: public action may properly be regulated by the government, especially to protect public health, safety, and welfare, and to vindicate individual rights; by contrast, the realm of private conduct (that is, actions undertaken in private, affecting only the particular individuals involved) is the zone of maximal individual liberty. To be sure, this is an abstract notion, complicated in practice. Technologies and practices that touch the beginnings of human life implicate the most intimate and private activities: procreation, child rearing, human suffering, and moral reasoning. In such matters, there is a strong legal and cultural presumption in favor of personal liberty. This presumption is only overcome by an equally compelling governmental and societal interest, typically the protection of life and limb. The tension between these concepts—public and private, liberty and the public good—should be borne in mind when considering these technologies and practices.

A fifth concept, related but different, is the distinction often drawn between publicly funded and privately funded activities. Some activities the law chooses silently to tolerate while withholding its official sanction or endorsement through public support. This distinction is especially significant in some arenas touched on in this discussion. Scientific research involving human embryos, for instance, is not legally prohibited, though federal government funding of nearly all such activity is prohibited. This distinction has played an important role in the political controversies surrounding embryo research, and is held by many people on all sides of the question to be of great significance.

A sixth crucial principle is the special role of parents in American law. They are considered the principal protectors of the well being of their children, including their as yet unborn children. As such, they are granted wide latitude by the law to make decisions that directly affect their children’s well being, and this is especially true in the context of assisted reproduction.

A seventh theme extant in American law relevant to the present inquiry is the presumption in favor of commerce and free enterprise. The values of freedom to contract, to participate in the free market, and to profit from the fruits of one’s labors, are memorialized in the Constitution, statutes, and decisional authorities that comprise U.S. law. Any governmental efforts to regulate biotechnology and related activities are written against this backdrop. Similarly, unlike many other nations, our health care system is not run by the government, and physicians jealously guard their prerogative to control their own economic activity. The largely private funding of medical care also places additional obstacles in the way of attempts at government regulation.

An eighth element that informs the present inquiry is the absence of human dignity as an explicit concept in American law. Much of the legal discourse in this country employs operative terms such as liberty, equality, and justice. Unlike some of our European counterparts, however, “human dignity” is not in our legal lexicon. Thus, legislators and courts lack the language (and thus the explicit authority) to fashion responses and remedies to conduct that threatens the dignity of the person.

Ninth, it is necessary to bear in mind the range and variety of activities that may be properly deemed “regulation” for purposes of this inquiry. Regulation comes in myriad forms, from various sources, with widely differing results. Regulation can include a variety of mechanisms, ranging from legal prohibition and statutory obligations, to mere monitoring and data collection. Methods of enforcement range from criminal prosecution to mere hortatory suggestion. Moreover, the source of regulation can be governmental (with the coercive power of the state as the principal mechanism for implementation) or nongovernmental (where market forces and peer evaluation are the chief means of implementation).

The final unique aspect of regulation in the United States is the nation’s deeply ingrained commitment to pluralism. An ambition to regulate assisted reproduction runs up against American individualism and a powerful aversion to “legislating morals.” Americans expect their governments to give compelling reasons before restricting individual liberty. Many people also harbor suspicions that governmental regulations and the bureaucracies needed to manage them are harmful, ineffective, and threatening to salutary personal freedoms and economic progress.

All these considerations make thinking about regulating biotechnologies touching the beginnings of human life extremely complicated, in ways peculiar to the United States. Although the Council has heard presentations on regulatory schemes used in other countries, this document does not deal with them. We are eager, first of all, to disclose and assess what is going on in our own country. And we are frankly doubtful that, given the noted peculiarities of American law and political culture, foreign practices can serve directly as models for what we can and should do here.

I. POWER TO INITIATE HUMAN LIFE BY ARTIFICIAL MEANS

The first and fundamental power under consideration is the power to initiate human life by artificial means. Because this power is the basis of all others touching the beginnings of human life, we give it central consideration. This power is chiefly exercised within the human context of assisted reproduction—that is, the established clinical practice developed to treat infertility and culminating in the birth of a live-born child. Accordingly, the following discussion of the domain of assisted reproduction will serve as a point of departure for the entire inquiry. Although readers are no doubt familiar with the main features of this activity, we shall give a detailed account in order to make clear the various aspects that could give rise to a need for monitoring, oversight, or regulation.

Techniques and Practices

Most methods of assisted reproduction involve five discrete phases: (i) collection and preparation of gametes; (ii) fertilization; (iii) transfer of the embryo to a woman’s uterus; (iv) pregnancy; and (v) birth. Each phase will be discussed separately, followed by a brief discussion of the ethical concerns that arise as a result. Additional issues connected with solicitation and intake of gamete donors will be discussed extensively in Section V (on commerce and commodification), below.

Collection and Preparation of Gametes

The precursors of nascent human life are the gametes: sperm and ova. In the context of assisted reproduction parents seeking to conceive usually provide their own gametes. In the United States in the year 2000, 75.2 percent of the ART cycles undertaken involved never-frozen, self-provided ova or embryos and another 13.1 percent involved frozen self-provided ova or embryos. Only about ten percent involved donated ova or embryos: 7.7 percent never-frozen, 2.8 percent previously frozen. ²

Sperm is acquired directly from the male prospective parent by well known means. The minority of men who cannot ejaculate, or who have a blocked reproductive tube, may undergo assisted sperm retrieval (ASR). Alternatively, sperm precursor cells obtained by testicular biopsy may be used for purposes of insemination (though this yields a lower pregnancy rate).

Acquiring ova from women for use in artificial reproduction is significantly more onerous, painful, and risky than is acquiring sperm. In the normal course of ovulation, one mature oocyte is produced per menstrual cycle. However, in the context of assisted reproduction, in an effort to increase the probability of success, many more ova are required. Thus, the ova source (who is typically also the gestational mother) undergoes a process of drug-induced ovarian stimulation intended to cause ovaries to produce many more mature oocytes during that cycle. This procedure, commonly referred to as “superovulation,” requires the daily injection of a synthetic gonadatropin analog, accompanied by frequent monitoring using blood tests and ultrasound examinations. This treatment begins midway through the previous menstrual cycle and continues until just before ova retrieval. The synthetic gonadatropin analogs give the clinician greater control over ovarian stimulation and prevent premature release of the ova. These hormones are contraindicated in the presence of pregnancy.

A very small percentage of women in 2000 (fewer than 1 percent of assisted reproduction patients) ³ opted not to undergo ovarian stimulation prior to ova retrieval.⁴ In such “unstimulated” procedures, the clinician monitors the development of an ovarian follicle (via ultrasound) and uses daily blood sampling to predict the moment of ovulation. Only one follicle develops and the timing of maturation and release is not controlled. As a result, this process yields a lower success rate than does IVF following ovarian stimulation.⁵

When blood testing and ultrasound monitoring suggest that the ova are sufficiently mature, the clinician attempts to harvest the ova. This is typically achieved by one of two means: laparoscopy or ultrasound-guided transvaginal aspiration. In laparoscopy, three abdominal incisions are made and the ova are extracted with vacuum aspiration. This procedure typically requires the patient to undergo general anesthesia. The clinician inserts a needle into the patient’s abdomen and fills the abdominal cavity with gas. An incision is made through the wall of the abdomen, and a laparoscope is inserted to permit viewing of the reproductive organs. Two additional incisions are made through which instruments are inserted to grasp the ovary and aspirate the mature follicles. In ultrasound-guided transvaginal aspiration a needle guided by ultrasound is inserted through the vaginal wall and into the mature ovarian follicles. The needle is used to withdraw an ovum from each follicle, along with a certain amount of fluid. This is an outpatient procedure. Risks and complications can include accidental puncture of nearby organs such as the bowel, ureter, bladder, or blood vessels, as well as the typical risks accompanying outpatient surgery (for example, risks related to administration of anesthesia, infection, etc.).

Once sperm and ova have been collected, they are cultured and treated to maximize the probability of success. Ova are transferred into a culture medium containing the mother’s blood serum. With sperm, the seminal fluid is removed and replaced with an artificial medium. For infertile men, the clinician removes excess material and concentrates the motile sperm. ⁱ

Fertilization

Once the ova and sperm have been properly prepared, the clinician attempts to induce fertilization—the union of sperm and ovum culminating in the fusion of their separate pronuclei and the initiation of a new, integrated, self-directing organism. It is common practice to attempt to fertilize all available ova.ⁱⁱ Fertilization can be achieved through a number of means including (i) in vitro fertilization (IVF), (ii) gamete intrafallopian transfer (GIFT), (iii) intracytoplasmic sperm injection (ICSI), and (iv) various methods of zona pellucida manipulation.

IVF is the most common method of artificial fertilization. In 2000, it was used by 98 percent of ART patients.⁶ As noted previously, both sperm and ovum are cultured to maximize the probability of fertilization. The ova are examined and rated for maturity in an effort to calculate the optimal time for fertilization. They are usually placed in a tissue culture medium and left undisturbed for two to twenty-four hours. The sperm is prepared as described above. Once the gametes are adequately prepared, thousands of tiny droplets of sperm are placed in the culture medium containing the ova. This process is repeated for all of the available ova. After a day, each of the oocytes is examined to determine whether fertilization has occurred.

Attempts at fertilization via gamete intrafallopian transfer (GIFT) are rare. In 2000, they accounted for less than 1 percent of all attempts at fertilization used by ART patients.⁷ As the name suggests, fertilization using GIFT occurs within the woman’s body. It was introduced in 1984 as an alternative to IVF. Ovarian stimulation and retrieval are performed in the same manner as in IVF. In a single procedure, ova are retrieved, combined with the sperm, and transferred back into the fallopian tube. Typically, two or more ova are transferred. It requires only one functional fallopian tube to work. Because fertilization takes place inside the woman’s body, substantially less lab work is required and there is no need for embryo culturing. However, GIFT requires laparoscopy for ova retrieval or for ovum/sperm transfer and exposes the patient to the increased risk of a multiple gestation. Additionally, because fertilization occurs inside the woman’s body, one cannot determine the cause of failure, for example, whether the ovum was not fertilized or the embryo did not implant.

A new and increasingly widespread means of fertilization is intracytoplasmic sperm injection. As the name implies, ICSI is a procedure in which ovum-sperm fusion is accomplished not by chance, but by injecting a single sperm directly into an oocyte. In ICSI, the oocyte is treated with an enzyme that removes certain cells that surround it (“nurse cells”). The sperm are placed in a viscous solution that greatly slows their motility. A single sperm is selected and drawn into a thin injection pipette from which it is injected into the cytoplasm of the ovum cell.

ISCI is indicated in cases of severe male-factor infertility, with male patients having either malformed sperm or an abnormally low sperm count. ICSI is ideal for situations in which the patient’s sperm would not otherwise penetrate the exterior of the oocyte.ⁱⁱⁱ But its growing popularity has more to do with the wish to increase the success rates for fertilization. ICSI was used in 47 percent of all ART cycles in 2000⁸, but 39.9 percent of the ICSI cycles in 2000 were undertaken by couples without male factor infertility.⁹ ICSI was first introduced by Belgian researchers in 1992. Two years later, relying on a two-study review of safety and efficacy, the American Society for Reproductive Medicine declared ISCI to be a “clinical” rather than “experimental” procedure.^iv

Clinicians can also attempt to induce fertilization artificially through manipulation of the zona pellucida, the thick extra-cellular covering that surrounds the ovum. To assist the sperm’s penetration of the ovum, clinicians perforate the zona pellucida using an acidic solution (“zona drilling”), or a needle or pipette (“partial zona dissection”). Alternatively, clinicians inject sperm underneath the zona pellucida, but not directly into the ovum’s cytoplasm (“subzonal insemination”). Zona drilling results in few pregnancies and has been linked to inhibition of early embryo growth, perhaps due to the acidic solution entering the ovum itself.¹⁰ Few embryos conceived through partial zona dissection have a normal appearance, perhaps due to the introduction of toxins or microorganisms into the ovum in the perforation process.¹¹ Subzonal insemination can be effective in the hands of a skilled practitioner, but frequently results in unfertilized oocytes or fertilization by multiple sperm, rendering the embryo unusable.¹² The safety risks associated with these procedures is discussed below.

A recently developed adjunct to in vitro fertilization is ooplasm transfer. This procedure has been used for women whose fertilized ova do not develop normally owing to a deficiency in their mitochondria. To remedy this problem at the time of fertilization, the oocyte is injected with donor cytoplasm, containing healthy mitochondria. Because the new cytoplasm contains the donor’s DNA, the resulting child will have DNA from three individuals: the father, the mother, and mitochondrial DNA from the ooplasm donor. Moreover, the donor mitochondria could be passed on to future generations through the resulting child. To date, there have been thirty children born worldwide as a result of this procedure.^{v 13} However, for reasons discussed elsewhere in this document this technique is not currently approved for use in clinical practice in the United States.

Following IVF, the new embryos remain in the culture medium. Nutrients (such as human or calf fetal serum) are added to the medium. Some commercially produced preparations exist, but it is typical for ART clinics to make their own preparations on-site. Some ART clinics co-culture developing embryos. That is, they culture the embryos in a medium containing other cells that enhance the growth of the embryos and remove toxins. Various cells have been used for such co-culture, including cells extracted from the uterus or fallopian tubes of patients or donors, rat liver cells, monkey kidney cells, cow uterine cells, and even human ovarian cancer cells. The embryos remain in culture and are warmed in an incubator until they are either transferred into the recipient’s uterus or cryopreserved.

Because in many cases not all embryos are transferred in each cycle, cryopreservation of embryos has become an integral process of ART.^vi Indeed, ASRM has deemed cryopreservation “essential” and provides extensive guidance as to the maintenance of cryopreservation facilities. Cryopreservation is a complicated process that requires embryo preparation, sophisticated freezing technology, reliable storage, and meticulous record keeping. To guard against the formation of ice crystals that could destroy the embryo, the clinician introduces a cryoprotectant solution into the early-stage embryo’s interior. The prepared embryos are then placed in a straw-like structure that is gradually frozen. Once frozen, these structures are stored in canisters kept at very low temperature (typically around minus 196 degrees Centigrade) by liquid nitrogen. Some researchers suggest that it is possible to safely cryopreserve embryos for fifty years or longer.¹⁴ A recently reported study by the Society for Assisted Reproductive Technology and RAND estimates that 400,000 embryos are in cryostorage in the United States.¹⁵

Most ART patients do not transfer cryopreserved embryos. In 2000, only 13 percent of all ART cycles involved transfer of frozen embryos.¹⁶ The rate of live births for cycles using cryopreserved embryos is significantly lower than it is for never-frozen embryos (20.3 percent versus 31.6 percent).¹⁷ The Society for Reproductive Medicine estimates that only 65 percent of frozen embryos survive the thawing process. ¹⁸ There are, however, incentives for couples to use cryopreserved embryos, as doing so eliminates the cost and effort of undergoing further oocyte retrieval. Indeed, this can decrease the cost of a future cycle by $6,000.¹⁹ Transfer of cryopreserved embryos might be preferable in cases in which the recipient is suffering from ovulation hyperstimulation syndrome (discussed below). Because pregnancy aggravates this disorder, delayed transfer can be helpful, and cryopreservation allows such delay. The additional control over the timing of transfer conferred by cryopreservation is also helpful to women whose uterine lining is not yet fully prepared to receive an embryo at the time of its creation. The option of cryopreservation also reduces the pressure to implant all embryos at once, thus reducing the risk of high-order multiple pregnancies.

Transfer

Following initiation of nascent human life by fertilization, the next discrete phase in the assisted reproduction process is transfer of the embryo into the uterus of the mother (or gestational surrogate).^vii

Typically, the embryos are transferred on the second or third day after fertilization, at the four to eight cell stage. To maximize the probability of implantation, some clinicians cultivate the embryo until the blastocyst stage (five days after fertilization) before transferring them to the uterus.²⁰ Prior to transfer, the embryos are evaluated by the clinician according to shape and appearance. There is believed to be some correlation between the external appearance of an embryo and its likelihood of implantation and successful development, but appearances may be misleading. There are many cases in which unhealthy-looking embryos implant and develop into healthy fetuses and children, as well as examples of healthy-looking embryos failing to implant or experiencing developmental problems.²¹ Other methods of embryo evaluation include analysis of chemicals produced by the embryos in culture and pre-evaluation of the quality of sperm and ovum.

A more recently developed method of embryo analysis is preimplantation genetic diagnosis. In PGD, one or more cells are extracted from the embryo by means of biopsy. The clinician tests the sample for chromosomal or genetic characteristics, including the sex of the embryo, with special attention to any genetic disorder for which the relevant mutation has been identified in the parents or an earlier child. (PGD will be discussed further in Section II below.)

Prior to transfer, however, some clinicians attempt to facilitate implantation by means of a process called assisted hatching. Several days after fertilization, an embryo must break out of the zona pellucida so that it can implant into the uterine wall. In some instances, the zona pellucida proves to be too hard to break (possibly due to exposure to culture media, effects of the cryopreservation process, or the absence of exposure to chemicals that the embryo would have encountered had it traveled through the fallopian tube en route to the uterus), and implantation fails as a result. To aid in hatching, clinicians use various chemical, lasers, or mechanical manipulation of the zona pellucida.²²

Once the embryos have been selected and prepared, they are transferred into the uterus. The total number of embryos transferred per cycle varies, usually according to the age of the patient recipient. According to the CDC’s 2000 report, the average number of embryos transferred per procedure was 3.1 for never-frozen embryos and 3.0 for frozen embryos.²³ For women under the age of 35, the average number of never-frozen embryos transplanted per transfer procedure was 2.9. For women aged 35 to 37, 38 to 40, and 41 to 42, the average numbers of never-frozen embryos transplanted per transfer procedure were, respectively, 3.2, 3.5, and 3.7.²⁴ The CDC report notes that in 34 percent of ART cycles using never-frozen, self-provided ova or embryos in 2000, 4 or more embryos were transferred.²⁵

Typically embryos are transferred into the uterus using a catheter. With the patient lying on her back or face-down with knees drawn to her chest, the catheter is inserted through her cervix and the embryos are injected into her uterus (along with some amount of the culture fluid). This procedure does not require anesthesia. Following injection, the patient must lie still for at least one hour. While the transfer procedure is regarded as simple, different practitioners tend to achieve different outcomes. Statistics show that the likelihood of implantation decreases with each attempted transfer procedure.

An alternative method of embryo transfer is zygote intrafallopian transfer (ZIFT). In ZIFT, the embryo is placed (via laparoscopy) directly into the fallopian tube, rather than the uterus. In this way, it is similar to the transfer of gametes in GIFT. Some individuals opt for ZIFT on the theory that it enhances the likelihood of implantation, given that the embryo matures en route to the uterus, presumably as it would in natural conception and implantation. Additionally, many patients prefer ZIFT to GIFT because the process of fertilization and early development of the embryo may be monitored.²⁶ However, ZIFT remains a rare choice, accounting for approximately 1 percent of all ART cycles in 2000.²⁷ This may be because ZIFT requires laparoscopy.

Pregnancy

Successful implantation in the uterine lining marks the beginning of pregnancy. In 2000, 30.7 percent of the ART cycles undertaken resulted in clinical pregnancy.^viii This number varied according to patient age.²⁸ After the inception of pregnancy, patients are carefully monitored and treated by an obstetrician. Pregnancies resulting from assisted reproduction are often treated as high risk.²⁹ Clinicians recommend prenatal diagnosis and testing for all pregnancies resulting from assisted reproduction.

There are a number of medications and procedures that may be indicated during a pregnancy facilitated by assisted reproduction. It is typical for a patient to receive progesterone injections to support key functions necessary to pregnancy. Under certain circumstances, patients receive medications to treat immunological problems.

Among pregnancies facilitated by assisted reproductive technologies, multiple gestations are common. The rate of multiple-fetus pregnancies from ART cycles using never-frozen, self-provided ova or embryos in 2000 was 36.1 percent.^ix For the same time period, the multiple infant birth rate in the United States was 3 percent.³⁰ The extraordinarily high rate of multiple pregnancies resulting from assisted reproduction is attributable both to the transfer of multiple embryos per cycle and to a high rate of twinning of single embryos implanted.^x ART patients have a much higher rate of identical twins than the normal population. This is not a result of multiple embryos implanted in the uterus (these would result in non-identical twins), but rather splitting of single embryos during embryonic development. Some commentators suggest that the phenomenon of twinning may be the embryo’s reaction to an external trauma. In the context of ART, this trauma could be caused by the various exposures and manipulations experienced throughout the process of assisted reproduction.

In an effort to reduce the risks of multiple pregnancy, practitioners sometimes employ a procedure termed “fetal reduction,” the reduction in the number of fetuses in utero by selective destruction. Fetuses are selected for destruction according to size, position, and viability (based on the clinician’s judgment). Guided by ultrasound, the clinician inserts a needle through the mother’s abdomen (transabdominal multifetal reduction) or vagina (transvaginal multifetal reduction), through the uterine wall, and into the selected fetus. The clinician then administers a lethal injection to the fetus—typically potassium chloride. The dead fetus’s body decomposes and is resorbed. This process is repeated until the desired number of living fetuses remains. To be effective, transabdominal multifetal reduction must be performed at ten to twelve weeks gestation. Transvaginal multifetal reduction must be performed between six and eight weeks gestation (eight weeks is recommended).

Delivery

In 2000, for never-frozen self-provided ova or embryos, the overall rate of live births per cycle^xi was 25.4 percent (31.6 percent live births per transfer).^{xii 31} Among these pregnancies, 82.6 percent resulted in live births.³² Of these resulting 19,042 live births, 35 percent resulted in multiple infant births (30.7 percent twins and 4.3 percent triplets or more). ^{xiii 33} One 1993 Canadian study showed that nearly 25 percent of all births facilitated by ART end prematurely, and 30 percent of the resulting infants had low birthweight.^{xiv 34} While this low birthweight may be attributable to the high rate of multiple pregnancies, one 1987-89 French study reported that even for singleton births facilitated by ART, the rate of prematurity and low birthweight was twice that of children conceived by natural means.³⁵ Another study suggests that women using ART are more likely to induce labor and undergo elective caesarian section delivery.³⁶

Disposition of Unused Embryos

As mentioned above, in many, if not most, cases, there are in vitro embryos that remain untransferred following a successful ART cycle. There are five possible outcomes for such an embryo: (1) It may remain in cryostorage until transferred into the mother’s uterus in a future ART cycle. (2) It can be donated to another person or couple. (3) It can be donated for purposes of research. (4) It can remain in cryostorage indefinitely. (5) It can be thawed and destroyed.

Ethical Concerns

The new power to initiate human life by artificial means raises a variety of ethical issues. Some concern the well being of the participants in assisted reproduction: gamete donors, prospective parents, and resulting children. Other issues arise from the increased ability to exercise control over procreation. Still other issues concern the use and disposition of nascent human life that is incident to these new powers and techniques. While these do not exhaust the ethical concerns that attend the advent of the new powers to initiate human life, they will be the chief focus of the following discussion. Though different people assign different weight to the various ethical issues, all have merit and are deserving of some serious attention.

The Intersection of Vulnerability and Untested Technology

The human context in which assisted reproduction is practiced raises an initial ethical concern. Where the process is successful, the overcoming of infertility is a source of joy for tens of thousands of parents each year. But success is not the rule; especially for older patients, and even where there are successful outcomes, the submitting to the process is anything but joyous. Infertility can cause deep anguish and feelings of desperation for the individuals and families affected by it. It frustrates one of the most fundamental and basic of human desires—the desire to have offspring, to have a child of one’s own flesh. The infertile come to practitioners of assisted reproduction usually after prolonged periods of failure and dismay, in a state of vulnerability. This vulnerability may lead some individuals to take undue risks, or may render them potentially susceptible to exploitation by rogue clinicians.

Safety, especially regarding the child-to-be, is a major concern in this area. Many assisted reproductive technologies have been used in clinical practice without prior rigorous testing, study in primates, or studies of long term outcomes. IVF itself was performed on at least 1200 women³⁷ before it was ever performed on chimps³⁸ although it had previously been extensively investigated in mice. The same is true for ICSI. The oldest child conceived by ICSI is now around eleven years old (thus, the first successful procedure was circa 1992),³⁹ whereas the oldest non-human primate conceived by ICSI is about five years old (1997)⁴⁰ and the first successful ICSI procedure in mice was reported in 1995.⁴¹ Absent such studies, it is unclear to what extent minor alterations in the ART process affect development of the child-to-be.⁴²

In the discussion of specific ethical concerns that follows, it is helpful to keep in mind this intersection of patient vulnerability and novel (in some cases untested) technology.

Well Being of Child-to-Be. An invisible—yet the central figure—in the process of assisted reproduction, directly affected by every action taken but incapable of giving consent to such actions, is the child born with the aid of ART. Actions undertaken and choices made during gamete retrieval and preparation, fertilization, transfer, pregnancy, and of course birth, may directly affect the health and status of the resulting child.⁴³

The health of the child-to-be may be affected by actions taken as early as gamete retrieval and preparation. Some studies show that superovulation decreases embryo and fetal viability.⁴⁴ One study of embryos created during stimulated cycles revealed a high level of “developmental arrest, embryonic aneuploidy, mosaicism, apoptosis and failure of cytokinesis.”⁴⁵

Surprisingly, there have been very few comprehensive or long-term studies of the health and well-being of children born using ART, although over 170,000 children have been born in the United States with its aid.⁴⁶Some recent studies have associated various birth defects and developmental difficulties with the uses of various technologies and practices of assisted reproduction. None of these studies provide a causal link between ART and the dysfunctions observed, and some commentators have taken issue with some of the methodologies used. Nevertheless, these findings have alarmed many observers. One such study concluded that children conceived by assisted reproduction are twice as likely to suffer major birth defects.⁴⁷ Specifically, among the children in the study conceived by IVF, 9 percent were diagnosed with a major birth defect or defects by the age of one year. Among children conceived using ICSI, the rate was 8.6 percent. The incidence of such abnormalities among children in the study conceived by natural means was 4.2 percent. Another study undertaken around the same time period reached similar conclusions.⁴⁸ Other recent studies have associated the use of assisted reproduction technologies with diseases and malformations including Beckwith-Wiedemann syndrome^xv, rare urological defects, retinoblastoma,⁴⁹ neural tube defects,⁵⁰ Angelman syndrome⁵¹, and hermaphrodite chimerism⁵².

It bears noting that while many are concerned about the increased risk suggested by these studies, the overall incidence of such harms is low enough that infertile couples have not been deterred in their efforts to conceive using IVF or ICSI. Indeed, ART clinicians (and in some cases the authors of these studies)⁵³ advise their patients that such data should not dissuade them from pursuing infertility treatment.

ICSI has raised specific concerns among some observers largely for the same reasons that it has proven so successful as a means of fertilization. Because ICSI circumvents the ovum’s natural barrier against sperm otherwise incapable of insemination, some suspect that removing this barrier may permit a damaged sperm (for example, aneuploid or with damaged DNA) to fertilize an ovum, resulting in harm to the child-to-be. Some male ART patients have a gene mutation or a chromosomal deletion that renders them infertile. If a sperm can be retrieved from one of these patients, he may be able to conceive a child via ICSI. However, this could mean that the genetic abnormality would be passed on to the resulting child. For example, two thirds of men with congenital bilateral absence of the vas deferens (rendering them unable to ejaculate) carry certain cystic fibrosis gene mutations. ICSI may permit these men to overcome their infertility, but the resulting child will (in 50 percent of the cases) bear this gene mutation. Similarly, another form of male factor infertility characterized by a very low sperm count is associated with a particular Y-chromosome deletion. The use of ICSI in such cases risks the transfer of this chromosome deletion to the resulting child, rendering any male child infertile, and, according to some studies, at risk for sex-chromosome aneuploidy. Additional studies have associated the use of ICSI with an increased incidence in novel chromosomal abnormalities and mental developmental delays. ⁵⁴

Finally, it is a matter of concern that there have not been many longitudinal studies analyzing the long term effects of ICSI on the children born with its aid. The Belgian group that pioneered ICSI has collected a database that details neonatal outcome and congenital malformations in children conceived through ICSI.⁵⁵ There do not seem to be any ongoing or published studies of this kind investigating the effects of ICSI beyond the neonatal stage.

Many adjuncts to the fertilization and transfer process raise similar safety concerns for the children born as a result.^xvi The enormous variation in the success rates of among ART clinics—a most important but little-known fact—suggest that differences in culture media and gamete isolation and processing may play a role. Factors such as culture conditions and length of time in culture may also affect the development of the child-to-be.⁵⁶ Specifically, some authorities claim that differences in salt or amino acids in the culture media can affect gene expression. Other commentators have raised safety concerns about co-culturing embryos with ovarian cancer cells. Additionally, one researcher notes that the process of extended culture in mice (for example, permitting extended embryo development prior to transfer) can cause imprinting problems and yields a higher rate of identical twins. ⁵⁷

Other adjuncts to fertilization and transfer are probably not risk-free. Cryopreservation might affect gene expression or lead to other molecular effects such as “telomere shortening and replicative senescence, damage to plasma and nuclear membranes, and inappropriate chromatin condensation.”⁵⁸ Similarly, ooplasm transfer has been linked to an unusually high rate of Turner’s syndrome.⁵⁹ Finally, assisted hatching (or any technique that results in manipulation of the zona pellucida) has been associated with a higher incidence of monozygotic twinning and an increased risk of twins carried in the same amniotic sac, which can lead to malformation, disparities in growth, and pregnancy complications.⁶⁰

Multiple gestations, far more common in the context of assisted reproduction than in natural conception,⁶¹ have adverse impacts on the health of the child-to-be.⁶² Such pregnancies greatly increase the risk of prenatal death.⁶³ Multiple pregnancies are more likely to end prematurely, and prematurity is associated with myriad health problems including serious infection, respiratory distress syndrome, and heart defects.⁶⁴ One in ten children born following high order pregnancies dies before one year of age.⁶⁵ Children born following a multiple pregnancy are at greater risk for such disabilities as blindness, respiratory dysfunction, and brain damage.⁶⁶ Moreover, infants born following such a pregnancy tend to have an extremely low birthweight, which has been associated with a number of health problems, including some that manifest themselves only later in life, such as hypertension, cardiac disease, stroke, and osteoporosis in middle age.⁶⁷ Interestingly, the phenomenon of low birthweight is not limited to infants born from multiple pregnancies. Even singletons born with the aid of ART tend to have an abnormally high incidence of low birthweight.⁶⁸

So-called “fetal reduction” would be expected to reduce the problems associated with multiple pregnancy. But fetal reduction is itself associated with a number of adverse effects on the children who remain following the procedure. One study shows that following transabdominal multifetal reduction there is a miscarriage rate of 16.2 percent, and 16.5 percent of the remaining pregnancies end in premature birth.⁶⁹ The alternative method, transvaginal multifetal reduction, carries a higher risk of infection and has been associated with a higher risk of infant mortality than its counterpart.⁷⁰ It has been observed that children born following fetal reduction (by either method) tend to be premature, thus exposing them to the complications described above.⁷¹ One study has suggested that children born following fetal reduction are much more vulnerable to periventricular leukomalacia—characterized by brain dysfunction and developmental difficulties.⁷²

Well-Being of Women in the ART Process

Another concern is for the well-being of the women who participate directly in the process of assisted reproduction, namely, the ova donors and child bearers. As mentioned previously, these are frequently the same person, but because the risks are distinct, they will be treated separately.

Ova Donors. There are a number of ethical questions implicated by the process of ovarian stimulation, monitoring, and retrieval. A principle ethical concern is for the health of the woman subject to this process. Aside from the discomforts and burdens of ovarian stimulation and monitoring (such as frequent injections of hormones, blood work, and ultrasound), there are also risks incidental to hormonal stimulation. One such risk is “ovarian hyperstimulation syndrome,” characterized by dramatic enlargement of the ovaries and fluid imbalances that are potentially life threatening. Complications can include rupture of the ovaries, cysts, and cancer. The reported incidence of severe ovarian hyperstimulation syndrome is between 0.5 and 5.0 percent.⁷³ Additionally, adverse side effects of the hormones administered during superovulation have included memory loss, neurological dysfunction, cardiac disorders, and even sudden death.⁷⁴ There do not appear to be any studies on the incidence of such side effects.⁷⁵

Child Bearers (Gestational Mothers). Another source of ethical concern is the risk to the health of women who become pregnant as a result of ART. As noted above, many such pregnancies are treated as “high risk.” These pregnancies tend to experience a higher incidence of complications than natural pregnancies. Some commentators have suggested that this is due to the age of the patients (who tend to be older than most childbearing women) and the high rate of multiple pregnancies. ⁷⁶

As noted above, multiple pregnancies are far more common in the ART context, owing both to the practice of transferring multiple embryos and the high incidence of spontaneous twinning with any single embryo. Multiple pregnancies pose greater risks to the mother than do singleton pregnancies. A woman carrying multiple fetuses is more likely to suffer from pre-eclampsia, high blood pressure, or anemia.⁷⁷ Because multiple gestation pregnancies are generally more taxing on the mother’s body, there is greater potential to aggravate pre-existing medical conditions.⁷⁸ Moreover, such pregnancies expose the woman to higher risks of uterine rupture, placenta previa, or abruption. One commentator has noted that the added expense growing out of complications from high order pregnancies is one of the primary reasons that assisted reproduction is not covered by insurance.⁷⁹

Meaning of Enhanced Control Over Procreation

A different set of concerns relate to how these new powers may affect the understanding of human procreation, as well as the structure of the family.

Concerns about the meaning of parenthood are directly raised by cryopreservation, ooplasm transfer, and the possible use of fetal oocytes. For example, cryopreservation of sperm and embryos makes posthumous parentage possible. For instance, some American soldiers have been reported to store up sperm on the eve of shipping out to a battle zone. And instances have been reported in which women have requested that their newly deceased husband’s sperm be harvested via assisted sperm retrieval and used for artificial insemination. If techniques for cryopreservation of ova are ever perfected, or if ova can be derived from adult stem cells, new opportunities for posthumous conception involving deceased women will arise.

Ooplasm transfer raises slightly different issues of parenthood. Because the donated ooplasm contains mitochondrial DNA from the donor, the resulting child receives a genetic contribution from three different persons. Moreover, because mitochondrial DNA is maternally inherited, if the resulting child is female, she will pass on to her child the genetic contribution of both her mother and the female ooplasm donor.

A projected technique that combines the ethical concerns of posthumous conception and ooplasm transfer is the harvesting and use of fetal oocytes. Some researchers have posited that oocytes (or their precursors) might be harvested from aborted fetuses and used as donated ova (once they have matured in vitro) or for tissue transplantation to patients who have impaired ovarian function. In the first instance, the aborted fetus could fairly be considered the genetic mother of a child-to-be, and in the second instance it would contribute some genetic information to the resulting child. If recent studies in mice deriving oocytes from embryonic stem cells⁸⁰ can be repeated in humans, a five-day-old embryo (source of the stem cells) could become the genetic mother of new children.

Fetal reduction raises its own set of concerns. In this procedure, parents effectively make the choice that some unborn children (each of which was conceived in the hope that it would become a live-born child to term) will live and some will die. Regardless of one’s views on abortion in general or the precise moral status one assigns to the fetus, such selective and deadly invasion of a life-yielding pregnancy is disquieting.

Use and Destruction of Nascent Human Life

The new powers to initiate life by artificial means also entail the loss of embryonic life, especially where superovulation is used and many ova are fertilized at once. Large numbers of embryos die at all stages of the process of assisted reproduction (in vitro and in vivo).^xvii An unknown number of additional embryos are destroyed when it is determined that they are no longer needed or desired. Some of these embryos are destroyed at the clinics where they were created. Still others are donated to researchers, who use them in experiments that involve or lead to their destruction. Thousands of embryos are cryopreserved for indefinite periods of time. As previously noted, there were an estimated 400,000 embryos in cryostorage in the United States as of April 11, 2002.

To the extent that the early human embryo is entitled to moral respect, actions that result in the end of embryonic life are significant and require careful consideration.

Current Regulation

The following detailed discussion provides an overview of the current state of regulation of the biotechnologies and practices discussed above. The discussion will be broadly divided into sections treating the governmental and nongovernmental regulation of assisted reproduction, both direct and indirect. Each source of regulation will be described in terms of its aims, animating values, jurisdictional scope and requirements, mechanisms of regulation, and efficacy.

Direct Governmental Regulation of Assisted Reproduction

A. Federal Oversight.

1. Consumer Protection and Embryo Laboratory Standards. There is only one federal statute that aims at the regulation of assisted reproduction as such: The Fertility Clinic Success Rate and Certification Act of 1992 (“the Act”).⁸¹ The purposes of the statute and its related regulations are twofold: (i) to provide consumers with reliable and useful information about the efficacy of ART services provide by fertility clinics, and (ii) to provide states with a model certification process for embryo laboratories.

(a) Success Rates. Under the implementing regulations of the ACT, each ART program or clinic in the United States is required to report annually to the CDC data relating to its rates of success.⁸² The Act defines ART as “all treatments or procedures which include the handling of human oocytes or embryos, including in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer, and such other specific technologies as the Secretary [of Health and Human Services] may include in this definition ...”⁸³ An “ART program or clinic” is defined as a legal entity practicing under state law, recognizable to the consumer, that provides ART services to couples who have experienced infertility or are undergoing ART for other reasons.⁸⁴ Each ART program is required to collect and report data for each cycle of treatment initiated. For these purposes, an “ART cycle” is initiated when a woman begins taking fertility drugs or starts ovarian monitoring with the intent of creating embryos for transfer. The data that must be collected includes: patient demographics; medical history and infertility diagnosis; clinical information pertaining to the ART cycle; and information on resulting pregnancies and births. Information is presented in terms of pregnancies per cycle, live births per cycle, and live births per transfer (including never-frozen and frozen embryos from both patients and donors). The statistics are also organized according to age (younger than 35, 35 to 39, and older than 39). Moreover, programs are required to report information on cancelled cycles, average embryos transferred per cycle, multiple birth rates per transfer, percentage of patients with particular diagnoses, and types and frequency of ARTs used (for example, the frequency with which ICSI is used).

The data, reported by the Society for Assisted Reproductive Technology (with whom CDC has contracted to implement the ACT) is subject to external validation through an auditing process.^xviii Specifically, SART’s Validation Committee performs its audits in conjunction with the CDC. This validation committee is composed of fourteen members assembled from both SART and non-SART member programs. Inspection teams of two Validation Committee members visit clinics (currently forty) randomly selected by CDC. All live births reported by the clinic are validated. Additionally, twenty other variables are validated from fifty randomly selected cycles. The data collected during the on-site inspections are compiled and jointly reviewed by the Validation Committee and CDC.

An ART program can satisfy these requirements by reporting its data to SART. Alternatively, an ART program is deemed to be in compliance if it is already a voluntary member of SART and participates in SART’s reporting program. If a clinic or program fails to comply with the requirements of the act, it is listed as “nonreporting” in the annual CDC publication that collects and analyzes the data reported. There are no other penalties for failure to report.

Have the reporting requirements of the Act been an effective means of informing and protecting consumers? Critics assert that because there are no stiff penalties for noncompliance, the law is merely hortatory. Supporters of the Act respond that the stigma of being listed as a “nonreporting” clinic creates sufficient market pressure to compel the vast majority of ART programs to report the required data. Indeed, in 2000, 383 of the nation’s 408 ART programs were deemed in compliance with the Act’s reporting requirements. Additional critics of the Act’s efficacy assert that the reporting requirements are incomplete. For example, there is no requirement that clinics provide the average cost per successful pregnancy. Moreover, focusing on success rates may create an incentive to transfer too many embryos per cycle, resulting in multiple pregnancies that can be extremely risky and costly. Emphasis on success rates may induce some clinicians to use ICSI, which adds costs and implicates the extra risks discussed above. Additionally, some point out that success rates are highly manipulable and thus not useful. For example, the Genetics and IVF Institute in Fairfax, Virginia, details on its website the ways in which clinics can manipulate success rates by such tactics as patient selection, reclassification of cycles, and transfer of high numbers of embryos. Finally, some critics go so far as to charge that the Act is little more than a fig leaf drafted and currently implemented by the ART industry as a shield against more meaningful regulation.

(b) Model Certification Program. The second function of the Act is to provide states with a model certification program for embryo laboratories. An “embryo laboratory” is defined as “a facility in which human oocytes are subject to assisted reproductive technology treatment or procedures based on manipulation of oocytes or embryos which are subject to implantation.”⁸⁵ Unlike the reporting system, adoption of the model program is entirely voluntary. The model certification program is intended to provide a resource for states that wish to develop their own programs, or professional organizations seeking to develop guidelines or standards for embryo labs. States can apply to the Secretary of Health and Human Services to adopt the program and qualifying states will be required to administer the program as provided by the regulations. To date, no state has done so.

The overarching purpose of the model program is to help states to assure consistent quality assurance and control, record keeping, performance of procedures, and quality of personnel. The specific standards applied were developed in conjunction with the College of American Pathologists and ASRM, borrowing generously from the guidelines used in the voluntary certification program (discussed further below).

The final version of the program, incorporating comments received by the CDC, was published in the Federal Register on July 21, 1999.⁸⁶ Under the program, embryo laboratories may apply to their respective states for certification. Those laboratories that choose to do so are inspected and certified by states or approved accreditation organizations. Certification is valid for a two-year period. The Secretary, through the CDC, has authority to inspect any laboratory that has been certified by a state to ensure compliance with the standards. The penalty for noncompliance under the model program is revocation of certification. A key limitation in the program is that neither the Secretary nor the states may establish “any regulation, standard or requirement which has the effect of exercising supervision or control over the practice of medicine in assisted reproductive technologies.”⁸⁷

Has this model program achieved the Act’s objective of helping states to assure quality and uniformity in embryo laboratory procedures and personnel? As previously noted, to date, no state has adopted the program. Some critics question the usefulness of the model program as a regulatory mechanism in any event. Even if a state were to adopt the program, there is no requirement that laboratories apply for certification; it is entirely voluntary.

B. State Oversight

There are a variety of state laws that bear directly on the clinical practice of assisted reproduction. The vast majority of state statutes directly concerned with assisted reproduction, however, focus mostly on the question of access to such services. These states have legislative directives as to whether and to what extent assisted reproduction services will be covered as insurance benefits. Other state statutes regarding assisted reproduction aim to prevent the malfeasance of rogue practitioners (for example, California criminalizes unauthorized use of sperm, ova, and embryos). Still others focus on the regulation of gamete and embryo donation (for example, California sets forth screening requirements for donated sperm). There are a host of states whose laws dictate parental rights and obligations in the context of assisted reproduction.⁸⁸ A few jurisdictions (such as New Hampshire and Pennsylvania) have statutes that provide for fairly comprehensive regulation of the practitioners and participants in ART. Many jurisdictions have statutes that bear generally on the treatment and disposition of embryos, but a subset of these jurisdictions explicitly speak to the treatment of embryos in the context of assisted reproduction (including Louisiana, New Mexico, and South Dakota). Some illustrative examples are provided below.

New Hampshire has an “In Vitro Fertilization and Pre-embryo Transfer” statutory scheme that provides that “IVF will be performed in accordance with the rules adopted by the [state] department of health and human services.”⁸⁹ The state additionally specifies who may receive IVF treatment, namely, a woman who is at least twenty-one years of age, who has been medically evaluated for her “acceptability” to undergo the treatment (it is unclear what this means), and who has undergone requisite counseling.⁹⁰ New Hampshire likewise extends the medical and counseling requirement to the woman’s husband.⁹¹

Pennsylvania also regulates ART as such, but focuses its efforts on record keeping and standards for maintenance of clinical facilities.⁹² All IVF practitioners are required to submit reports and be available for inspection. The reports must include the names of the practitioners, their locations, the number of ova fertilized, the number of embryos destroyed or discarded, and the number of women “implanted with a fertilized egg.”

New Mexico, Louisiana, and South Dakota all have embryo experimentation statutes that directly speak to the context of assisted reproduction.⁹³ The New Mexico statute prohibits any “clinical research activit[ies] involving fetuses, live-born infants or pregnant women.”⁹⁴ Clinical research “includes research involving human in vitro fertilization, but ... shall not include human in vitro fertilization performed to treat infertility; provided that this procedure shall include provisions to insure that each living fertilized ovum, zygote or embryo is implanted in a human female recipient ...”⁹⁵ There have been no court opinions interpreting this language, but some commentators suggest that this effectively proscribes the practice of IVF except in cases in which all embryos are transferred to the mother.⁹⁶

South Dakota, like New Mexico, prohibits “non-therapeutic research” on embryos. In contrast to New Mexico, however, it explicitly exempts from this definition “IVF and transfer, or diagnostic tests which may assist in the future care of a child subjected to this test.” Again, there are no cases interpreting this language, but it seems that this statute would not require the transfer to a uterus of all embryos created in the process of IVF.

Louisiana’s regulation of ART provides the highest level of protection to the embryo in any U.S. jurisdiction. It defines the embryo as a “juridical person” with nearly all of the attendant rights and protections of infants. It stipulates that the use of an in vitro embryo is solely for “the support and contribution of the complete development of human in utero implantation.” Embryo farming or culture for any other purpose is proscribed. The embryo is not the property of the clinician or gamete donors. If the in vitro patients identify themselves, they are deemed parents according to the Louisiana Civil Code. If the in vitro patients do not identify themselves, the “physician shall be deemed to be the temporary guardian ... until adoptive implantation can occur.” The physician who creates the embryo through IVF is directly responsible for its safekeeping. The gamete donors owe the embryo “a high duty of care and prudent administration.” They may, however, renounce their parental rights through a formal proceeding, after which the embryo shall be available for adoptive implantation. Donors may convey their parental rights to another married couple, but only if “the other couple is willing and able to receive” the embryo. Under Louisiana law, the judicial standard governing any disputes involving the embryo is “the best interests of the embryo.” This means, of course, there can be no intentional destruction of a viable embryo.

In addition to providing such a high level of protection to embryos in the context of ART, Louisiana has set standards for who and where IVF may be performed. It may only be practiced by a licensed physician in medical facilities that each meet “the standards of [ASRM] and the American College of Obstetricians and Gynecologists ..."

Some states have statutes that preclude “experimentation” on embryos. Given the experimental nature of certain ART procedures (such as preimplantation genetic diagnosis, or even arguably IVF itself), these statutes might be construed broadly to reach such practices. Individuals have challenged such statutes on constitutional grounds, arguing that the operative terms are so vague as to violate the Constitutional guarantee of due process. Practitioners have argued that they were not adequately on notice of which procedures could expose them to criminal liability. Courts in three jurisdictions have invalidated such statutes on these grounds.⁹⁷ One Court among these three struck the statute on the additional ground that it impermissibly infringed the plaintiff’s right to choose a particular means of reproduction, noting: “It takes no great leap of logic to see that within the cluster of constitutionally protected choices that includes access to contraceptives, there must be included within that cluster the right to submit to a medical procedure that may bring about, rather than prevent, pregnancy.”⁹⁸

Indirect Governmental Regulation of Assisted Reproduction

There are a number of state and federal governmental authorities that do not explicitly aim at the regulation of ART, but indirectly and incidentally provide some measure of oversight and direction.

A. Federal Oversight

1. Safety and Efficacy of Products and Public Health. The U.S. Food and Drug Administration (FDA) is the federal agency that regulates the articles used in assisted reproduction, but does not, as a general matter, oversee the practice of assisted reproduction.

FDA regulates drugs, devices, and biologics that are or will be marketed for use in the United States. Its principal purpose is to ensure the safety and efficacy of products according to their approved use.⁹⁹ The FDA is also broadly authorized to take measures to prevent the spread of communicable disease.¹⁰⁰ Additionally, it exercises regulatory authority over clinical trials of unapproved products subject to its regulations. The FDA does not, however, have the authority to regulate “the practice of medicine” (which is the province of the states). Thus, physicians may, in the course of administering medical treatment according to acceptable standards of care, employ approved articles in a manner that is outside the scope of their approved use. This is sometimes called “off-label” use.

The FDA’s jurisdiction is chiefly based on the interstate commerce clause of the United States Constitution. Specifically, FDA’s principal powers derive from the authority conferred by the Food, Drug, and Cosmetic Act (FDCA) and the Public Health Services Act (PHSA) to regulate the introduction of certain products (and their components) into interstate commerce. Given the Supreme Court’s historically expansive interpretation of what constitutes “interstate activity” for purposes of deciding cases involving the commerce clause, this has not proven to be a meaningful limitation on the FDA’s authority. Nevertheless, it is conceivable that one might mount a credible constitutional challenge to FDA regulation of any activity that is wholly intrastate.

FDA regulatory mechanisms are driven by the statutory definitions provided by the FDCA and PHSA. If FDA determines that a given article falls within the broad statutory definitions of “drug,” “device,” or “biologic,” it will exercise jurisdiction, provided the interstate nexus is satisfied. Thus, to describe the breadth and depth of FDA’s authority, particularly as it relates to assisted reproduction, it is necessary to explain in some detail these statutory definitions and related provisions.

“Drug” is defined by the FDCA in an extremely expansive way, encompassing any officially recognized article that is (i) intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man ... and (ii) (excepting foods) intended to affect the structure or any function of the body of man, and (iii) intended for use as a component of any of the foregoing articles.¹⁰¹ It is unlawful to introduce a “new drug”—which encompasses nearly every prescription and many non-prescription drugs—into interstate commerce without an FDA-approved New Drug Application.¹⁰² The NDA process is onerous and expensive, requiring the sponsor to provide large amounts of information to the FDA including details regarding the composition of the drug, “the chemistry of the formulation for delivering the active ingredient, methods of manufacture and packaging, proposed labeling, and, most critically, the results of clinical studies that will support a conclusion that the drug product is safe and effective.”¹⁰³ As Professor Richard Merrill points out, the FDA’s proscription on distribution of unapproved drugs, combined with its demand for clinical trials as a pre-requisite to new drug approval, seems to create a paradox.¹⁰⁴ For how can a “new drug” be tested for safety and efficacy if it cannot move in interstate commerce? FDA resolves this tension by creating a limited exemption for distribution of an “Investigational New Drug” (IND)¹⁰⁵—that is, a special approval for purposes of a clinical trial. Upon receipt of an IND application, FDA imposes a thirty-day waiting period during which it reviews the proposed protocols. FDA can withhold an IND (called a “clinical hold”) and effectively prevent clinical trials for a new drug if it finds that (i) human subjects would be exposed to unreasonable and significant risk of illness or injury or (ii) the IND does not contain sufficient information required ... to assess the risks to subjects of the proposed study.

Pursuant to Section 351 of the PHSA, the FDA has the authority to regulate “biological products,” defined as “any virus, therapeutic serum, toxin, anti-toxin, vaccine, blood, blood component or derivative, allergenic product or analogous product, applicable to the prevention, treatment or cure of diseases or injuries to humans.”¹⁰⁶ This is, on its face, a very broad definition, particularly in light of the somewhat ambiguous phrase “analogous product.” Under Section 351, it is unlawful to introduce any biological product into interstate commerce without an approved biologics license application (BLA).¹⁰⁷ The BLA process is much akin to the NDA process in that applicants are required to demonstrate that the biological product is “safe, pure, and potent,” and manufactured in a facility meeting certain specifications.¹⁰⁸ The data in support of the application must be developed through clinical and nonclinical studies. The same regulations governing preclinical testing and testing of new drugs in the IND context¹⁰⁹ govern these activities in the BLA process as well. Indeed, the definition of “biological product” falls within the statutory definition of “drug” in the FDCA. However, if a biologic is licensed under Section 351, it need not be approved under the parallel FDCA provisions.¹¹⁰

Pursuant to its authority to regulate biological products, FDA’s Center for Biologics Evaluation and Research (CBER) has also undertaken regulation of cellular and gene therapy products. Researchers developing gene therapy products must receive an IND before studying gene therapy products in humans and must meet FDA requirements for safety and efficacy before such products can be marketed. The regulation of such activities is discussed extensively in Section IV below.

Section 361 of the PHSA empowers the FDA to prevent the spread of communicable diseases.¹¹¹ Under this authority, CBER has issued regulations and proposed regulations for Human Cellular and Tissue-Based Products (HCT/Ps), which include a variety of medical products derived from the human body and used for the replacement, reproductive, or therapeutic purposes such as semen, ova, and embryos used for reproductive purposes.^{xix 112} Sperm, ova and embryos were originally exempted from this definition, but were later added out of concern for the transmission of disease. In 1997, FDA issued guidance documents on a proposed scheme for the comprehensive regulation of HCT/Ps. In 1998, the FDA published a proposed rule regulating these products.¹¹³ The scheme would require “minimally processed or manipulated” tissues transplanted from one person to another for their normal structural functions to be screened for infectious diseases and subject to FDA’s good tissue practices. These tissues would not, however, be subject to the onerous requirements of premarket approval. “Minimal manipulation” was defined as “processing that does not alter the relevant biological characteristics and, thus potentially, the function or integrity of the cells or tissues.”¹¹⁴“More than minimally manipulated” tissues and cells that are (i) combined with non-cellular or non-tissue components, (ii) labeled or promoted for purposes other than their normal function, or (iii) have systemic effect (except in cases of autologous use, transplantation into a first degree blood relative or reproductive use) would require FDA’s more stringent premarket review and approval described above.

The only portion of the proposed HCT/P scheme applicable to reproductive tissue that has been enacted as a final rule is the requirement that owners and operators of establishments or persons engaged in the recovery, screening, testing, processing, storage, or distribution of HCT/Ps, must register and list those human cells, tissues and cellular and tissue-based products with CBER.^xx However, there are several important exceptions to these registration requirements. Specifically, registration is not required if: (i) an establishment removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure; (ii) an establishment does not recover, screen, test, process, label, package, or distribute, but only receives or stores HCT/Ps solely for implantation, transplantation, infusion, or transfer within the facility; or (iii) an establishment that only recovers reproductive cells or tissue and immediately transfers them into a sexually intimate partner of the cell or tissue donor.¹¹⁵

Like the statutory terms discussed above, “device” is defined in a similarly expansive manner, covering any “instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar related article, including any component . . . that is” officially recognized, intended for the diagnosis, treatment, cure, mitigation, or prevention of disease in man, or intended to affect the structure and function of the body of man, “and which does not achieve its primary intended purpose through chemical action within or on the body of man ... and which is not dependent upon being metabolized for achievement of its primary intended purpose.”¹¹⁶ Devices are categorized according to the risk of harm associated with their use.¹¹⁷ Those devices (Class I or II) that present a low safety risk are subject to a simple approval process known as “premarket notification.”¹¹⁸ Devices that present the greatest risk (Class III), such as those used to sustain or support life, or are implanted in the human body, are subject to premarket approval akin to the NDA procedure, that demonstrates safety and efficacy for intended use.

FDA has a number of means at its disposal to enforce the foregoing regulations under the PHSA and FDCA. FDA has authority to conduct inspections to determine compliance with these requirements.¹¹⁹ Approved BLAs or NDAs can be suspended or revoked.¹²⁰ Although rarely exercised, FDA has the authority to recall previously approved products.¹²¹ If a manufacturer or sponsor is found to be in violation of any of the foregoing provisions, they may be subject to seizure of the offending articles, injunction, or even criminal prosecution.¹²²

In what ways do the above regulations of drugs, devices, and biologics impact the practice of assisted reproduction? First, to the extent that articles used in ART meet the statutory definition of drug, device, or biologic, they must be approved pursuant to the relevant procedures prior to marketing and use.^xxi This is, however, principally a regulatory mechanism applicable to the manufacturers of these articles—rather than the clinicians who use them following their approval. Once the given article is approved, the FDA loses much of its regulatory authority. Clinicians treating infertile patients are regarded as engaged in the practice of medicine, which is beyond the regulatory reach of the FDA. Consider the following:

The physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert, without informing or obtaining the approval of the Food and Drug Administration. ... [T]he Act does not require a physician to file an investigational new drug plan before prescribing an approved drug for unapproved use or submit ... data concerning the therapeutic results and adverse reactions.¹²³

Further, federal courts have held that a licensed physician can prescribe a lawful drug for a non-FDA approved purpose in treatment of a patient.¹²⁴ If the FDA wants to control (or influence) off-label use of approved products it would likely impose some new labeling requirement warning users of the dangers animating its concern. Again, this would regulate of the manufacturer more than the clinician administering these articles in the practice of medicine. Theoretically, if the FDA were concerned that the risks of widespread off-label use utterly outweighed the benefits of the approved use, it could withdraw its approval. But this is almost never done.

The FDA’s tissue regulations, if and when they go into effect, may have some impact on assisted reproduction. These regulations would require certain owners and operators of facilities that work with reproductive tissues to register and list such tissues with CBER. However, many fertility clinics would be exempt from these requirements pursuant to the broad exceptions described above.

In the main, FDA has abstained from regulating the field of assisted reproduction. This is understandable, given that assisted reproduction falls under the aegis of the practice of medicine. Additionally, because the subject matter is so intensely personal, regulation would be fraught with political difficulties. Given that FDA’s authority is largely driven by the definition of “articles” under its purview, extension of this authority to the context of assisted reproduction would require analytically dubious re-categorization of certain aspects of human procreation. For example, in order to acquire jurisdiction, it might be necessary for the FDA to construe an embryo as a “drug,” “biological product,” or “device.” What would safety and efficacy mean in such a context? Finally, the FDA may have been historically hesitant to assert jurisdiction over assisted reproduction because of the nature of the regulatory mechanisms themselves. The categorization and approval mechanisms through which FDA exercises much of its authority are not graduated or flexible. Thus, when FDA asserts jurisdiction over an article by defining it as a “new drug” subject to the relevant approval requirements, it becomes immediately unlawful to distribute it. FDA’s unwillingness to regulate assisted reproduction may be partly borne of a concern that to do so would effectively shut down the entire ART industry.

There are, however, some notable exceptions to FDA’s reluctance to step into the arena of assisted reproduction. Already mentioned is the regulation of sperm, ova, and embryos as reproductive tissue through HCT/P registration requirements. A more controversial example is the FDA’s recent pronouncements on cloning for reproduction—if cloning for reproduction can fairly be characterized as a method of assisted reproduction. Here, the FDA has invoked its authority by asserting that the implantation of a cloned embryo into a woman’s uterus is tantamount to the clinical study of an unapproved new drug, requiring an IND.¹²⁵ Because of safety concerns, FDA declared that a clinical hold would be issued. To date, no IND has been submitted. It bears noting that the animating principles of FDA’s regulation in this context are, as usual, safety and efficacy. A former head of CBER, Katherine Zoon, told a congressional committee that if concerns over safety are properly addressed, FDA would likely approve an IND for cloning for reproduction.¹²⁶

Finally, the FDA has also ventured into the field of assisted reproduction to halt the practice of ooplasm transfer. In 2001, FDA asserted that clinicians at St. Barnabas Hospital in New Jersey were required to submit an IND before performing further procedures involving ooplasm transfer, on the grounds that it is a form of gene transfer research, as the procedure results in the transfer of mitochondrial DNA. This sent a shock wave through the ART community, and most if not all practitioners halted the procedure altogether rather than submit to the IND process.

These examples serve to illustrate the contours and limits of FDA’s authority in the context of assisted reproduction. First, it is clear that the FDA will act if it perceives a sufficiently grave harm that can be formulated in terms of FDA’s mandate—safety and efficacy. However, to assert jurisdiction, FDA must sometimes engage in unsatisfying (or even offensive) definitional contortions. By most lights, for example, human embryos are not drugs. Finally, these examples demonstrate that the line between clinical experimentation and the practice of medicine is not always easy to draw.

2. Quality Assurance and Control in Clinical Laboratories. Another Federal authority that indirectly affects assisted reproduction is the Clinical Laboratory Improvements Act of 1988 (CLIA).¹²⁷ This statute (and regulations issued thereunder by the Centers for Medicare and Medicaid Services, or CMS) requires laboratories engaged in the “examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment” to meet certain quality control requirements. Specifically, CLIA requires that such laboratories must satisfy requirements relating to quality assurance, personnel qualifications, patient test management, and the like. Moreover, such labs must submit to inspections (announced or unannounced) by federal officials. Failure to comply can result in revocation of certification and inclusion in a published list of sanctioned laboratories. States can opt out of CLIA if they have their own certification program that is equally or more rigorous.

CLIA does not apply to assisted reproduction laboratory facilities as such. Rather, it applies to andrology and endocrinology diagnostic tests (such as semen and blood hormone analysis) in such laboratories only when performed for their own sake. These tests are not covered by CLIA when undertaken as an adjunct to the delivery of assisted reproduction services. This creates what some consider to be a confusing regulatory atmosphere. The American Board of Bioanalysis (which advocates on behalf of clinical laboratory directors) brought a lawsuit in 1999 to compel HHS to apply CLIA to all ART embryo laboratories. The case was dismissed on the grounds that the ABB lacked standing to sue. The Court agreed with HHS’s contention that the department should be allotted more time to consider the question of CLIA’s application.

Regulation of Unfair Trade Practices

The Federal Trade Commission is charged with providing safeguards against anti-competitive behavior and promoting truth in advertising in interstate commerce. FTC thus has the authority to investigate deceptive claims in advertising by health care providers, including fertility clinics, for example, claims of pregnancy success rates. The jurisdiction and enforcement activities of the FTC in this context are discussed extensively in Section V.

B. State Oversight

1. Regulation of the Practice of Medicine. To fully and fairly describe the current regulation of assisted reproduction, it is necessary to treat in some detail the regulation of the practice of medicine more generally. The bulk of external governmental regulation of assisted reproduction is subsumed in this more general context. The following requirements apply to the practice of assisted reproduction, and are generally cited by practitioners of ART in support of the proposition that the field is subject to close regulatory scrutiny.

(a) Informed Consent. One of the core principles of ethical medical practice, supported also by legal standards, is the requirement that patients provide their informed consent to medical treatments and procedures. While informed consent is necessary in all medical contexts, it is statutorily required under the federal human subject research regulations and, in most states, is explicitly provided for in the state’s patient’s rights laws.¹²⁸ The doctrine of informed consent has also been long recognized in case law through recognition that treatment without consent constitutes a battery. Even outside of the human subject research context, most all hospitals require written informed consent in circumstances where complicated or risky procedures or treatments are being administered (for example, chemotherapy treatments or surgeries). This is also true where experimental procedures are being utilized in the treatment context. Under such circumstances, the informed consent form is commonly drafted in accordance with the human subject research requirements.

(b) Licensure. The practice of medicine is regulated under state licensing statutes. States regulate the practice of medicine pursuant to their authority to defend the health, safety, and general welfare of the community (the so-called “police power”). Each state has enacted a medical practice act governing the practice of medicine. The model Medical Practice Act (set forth by the Federation of State Medical Boards) defines the practice of medicine quite broadly.^xxii

Persons practicing medicine must be licensed by the state to do so and are subject to the state’s Medical Practice Act and the regulations promulgated by the licensure Board. Licensure boards oversee the initial and continuing licensure of physicians practicing in the state. These Boards are also responsible for disciplining physicians who render incompetent or unprofessional care in violation of applicable regulations and standards. The Federation of State Medical Boards, in cooperation with the National Board of Medical Examiners, creates and administers the required United States Medical Licensing Examination (USMLE).

(c) Registration with DEA. Licensed physicians are required by the Controlled Substances Act¹²⁹ to register with the United States Drug Enforcement Agency if they will be prescribing or dispensing controlled substances. The Controlled Substances Act is a federal criminal statute. DEA registration permits physicians to possess and dispense (prescribe) controlled substances and certain listed chemicals to patients and research subjects to the extent authorized by their registration and in conformity with the Controlled Substances Act and related regulations. There are state law counterparts to the Controlled Substances Act that may impose additional requirements on physicians beyond the federal law.

(d) Hospital Credentialing. Hospitals require physicians to apply for medical staff privileges in order to practice at the hospital. The process for obtaining privileges is often referred to as “credentialing” because it is a method of ensuring a physician has the appropriate credentials prior to granting permission to practice at a hospital. The credentialing process is set forth in a hospital’s medical staff bylaws. At a minimum, initial credentialing includes a lengthy application process including proof and verification of medical education, United States Medical Licensing Examination (USMLE) scores, residency training, all past employment, criminal background checks, and professional recommendations. The hospital’s governing board must approve all credentialing appointments and reappointments (which by Joint Commission on Accreditation of Healthcare Organizations (JCAHO) accreditation standards must be every two years at a minimum), as the hospital is generally considered legally responsible for the acts of its medical staff.

(e) Board Certification. In an effort to ensure that a hospital only has physicians practicing good medicine and providing the “standard of care,” many hospitals now require Board certification in order for a physician to obtain clinical privileges in a specialty or to be granted privileges to perform certain procedures. A hospital’s medical staff bylaws establish this requirement, which is enforced through the credentialing appointment and reappointment process.

(f) National Practitioners Data Bank. The Health Care Quality and Improvement Act¹³⁰ was enacted in 1986 and, among other things, established a national data bank for information on physicians, the National Practitioners Data Bank. This is a national, centralized source of information on physician disciplinary actions related to professional competence or conduct and medical malpractice and settlements. State licensing boards and all licensed hospitals are required to report disciplinary actions to the Data Bank. Hospitals have a statutory duty to request information from the Data Bank upon credentialing a new physician for clinical privileges to practice at the hospital and, at a minimum, every two years for every medical staff member and privileged physician. The Data Bank is not accessible to the public, and is accessible to plaintiff attorneys in only very limited circumstances. This national mechanism helps to prevent a physician found by one state licensing board to be practicing below standard or violating professional standards from continuing to practice medicine legally by moving to another state.

(g) Facility Licensure. The Joint Commission on Accreditation of Healthcare Organizations is a private accrediting body whose standards are voluntary and do not have the force of law. However, the Medicare regulations provide that a hospital’s compliance with JCAHO standards is “deemed compliance” with the Medicare conditions of participation—a requirement for all hospitals participating in the Medicare program (that is, receiving any reimbursement from the government for the provision of health care).¹³¹ As a result, virtually all hospitals in the United States with more than twenty-five beds are JCAHO accredited. These detailed standards cover hospital policy, procedures and operations with respect to several areas including, for example, clinical practice. Facilities delivering health care are regulated by the state within which they are located. Most states have specific standards applicable to licensure of hospitals, clinics, free-standing surgical centers, and other facilities where health care is provided. Note, however, that most states do not require a doctor’s office to be licensed as a health care facility.

(h) Malpractice Insurance Coverage. As part of the credentialing process, hospitals require physicians to meet certain clinical standards in order to obtain and maintain appropriate malpractice insurance. Carriers are increasingly requiring hospitals through contract to mandate specialty training and board certification in order to maintain insurability for certain types of procedures and treatments. Additionally, many states require practicing physicians to maintain minimum levels of malpractice insurance coverage as a condition of licensure.

(i) Disciplinary Proceedings by State Licensure Board. In cases of suspected unprofessional behavior or substandard care, the Board may investigate, hold a hearing and discipline physicians. Discipline actions may include suspension or revocation of licensure. Such actions are reported to the National Practitioners Data Bank.

(j) Medical Malpractice Litigation. A crucial mechanism for the regulation of the practice of medicine is the tort system. Specifically, medical malpractice litigation is the primary tool available to patients who have been harmed by a physician in the delivery of medical services. To sustain a claim for medical malpractice, an injured patient must demonstrate that the defendant breached a duty owed to the patient, and that this breach resulted in harm. A physician breaches his duty to a patient when he provides services that fall below the recognized “standard of care.” Standard of care is defined with respect to all applicable benchmarks, including licensure standards, specialty protocols and standards, and professional codes. The standard of care has been formulated as “professional competence and care customary in similar communities among physicians engaged in the particular field of practice.” This duty attaches once the physician-patient relationship is formed.

In the context of assisted reproduction, there are a number of tort theories that an injured party might rely upon in seeking relief. The most common litigation arising out of the context of assisted reproduction relates to the custody or disposition of untransferred embryos, and the rights and obligations of people standing in direct relation to these embryos. Courts are currently struggling with how to handle such cases, and draw on concepts from family law, constitutional law, and contract/informed consent law to resolve the disputes. Some courts have held that contracts that provide for transferal into a uterus of in vitro embryos are unenforceable as a matter of public policy, as donors of embryos have a right not to be made biological parents against their will.

Medical malpractice, as described above, is another theory under which injured parties seek relief. In vitro fertilization is considered a specialty for purposes of the standard of care. However, courts are sometimes reluctant to entertain claims for harms in this context, to the extent that the harms alleged are to future persons not yet born. Moreover, it is often difficult for claimants to demonstrate that the actions of the clinician proximately caused the harm alleged. For example, when the efforts at assisted reproduction fail it can be difficult to prove that the cause of such failure was the result of the clinician’s negligence rather that the underlying infertility.

Another tort theory on which injured parties might rely in the context of assisted reproduction is wrongful conversion.¹³² This theory has been invoked to sue individuals who have destroyed in vitro embryos without the patients’ consent. In one case, Del Zio v. Presbyterian Hospital, a couple sued a hospital and its chief of Obstetrics and Gynecology for $1.5 million for deliberately destroying the couple’s in vitro embryos prior to implantation. In addition to wrongful conversion, the couple alleged intentional infliction of emotional distress. The jury awarded $50,000 to the wife for emotional distress, and the husband received nominal damages. The jury rejected the couple’s claim for wrongful conversion.

Suits may also be filed for prenatal and even preconception injuries to the unborn child. Many states permit such suits only if the child is born alive. Other states permit such suits only if the child was “viable” at the time of injury. Suits on behalf of children born through assisted reproduction can be brought as wrongful death actions if the child is stillborn or born alive but soon dies thereafter. A majority of states permit the administrator of the estate of an unborn child to recover damages. A more controversial species of suit on behalf of the child is a “wrongful life” claim. This claim alleges that the injury suffered is the child’s life itself or is inextricably bound up with his coming-into-being. Such cases most frequently arise in circumstances in which a physician negligently fails to diagnose prenatally a debilitating disease or disorder. The theory is that if the doctor had complied with the relevant standard of care, the pregnancy would have been terminated and the impaired child would not be presently burdened with the expenses and suffering associated with its current existence. Many courts reject such claims on public policy grounds or on grounds that the law is incapable of comparing, for purposes of calculating damages, the plaintiff’s impaired state with a state of non-existence. Other courts, however, have sustained such claims. A related tort theory, “wrongful birth,” is brought to vindicate the harms suffered by the parents of a child whom they would have aborted if a physician had satisfied his standard of care by performing relevant tests for birth defects. Most states permit a claim for wrongful birth. The damages awarded in such suits are generally for pain, suffering, and expenses incurred as a result of the birth itself, rather than for the very existence of the unwanted child.

Nongovernmental Regulation

I. Safety, Efficacy, and Privacy of ART Patients. The key source of nongovernmental guidance and oversight for the practice of assisted reproduction are the standards propounded by the American Society for Reproductive Medicine, published in conjunction with its sister organization, the Society for Assisted Reproductive Technology. SART clinics must agree to adhere to these guidelines as a condition of membership. SART additionally requires certification of its members’ embryo labs by the College of American Pathologists, JCAHO, or the New York State Tissue Bank program. Moreover, SART requires its members to comply with the reporting provisions of Fertility Clinic Success Rate and Certification Act. According to its website, 95 percent of the assisted reproduction clinics in the nation are SART members.

ASRM provides guidance by means of published practice and ethics committees’ statements, opinions, and guidelines. The chief values ASRM seeks to promote through its opinions and guidelines are safety (of ART participants), efficacy (of techniques and procedures), and privacy (of ART patients). According to ASRM, these documents are framed in a variety of ways:

Some, like the Practice Committee’s “Guidelines for Gamete and Embryo Donation” take the form of a list of considerations to be made or steps to be followed, while others take the form of a survey or review of research on a particular medical topic, i.e., “Aging and Infertility in Women.” Ethics Committee documents are usually framed as a discussion of issues, sometimes leading to a particular conclusion and other times recommending a number of approaches based on different circumstances that can arise. ¹³³

The practice guidance documents provide direction as to minimal standards for IVF (such as personnel requirements, laboratory requirements, quality assurance, and control standards). Specific examples of subjects covered by such documents include guidelines for gamete donation, ICSI, informed consent, induction of ovarian follicles development and ovulation with exogenous gonadatropins, number of embryos transferred, and preimplantation genetic diagnosis. Practice committees also evaluate novel procedures. These committees review the existing literature or randomized clinical trials. If two peer-reviewed published studies show that the risk-benefit ratio is acceptable, the procedure is elevated from “experimental” to “practice.” ICSI has been elevated to practice status in this way, as have PGD and blastocyst transfer.

The ethical guidelines published by ASRM address a number of subjects including advertising, informed consent, and disposition of abandoned embryos. Most are framed in terms of discussions that merely highlight concerns rather than prescribe or proscribe specific courses of conduct among members. However, as ASRM’s president, Dr. Sandra Carson, pointed out in her presentation to the President’s Council in March 2003, ASRM “actively discourages” some procedures on ethical grounds. She gave the examples of PGD for elective sex selection, oocyte donation after natural menopause,^xxiii posthumous reproduction in absence of advanced directives, and cloning for reproduction.

In conjunction with the College of American Pathologists, ASRM has adopted a Reproductive Laboratory Accreditation Program (RLAP). RLAP requires accredited laboratories working with infertility programs to meet minimum standards, submit to onsite inspections (every three years), and complete proficiency testing surveys for evaluating performance. The process is expensive and time consuming.

As mentioned above, in 2003 ASRM and RAND published a study estimating the number of embryos in cryopreservation at 400,000 in 2000. ASRM also collects information on congenital abnormalities of IVF and ICSI births, but this process is non-rigorous and the data is inadequate, according to Dr. Carson. During her presentation, she noted that to undertake a comprehensive and effective study on the association of ART with birth defects would be extremely expensive. It would require neonatalogists, epidemiologists, statisticians, and child development specialists. ASRM has no current plans to undertake such a study. Dr. Carson noted, however, that she believes that there is an ICSI follow-up study in progress.

ASRM committee opinions are advisory and are not formulated as “commandments.” ASRM’s system of professional self regulation is voluntary and there appear to be no penalties for or consequences of noncompliance. SART membership has a number of requirements and conditions, but membership itself is voluntary.

2. Safeguarding Integrity of Profession and Promoting Ethical Practice of Medicine.

(a) Professional Medical Associations. There are numerous professional medical associations that have specific codes of practice or guidelines to which its members agree to adhere. The most notable example is the American Medical Association (AMA) Code of Ethics. This code consists of the Principles of Medical Ethics, which are adopted by the AMA’s House of Delegates, and the Current Opinions of the Council on Ethical and Judicial Affairs, which interpret the principles. The AMA’s Code of Ethics is widely disseminated and has provided the most commonly cited standard for courts, legislatures, administrative agencies, medical boards, and other peer review entities. Most medical societies, and virtually all state medical societies, accept the code as the profession’s code.

The AMA has a specific code regarding assisted reproductive technology ¹³⁴ which states four main principles: (i) The medical profession should continue to develop technical and ethical guidelines including educational materials on clinic-specific success rates; (ii) All fertility labs should participate in credible professional accreditation and should voluntarily adhere to ethical standards. Physicians should report unethical behavior; (iii) Patients should be fully informed of all aspects of ART and payment based on clinical outcome is unacceptable; and (iv) Physicians practicing ART should, in any marketing materials, accurately describe available services, success rates, fee structures, and payment obligations.

The American Board of Obstetrics and Gynecology certifies obstetricians and gynecologists in the United States, and is one of twenty-four specialty boards recognized by the American Board of Medical Specialties. New certificates and maintenance of certification certificates issued by the American Board of Obstetrics and Gynecology are valid for six years.

ABOG has a Division of Reproductive Endocrinology and Infertility. A reproductive endocrinologist is a sub-specialist in obstetrics and gynecology who is capable of managing complex problems relating to reproductive endocrinology and infertility, and whose current professional activity involves the practice of reproductive endocrinology in a setting wherein essential diagnostic and therapeutic resources are available and being used appropriately. The stated objectives of this Division is to promote health care in this field, help maintain professional standards, and establish standards and procedures for candidates for this specialization.

The American Academy of Pediatrics also has stated positions that relate to the practice of assisted reproduction, albeit in an attenuated way. AAP does not consider an in vitro embryo a “person” or a pediatric patient. However, one AAP statement entitled “Ethical considerations in Fetal Therapy”¹³⁵ indicates that with recent advances in prenatal medicine, the pregnant woman and her fetus are increasingly viewed as two treatable patients.

Conclusion

How well does the current regulatory landscape address the various relevant ethical concerns noted above? The current regulatory landscape is a patchwork, with authority divided among numerous sources of oversight. A first question might be whether such a system of regulation, involving a plurality of sources, is well-suited to address the concerns. To the extent that the harms are sufficiently grave and commonly recognized, one might be better off with a uniform rather than a patchwork system. On the other hand, to the extent that the ethical concerns reflect matters of personal morality and autonomy, a system of diverse or decentralized regulation might be preferable.

The current system of regulation of assisted reproduction is diverse not merely in terms of its sources of authority, but also in the regulatory mechanisms brought to bear on practitioners and participants. Such mechanisms fall at every point on the regulatory spectrum, from criminal enforcement by the federal government to hortatory and merely aspirational statements of policy by professional organizations.

The objectives of current direct federal oversight of ART are consumer protection and quality assurance for embryo laboratories. While these are important goals, they do not aim directly at the ethical concerns described above. The objectives of analogous state regulation vary widely, including access to infertility services, policing rogue clinicians, providing standards for donors of human tissue, parental rights and obligations, protecting nascent human life, quality assurance for practitioners of ART, and protecting consumers in the context of ART. Although some of these state regulations do, in fact, aim at the same ethical concerns animating this inquiry, there is a marked lack of uniformity.

Indirect federal oversight of assisted reproduction aims principally at safety and efficacy of products for their approved uses and defense of the public against communicable disease (FDA). However, this chiefly provides regulation of manufacturers and developers of products, and does not reach off-label use in the practice of medicine. Moreover, because the FDA’s authority is based largely on the definitions of the articles it regulates, reaching ART requires some troubling re-definition of aspects of human procreation (for example, declaring the human embryo transferred to a womb to be a “drug”). Finally, FDA lacks the mandate and institutional competence to make decisions about moral and ethical concerns akin to those at the heart of this inquiry; even securing the health and well-being of the children born as a result of using ART is not within FDA’s jurisdiction.

The application of CLIA, ensuring quality control in diagnostic clinical laboratories, to ART labs is minor—applying only to andrology and endocrinology diagnostic activities when performed for the sake of themselves; CLIA is inapplicable when these tests are performed as an adjunct to the provision of ART services. The FTC’s oversight of truth in advertising and competition may promote better informed consent by ART patients. But it does not go so far as to govern the sorts of risks to which these individuals may be exposed.

The regulation of the practice of medicine by states aims at safety of some ART participants, but seems to neglect the remaining ethical concerns for the child-to-be, family structure, and the use and destruction of nascent human life. Another mechanism of indirect regulation, namely, the tort system, is driven by a concern for the rights and interests of injured parties. The definitions of duty, breach, causation, and injury in the context of assisted reproduction make this a problematic source of regulation. While the tort system does regulate assisted reproduction in ways that implicate the ethical concerns raised above, it is doubtful whether an adversarial process that reduces questions of procreation to theories of torts and contracts is adequate and fitting for the profound human goods at stake.

Nongovernmental regulation by ASRM is chiefly focused on the safety, efficacy, and privacy of participants in the ART process. ASRM provides practice guidelines and ethical opinions to promote these values. As a procedural matter, the enforceability of these guidelines is very weak. Indeed, one might argue that the standards are merely hortatory and aspirational—evidenced by the fact that one prominent member of SART openly advertises a service that ASRM “actively discourages” on ethical grounds (PGD for elective sex selection). As a substantive matter, the guidelines provide no affirmative protection for the well being of children-to-be, relying instead on the prospective parents to safeguard these interests. This is certainly the norm in most situations involving the delivery of medical care to children. In such cases, however, the controlling criterion is the best interests of the patient, namely, the sick child. By contrast, in ART, the patient is the infertile individual and his or her interests are paramount. It is not necessarily the case that the best interests of the ART patient and the child-to-be are co-extensive. Thus, using the interests of the infertile individual as a proxy for those of the child-to-be is potentially problematic. The ASRM guidelines make no allowance for any potential conflict of interest in this regard.

ASRM’s chief animating principles, namely, safety, efficacy, and privacy are neutral toward all other relevant values. They are not oriented towards concerns arising out of the new control over procreation conferred by the new powers discussed above.

Finally, indirect regulation by professional medical associations aims generally at the well being of patients in the physician’s care. Yet, the AMA’s guidelines relating to ART do not seem calculated to meet the ethical concerns raised above. The same could be said of ABOG’s guidelines. The AAP guidelines seem to suggest that the child-to-be and the mother may both be patients and thus entitled to all the attendant duties and obligations of care. They do not seem to take a position on the structure of the human family. Such guidelines do not seem to reflect in a concern for the use and destruction of nascent human life outside the body.

All of the foregoing professional society guidelines have limited mechanisms of enforcement, and rely primarily on the good will of practitioners. For most ethical matters of concern to this Council, beginning with the well-being of children, well-developed practices of monitoring, data collection, or investigation are essentially nonexistent.

II. POWER TO SCREEN AND SELECT FOR
GENETIC CONDITIONS AND TRAITS

The power to screen developing human beings for chromosomal abnormalities and genetic conditions and traits has been with us for some time. The older means of such testing include the in utero testing of the fetus, either through the genetic analysis of cells obtained from the amniotic fluid by amniocentesis (in the second trimester) or through genetic analysis of chorionic villus samples obtained from the placenta by biopsy (in the first trimester). The “selection” that follows such testing is achieved by means of abortion; it is purely “negative,” a process of “weeding out.” More recently, however, innovations in assisted reproduction and molecular genetics have conferred new powers to test early-stage IVF embryos in vitro for genetic markers and characteristics. Only those embryos that pass the test are transferred to initiate a pregnancy; in contrast to the older form of screening, this approach is genuinely and “positively” selective, the practice of “choosing in,” not of “weeding out.” The following discussion focuses on preimplantation genetic diagnosis and sperm sorting.

Uses and Techniques

Preimplantation Genetic Diagnosis of Embryos

Preimplantation genetic diagnosis (PGD) is a technique that permits clinicians to analyze embryos in vitro for certain traits or markers, and select accordingly for purposes of transfer. PGD is practiced in approximately fifty clinics worldwide, the majority of them located in the United States. Approximately 6,000 cases of PGD have been carried out with human embryos since its development in the late 1980s.¹³⁶ PGD was first used in 1989.¹³⁷ Since then, roughly 2,000 babies have been born using this technique.¹³⁸ PGD was initially used for sex identification to avoid transfer of embryos with X-linked genetic diseases such as Lesch Nyhan syndrome, hemophilia, and X-linked mental retardation. PGD is now most commonly used to detect aneuploidies (an abnormal number of chromosomes, for example, trisomies and monosomies) in embryos.¹⁴⁰ Some aneuploidies prevent implantation, whereas others are associated with disorders such as Down’s syndrome and Turner’s syndrome. PGD is also used to detect monogeneic diseases such as cystic fibrosis and Tay-Sachs disease. More recently, PGD has been used to select embryos that would make the resulting child a compatible tissue donor for an older sibling in need of a transplant. In still other instances, PGD has been used for elective (non-medical) sex selection.

At present, PGD can identify genetic markers associated with more than one hundred diseases, including diseases such as early onset Alzheimer’s.¹⁴¹ As genomic knowledge increases and more genes are identified that correlate with diseases, the applications for PGD will likely increase greatly. Dr. Francis Collins, director of the National Human Genome Research Institute, recently speculated that within five to seven years the major contributing genes for diabetes, heart disease, cancer, mental illness, Parkinson’s, stroke, and asthma will be identified.¹⁴² Many couples with family histories for these diseases may be attracted by PGD, even in the absence of infertility. Moreover, as the genetic associations with other, non-medical conditions are identified, PGD may be used to screen for positive traits and characteristics such as height, leanness, or temperament.^xxiv One clinician recently predicted that PGD will soon be as common as amniocentesis.

PGD is a multi-step process that requires a high degree of technical skill and expertise in the fields of genetics and reproductive medicine. Because the testing is performed on early embryos in vitro, individuals electing to use PGD must undergo all of the phases of IVF described in Section I above.^xxv At least one-third of individuals who use PGD are otherwise fertile.¹⁴³ Typically, three days following fertilization, when the embryo is at the six to eight cell stage, the researcher makes a small hole in the zona pellucida using a sharp pipette, acidic solution, or laser. He inserts a suction pipette into the opening and removes one or two cells (“blastomeres”). These blastomeres are then analyzed by means described below. Some researchers wait until the embryo reaches the blastocyst stage (approximately five to six days after fertilization, approximately one hundred cells) to undertake this biopsy procedure. This is technically less demanding, and more cells can be removed and analyzed. Here, the researcher removes approximately ten cells from the trophectoderm (the blastocyst’s outer ring of cells that are the precursors of the fetal portion of the placenta).

Once collected, the blastomeres or trophectoderm cells can be analyzed by a variety of means, depending on the purpose of the test. PGD for detection of monogeneic diseases is performed using a technique called “polymerase chain reaction” (PCR). PGD for sex identification and chromosomal abnormalities is performed using a technique called fluorescence in situ hybridization (FISH). PCR allows the clinician to amplify sections of the DNA sequence such that he can then identify specific gene mutations. In FISH, labeled markers bind to chromosomes permitting the researcher to observe and enumerate such chromosomes. New innovations (such as comparative genomic hybridization and whole chromosome amplification) allow researchers using FISH to visualize all forty-six chromosomes and compare a particular embryo’s genome with a normal reference sample.
Following transfer of selected embryos and initiation of pregnancy, clinicians routinely follow up with chorionic villus sampling and amniocentesis to confirm the results of PGD.

Timing is critical. The clinician must complete his analysis before the embryo develops beyond the stage at which it can be successfully transferred. If the biopsy is performed on Day 3, the practitioner has approximately forty-eight hours in which to complete his analysis, verify results, and discuss options with the parent or parents.

The error rate for PGD has been estimated between 1 to 10 percent, depending on the assay used.¹⁴⁴ Several technical difficulties may compromise accuracy. Working with such a limited number of cells—in many cases only one or two—leaves little room for technical error. PCR can be problematic. In some instances, one allele fails to amplify to a detectable level. This phenomenon is called “allele dropout” and can lead to misdiagnosis. Contamination of the PGD sample can also lead to misdiagnosis. Technical difficulties associated with FISH may also effect accuracy of diagnosis, including background staining, signal overlap, weak signals, split spots, and loss of nuclei when spreading single blastomeres.

Genetic Analysis of Gametes

In addition to tests of early embryos, some efforts are being made to test and screen gametes—ova and sperm—prior to fertilization.

Preimplantation Genetic Diagnosis of Ova. As an alternative to embryonic PGD, clinicians can perform a similar analysis on the oocyte. Specifically, clinicians can test DNA from the polar bodies—protrusions that are ultimately shed from the maturing oocyte.¹⁴⁵ Once acquired, PCR or FISH can be applied to test for, respectively, monogeneic diseases or chromosomal abnormalities (most aneuploidies are maternally derived). The utility of polar body analysis is limited, however, in that it only reveals the maternal contribution to the child’s genotype.

Sperm Selection. Another form of gamete screening is sperm sorting. There are a number of techniques, all of which are aimed at controlling the sex of the child ultimately conceived from these gametes. Most techniques aimed at sperm sorting have proved unreliable. These have included albumin gradients, percoll gradients, sephadex columns and modified swim-up techniques. One technique—called MICROSORT—has proven more successful. This technique is based on the difference in total DNA content between x-containing (female-producing) sperm and y-containing (male-producing) sperm. The researcher collects the sperm sample and stains it with a fluorescent dye, bisbenzimide, which binds to the DNA in each sperm. A female-producing sperm shines brighter because it has 2.8 percent more DNA than the androgenic sperm, given the difference in size between the X and Y chromosome. The researcher then sorts the sperm into X-bearing and Y-bearing preparations. The appropriate preparation is selected according to the couple’s preference and used to inseminate the woman. The latest statistics report a 90 percent success rate for conceiving female children, and 72 percent success for conceiving male children.

Ethical Concerns

IVF-Related Concerns

IVF, and arguably ICSI, are prerequisites to the practice of PGD. Thus, all of the ethical concerns attending these techniques of assisted reproduction discussed in Section I above are likewise concerns here. These concerns may be amplified by the fact that some individuals who do and will increasingly choose PGD are otherwise fertile (though some have histories of genetic disease) and would not otherwise be subject to the risks and concerns inherent in IVF. In what follows, we shall confine our attention to new issues raised by the fact of genetic selection. (Some of these issues may overlap those raised by the established practice of prenatal diagnosis.)

Well-being of Children-to-Be

There are as yet no comprehensive studies on the effects of PGD on the physical well being of those involved. Specific concerns have been raised about the unknown effects that the process of PGD, particularly embryo biopsy, may have on the development of the child-to-be.¹⁴⁶ Some prospective studies are currently underway in Europe, but it is unclear how well funded or comprehensive they will be.

Increased Control over the Character of Children

The new ethical concerns arise out of the increased new power PGD appears to confer on parents to select the genetic makeup of their children. Yet at least for now, the power is very limited. Current technical limitations on the number of embryos that can be produced in a single PGD cycle and on the number of tests that can be performed on a single blastomere severely restrict the number of characteristics for which practitioners can now test. Similarly, the complexity of the relationship between identifiable single genes and phenotypic characteristics will complicate the development of genetic tests for many traits and characteristics of interest (for example, where traits have polygenic contributions or result from complex gene-environmental interactions). Thus, the capacity to use PGD to select for a largely predictable phenotype—a “designer baby”—is not on the horizon.

Nevertheless, within the present applications of PGD—selection for medical conditions, elective sex selection, and for creating a matching tissue donor—there is still some cause for ethical concern about the impact on children. PGD used for these purposes might instrumentalize the child as a means to the parents’ ends. This concern is amplified as the reasons for embryo screening move from “medical” purposes to non-medical or enhancement purposes, from prevention of disease to the improvement of the given (though this line is, admittedly, hard to draw). Because the child-to-be is deliberately selected out of a pool of possible embryonic siblings, PGD—even more than pre-natal diagnosis and abortion—normalizes the idea that a child’s particular genetic make-up is quite properly an extension of parental reproductive choice. PGD could thus lead to “consumeristic” thinking and practice regarding procreation, where children are seen and selected according to certain specifications. Children may experience increased pressures to meet parental expectations, especially in those cases in which selection has been on non-medical grounds (such as elective sex selection or trait selection).

The use of PGD to identify a prospective child as a tissue donor match poses a unique ethical concern: the deliberate creation and selection of a child as a means for the benefit of another. It is, of course, likely that in most families such children would be loved by their parents and by the siblings who would benefit directly from their tissue donation. But even here there is a dramatic shift in how the new PGD-selected donor-child is conceived and regarded by the parents and family. Is it proper to assign to an unconceived child the burden of being a savior of his sibling, and then give him life on condition that he fulfill that role? Some of these children may be viewed as mere means rather than as ends, and may suffer in the event that the transplant fails.

A closely related ethical concern is that this sort of selection could actually reduce the scope of reproductive choice. As the aggregate effect of parental choices reshape society’s understanding of “normal” or “acceptable” phenotypes, women might feel social pressures to undergo PGD. In addition, women might feel pressured to use PGD for financial reasons; it is conceivable that HMOs or health plans might someday require PGD for selection against certain potentially costly diseases. In some ways women’s reproductive choices may actually be narrowed by PGD.

PGD for Late Onset Disease

PGD can be used not only to identify diseases likely present in the embryo at the time of testing, but may also be used to identify susceptibility to disease or a late-onset disease. Is PGD justified to avoid the birth of a child who will live only thirty years? Is it justified to avoid the birth of a child who is especially susceptible to a late-onset disease like breast cancer?

Eugenics and Inequality

For some critics, PGD calls to mind the specter of eugenics, seeing as it is a technology that facilitates the selection of the “best” children. Some worry that as PGD becomes more widespread, its use will serve to further stigmatize the disabled and promote the notion that some lives are not worth living. Such concerns are already raised by the more widespread practice of pre-natal diagnosis. This is nothing new—the use of amniocentesis and pre-natal diagnosis is common. A eugenic mentality, if not an actual eugenic practice, will be augmented to the extent that PGD can be used to select for desirable traits, not just against the markers for disease. Some commentators additionally worry that widespread use of PGD (so long as it is not covered by insurance or subsidized by taxpayers) could create an even greater and more significant gap between the “haves” and the “have nots” in society, as access to PGD is restricted to those who can afford it.

Reductionist View of Human Condition

An additional concern about the widespread use of PGD (and other genetic screening) is that it promotes an excessively reductionist view of the human condition. It may lend credence to the notion that human characteristics and conditions can be explained and understood as genetically determined—a too-narrow understanding of human freedom, agency, and experience, and even of biology.

Regulation

There is currently no direct regulation of either PGD or sperm sorting as such. There are, however, sources of regulation, described below, that touch these practices to some extent.

Federal Regulation

CLIA, the Clinical Laboratory Improvement Act, which as noted previously regulates laboratories that perform diagnostic tests for health assessment on human specimens, does not apply to tests performed in the context of IVF, and it does not cover tests performed merely for purposes of research. Because these are the contexts in which PGD and related techniques for selection are practiced, the provisions of CLIA are inapplicable. If, in the future, CLIA were deemed applicable to PGD and related activities, it would function to ensure quality assurance and control, as described in Section I above.

Similarly, the FDA has a limited role in the regulation of PGD and related activities. The FDA governs any articles that may be used in these activities, ensuring that they are safe and effective for their intended uses. Specifically, the FDA regulates as devices any test kits that are manufactured and sold for purposes of genetic testing. However, it seems that there are no such kits for PGD or the related activities discussed above. Most labs use assays that they develop themselves. The FDA has the authority to regulate as medical devices certain “analyte specific reagents” (ASRs). FDA imposes labeling and manufacturing requirements (for example, good manufacturing practices) on ASRs, but does not subject them to pre-market approval.

To the extent that PGD and related activities occur in the research setting, they may be subject to the human subjects protections discussed in Section IV below (IRB approval, informed consent, etc.). That is, under certain circumstances, the donors of embryos or reproductive tissue for such experiments will be considered “human subjects” and protected accordingly.

State Laws

There are presently no state laws that directly govern PGD or related practices. Some statutes that govern embryo research may reach these activities, as discussed in Section IV below. In the main, however, there is no significant state regulation.

Tort Litigation

Just as in the context of ART, individuals can use litigation as a means of regulating the practice of PGD and related activities. To prevail on a theory of malpractice, a plaintiff would have to demonstrate that a clinician owed a duty to the plaintiff, which he breached resulting in injury. The viability of tort claims as an effective regulatory mechanism remains to be seen, though one might imagine the difficulties inherent in demonstrating causation and harm. There seem to be only two reported cases in which malpractice suits were brought against practitioners of PGD for negligence and fraud. In one such case, Paretta v. Medical Offices for Human Reproduction¹⁴⁷, a couple sued an IVF clinician for medical malpractice for his failure to perform PGD on an embryo to test for cystic fibrosis, where he knew that the ova donor was a carrier for the disease. The defendant moved for summary judgment (that is, a ruling from the court that in light of undisputed material facts, the defendant is entitled to judgment in his favor as a matter of law). The Court held that a right of recovery did not exist for the child’s birth with cystic fibrosis or for the parents for emotional distress, because to rule otherwise would “give children conceived with technology more rights and expectations than those conceived without such assistance ...” However, the Court ruled that a right of recovery did exist for the monetary expenses incurred for the infant’s treatment and care. Remaining questions such as whether the clinician was grossly negligent or fraudulent “in failing to prevent patient and her husband from bearing a child, conceived through in-vitro fertilization, that had cystic fibrosis” involved disputes of important facts that could not be resolved in the context of a motion for summary judgment. The Court refused to rule out, however, the possibility that, if successful, the plaintiffs might ultimately be entitled to monetary losses resulting from the mother’s decision to stay home to provide special care to the sick child.

Professional Self Regulation

The chief source of guidance and regulation for the practice of PGD and related activities grows out of the guidelines propounded by professional societies. ASRM provides guidance to clinicians who practice PGD and related activities. Its Practice Committee has published an extensive guideline on the practice of PGD, indicating that it should be treated as a clinical (rather than experimental) procedure.^xxvi Thus, it may be practiced without oversight by an IRB or the substantial equivalent. Additionally, the Ethics Committee of ASRM has published a report entitled “Sex Selection and PGD”¹⁴⁸ that deems sex selection in this context as ethically acceptable for medical indications, but discourages purely elective use on the grounds that it might promote gender discrimination and other harms. It is not clear what is meant by the injunction to “actively discourage” this use, but it is instructive that there are SART member clinics that presently advertise this application of PGD, even though as the reader will recall, SART requires, as a condition for membership, adherence to ASRM guidelines, including Ethics Opinions. A related ASRM Ethics Opinion entitled “Preconception Gender Selection for Nonmedical Reasons”¹⁴⁹ deals with sperm sorting for sex selection. It discusses the same ethical concerns as in “Sex Selection and PGD,” but reasons to a different conclusion, namely, that such practices (achieved through techniques such as MICROSORT) are ethically acceptable, provided couples understand the risks and affirm that they will accept a child of the opposite sex, should the procedure fail. ASRM notes, however, that the techniques for preconception sex selection are experimental, and should be treated accordingly. The American College of Obstetricians and Gynecologists echoes the views of ASRM, declaring PGD for sex selection acceptable if it is for medical indications, but rejects as unethical its use for purely elective purposes. The American Medical Association’s Code of Medical Ethics seems to go even further than ACOG or ASRM, and explicitly states that it is “unethical to engage in selection on the basis of non-disease related characteristics or traits.” None of these opinions have more that exhortatory power. In the absence of public policy governing the permissible uses of sex control of children, this laissez-faire situation makes it likely that a small number of medical specialists will render this practice acceptable simply by doing it without any adverse consequences or public reaction.

The American College of Medical Genetics provides voluntary guidelines for quality control and quality assurance of laboratories performing genetic testing. However, it does not regulate PGD or related activities as such.

Conclusion

While currently a small practice, PGD is a momentous development. It represents the first fusion of genomics and assisted reproduction—effectively opening the door to the genetic shaping of offspring. It is striking that this new power arrived with little fanfare—slipping into routine practice essentially unmonitored, unstudied, and unregulated. There is presently no governmental body (state or federal) exercising monitoring or regulatory authority over the use of PGD.^xxvii There are no regulatory efforts to address the well-being of children born after PGD or to assess the risks to them presented by embryo biopsy. There are practice guidelines issued by professional societies on the use of PGD for elective sex selection, but these are aspirational statements rather than enforced standards.^xxviii There are also no governmental or nongovernmental guidelines regarding the boundary between using PGD for producing a disease-free child and using it for so-called enhancement purposes or to produce siblings for children needing transplant donors.

III. POWER TO MODIFY TRAITS AND CHARACTERISTICS

Advances in molecular biology and increases in genomic knowledge have begun to raise the possibility that scientists may soon acquire the power not merely to screen and select embryos (or gametes) for particular traits and characteristics, but also to modify and engineer them. Should this power arrive, it would provide greatly increased control over the character of future generations. Such power could, in principle, be used both to treat genetic abnormalities and to try to “enhance” the “normal.” The following section will discuss this new power, including the techniques and practices that may soon confer it, the ethical questions that would likely arise as a result, and the current state of regulation.

Techniques and Practices

Currently, genetic modification of human embryos is purely hypothetical. Possible means of effecting such interventions seem to be limited to two techniques: direct genetic modification of a developing embryo through gene transfer (insertion of genetic material in cells to repair or replace defective genes), or indirect, prospective genetic modification of an embryo not yet conceived through genetic changes made in the progenitor’s gametes. Both are discussed below.

Human gene transfer is the process by which a DNA sequence containing a functional gene is inserted and integrated into human cells, resulting in the expression of a gene product. This transfer is achieved by means of a “vector”—usually a modified virus that penetrates the targeted cells and incorporates the new genetic information in a stable way. There are two broad categories of human gene transfer, which are defined according to which cells are modified. “Somatic gene transfer” is the delivery of genes to the differentiated cells of the body, with the effects of genetic modification in principle limited to the individual who receives the new DNA sequence. By contrast “germ line gene transfer” refers to a delivery of genes that ultimately affect the reproductive cells, thus causing a genetic modification that is heritable.^xxix

In the human context, somatic gene transfer is presently being developed solely for therapeutic purposes (“gene therapy”), in an effort to correct genetic abnormalities or cure genetic diseases. The first such effort was undertaken by researchers at NIH in 1990 to treat a young woman with severe combined immunodeficiency syndrome (SCIDS).¹⁵⁰ Currently, there are more than 500 gene transfer research protocols under development.¹⁵¹ All of these protocols are limited to genetic modification of somatic cells. While some people have suggested that germ line gene transfer might be a useful means of preventing the transmission of genetic abnormalities to offspring, there are currently no protocols for such treatment in humans.

Several experimental methods of germ line modification are, however, being studied in animals, and not only for the treatment of genetic disease. One method, using mouse embryos, employs gene transfer into the fertilized ovum. This has the impact of modifying all of the cells of the developing embryo, including the reproductive cells. In research to date, the resulting offspring expressed the new genetic information in variable ways—many of which have resulted in harmful abnormalities.¹⁵² Those offspring that express the new genetic materials in the desired manner are bred to produce a line containing the new genetic character. This approach has succeeded in primates.¹⁵³ An alternative method, currently in the very early stages of development, effects inheritable genetic modification by inserting an artificial chromosome that carries new genetic information into the reproductive cells of the recipient animal.¹⁵⁴ Yet another alternative of effecting inheritable (albeit less controlled) genetic modification, previously discussed, is by means of oocyte nuclear transplantation or ooplasm transfer. In each of these instances, modification of the ova immediately prior to fertilization (either by reinforcing with donor cytoplasm or replacing the nucleus) ultimately gives rise to a child receiving a genetic contribution from at least three individuals that can then be passed on to future generations.

Two principal obstacles to the safe and effective use of gene transfer (in children or adults) are the difficulty of controlling the exact locations in the host DNA into which new genetic information is incorporated and the extent to which the new genes are properly expressed (without inducing other unwanted gene expression). Unintended and unforeseen genetic expression has been responsible for the development of leukemia in two French boys participating in clinical trials investigating gene transfer for SCIDS.¹⁵⁵ These difficulties are amplified in the context of modifying the germ line. The practitioner must contend not only with difficulties of placement and function of the new gene in the recipient. He must also try to anticipate and control these effects for the future generations who will inherit the genetic change. For these reasons, germ line gene transfer in human beings is risky, and unintentional germ line modification is a danger to be avoided.
The problem of controlling placement and gene expression would be greater in the hypothetical case of gene modification of embryos. There are presently no effective means of ensuring the appropriate distribution, levels, or timing of expression of an inserted gene in an embryo. The risks of germ line gene modification in this context would be profound.

Ethical Concerns

Many of the ethical concerns raised by the potential new powers to modify and engineer specific traits or characteristics in developing human beings are much the same as those discussed in Section II, namely, concerns relating to effects on procreation and family, attitudes toward children, possible effects on human capacities and human nature, potential eugenic applications, commodification, discrimination, and the promotion of a reductionist view of the human condition. However, this new power brings with it certain unique concerns and amplifies the concerns previously discussed. These distinct concerns are discussed briefly below.

Safety of Embryonic Genetic Modification

There are presently no safe and effective means of genetic modification of early embryos. For reasons described above, direct gene transfer into an embryo is unpredictable—there is no reliable way to control the insertion, function, and heritability of the new genetic information.^xxx There is no reliable way to guarantee that the gene will express itself in the intended way. Similarly, there is no reliable way to prevent the gene from expressing itself (or triggering other genetic expressions) in an adverse manner. Prospective genetic modification of offspring by germ line gene transfer to the parents (or to isolated ovum and sperm) is equally, if not more, problematic, given that the effects of the gene insertion are even more attenuated (by the vagaries of sexual recombination) and thus less controllable. This problem is aggravated by the fact that harms resulting from germ line gene modification may not be apparent for generations.^xxxi There is widespread agreement in the scientific community that genetic modification of human embryos or gametes is not presently safe.

Enhanced Control over Children

The possible future creation of children with specific genetic characteristics raises the same ethical concerns as do genetic screening and selection, but is distinct in some noteworthy respects. A child who is created to certain specifications is more of an artifact than a child who is merely selected for his or her existing characteristics. In this way, genetic modification of developing human beings, should it become feasible, holds the potential to complete the transformation of the reproductive process from procreation to manufacture. Moreover, genetic modification raises unique questions relating to consent. Is it acceptable for parents to bind their children, and possibly future generations, to a particular genetic fate of their choosing and design?

Human Capacities and Human Nature

Potential genetic modification of developing human embryos, should it ever become safe, would present unique new possibilities and thus ethical concerns, not only with regard to treatment of disease but also for improving human capacities and thus human nature. It bears reiterating that “designer babies” and “super babies” are not likely in the foreseeable future, and even introduction into embryos of any specific genes seeking modest improvements are, as already indicated, not now feasible or safe. That said, the possibilities for enhancement are more acutely presented in the context of modification than in selection. One would not be confined to picking the best available—one might be able to pick the best possible. Present capacities for enhancement of children and adults through somatic gene transfer can have significant effects on strength, endurance, and performance of muscles. As genomic knowledge increases, and as our ability to effect enhancement through somatic genetic modification, we might eventually learn also how to engineer traits and characteristics in developing embryos. Should this happen, this would no doubt be of considerable ethical importance for individuals, family, and society.

Current Regulation

There is currently no regulation specifically governing attempts at genetic modification of early embryos, perhaps because no one is presently engaged in such activity. The extensive federal regulations on gene transfer research, however, are sufficiently broad to cover any such activities. There is no state regulation of genetic modification. There have been instances of individuals using tort litigation as a means of bringing regulatory pressure to bear on the practice of genetic modification, but this is a relatively new phenomenon.

Federal Regulation of Gene Transfer Research

There are two principal sources of federal regulation of gene transfer research: the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). The long and complicated history of the roles played by these institutions in the regulation of gene transfer research need not be recited here, but the ultimate result is that FDA has chief responsibility for ensuring that not only all gene transfer products but also all gene transfer research protocols are safe and effective. NIH, by contrast, provides more limited oversight through its Recombinant DNA Advisory Committee (RAC), which considers the ethical implications of, and offers advice to the NIH Director about, novel gene transfer research protocols that have some funding connection with NIH.

FDA oversight. No gene therapy products are currently approved for use in human beings. Accordingly, any transfer to a human subject of products which introduce genetic material into the body to replace faulty or missing genetic material for the treatment or cure of disease constitutes a gene transfer clinical trial, requiring prior approval by the FDA.^xxxii“Gene therapy products” include biologically based articles, such as a subject’s own cells that have been extracted and modified outside the body prior to re-transfer into the human subject, or articles (natural or synthetic) that are directly transferred to the human subject with the intention of genetically altering his or her cells.

FDA has asserted authority over gene transfer regarding it as an extension of its powers to regulate biologics, drugs, and devices under the federal Food Drug and Cosmetic Act and Public Health Service Act. FDA claimed this authority as early as 1984, when it issued a policy statement noting that “nucleic acids used for human gene transfer research trials will be subject to the same requirements as other biological drugs.¹⁵⁶ Since that time, FDA has provided guidance to industry through a series of informational publications. One such guidance document issuing comprehensive direction as to technical and safety requirements was issued in 1998.¹⁵⁷ It included advice on matters such as preclinical safety data, molecular sequence of gene vectors, characterization of cell lines used in vectors, and the long term monitoring of health of human subjects.¹⁵⁸

The most comprehensive articulation of FDA’s authority to regulate in this area came in the form of a Federal Register notice in 1993.¹⁵⁹ Gene therapy products are defined as those articles that “contain genetic materials administered to modify or manipulate the expression of genetic material or to alter the biological properties of living cells.”¹⁶⁰ These are products subject to the licensing, false labeling, and misbranding provisions for biologics (under PHSA¹⁶¹ ) and drugs under the (FDCA^xxxiii ). In the case of gene transfer, the product in question will fall into one or both categories, depending on whether it is of synthetic or biological origin. The biological products that are the source materials for gene transfer are also subject to the aforementioned licensing requirements. The FDA additionally claims jurisdiction to regulate gene therapy products pursuant to its authority to prevent the interstate spread of communicable disease under Section 361 of the PHSA.

Given their status as biologics and drugs, manufacturers and developers of gene therapies must apply for a premarket approval in the form of a Biologics License Application (BLA), in the case of biologics, or a New Drug Application (NDA), in the case of drugs.¹⁶² To qualify for such a license, manufacturers of gene therapy products must provide the FDA with voluminous information demonstrating safety, purity, and potency.¹⁶³ Additionally, as described in previous sections, FDA requires such manufacturers to test the gene therapy products in human subjects in a clinical trial. A clinical trial, however, may be initiated only after the issuance of an Investigational New Drug Application. The IND requires the sponsor to explain to the FDA the nature of the study, the risks to the human subjects, the relevant human subject protections in place (including IRB approval), and the data supporting the study.¹⁶⁴

As discussed previously in Section I, FDA has exercised its authority over gene therapy products in a high profile way in the context of assisted reproduction. Upon learning of the efforts of clinicians at St. Barnabas Hospital in New Jersey to perform ooplasm transfer, FDA asserted its authority on the grounds that such activities constituted unauthorized clinical trials in gene transfer. Thus, FDA informed St. Barnabas that it must halt all such activity and submit an IND seeking permission.

Since the death in 1999 of Jesse Gelsinger, a young man participating in a gene transfer clinical trial for ornithine transcarbamylase deficiency (OTC), FDA has increased its vigilance in this context. It has instituted the “Gene Therapy Trial Monitoring Program,” whereby sponsors of clinical trials are required to designate independent monitors who are supervised by FDA. Additionally, FDA issued a “Dear Sponsor” letter to all IND sponsors requesting that they include detailed information in their IND applications regarding products used in the manufacture and testing of gene therapy products, and evidence of quality control mechanisms. Additionally, FDA officially promised to advise NIH’s Office of Biotechnology Activities of any alterations in gene transfer research protocols. In January 2003, FDA ordered a temporary halt to all gene transfer research trials using retroviral vectors and blood stem cells.

As of 2000, FDA was overseeing more than 200 gene transfer research clinical trials.¹⁶⁵ None involve germ line gene modification, for it cannot presently be undertaken in a manner sufficiently safe and effective to satisfy the IND requirement. Indeed, any gene transfer research protocol that carries a serious risk even of inadvertent germ line modification is unlikely to meet IND requirements. Although one might think that the proscription on germ line modification exists for the benefit of the unconceived children-to-be, FDA actually has no authority to consider the safety of future generations; its justification for treating germ line therapy with such caution is framed entirely in terms of safety, efficacy, and the protection of human subjects in clinical trials.

NIH/RAC Oversight. NIH is the “major funder of human gene transfer research and the basic science that underpins it.”¹⁶⁶ As such, it shares with FDA some responsibility for oversight of gene transfer research. Any project funded by NIH, or conducted at an institution that receives NIH funding for recombinant DNA research, is subject to NIH approval. NIH also accepts and reviews protocols from researchers who voluntarily submit them, regardless of funding source. The approval process itself is directed at consideration of the ethical, scientific, and safety dimensions of each protocol. The operative document that governs this process is the NIH Guidelines for Research Involving Recombinant DNA Molecules, which provides the standards for researchers to follow to ensure safety and safe handling of the articles used and derived in such research. The NIH Guidelines additionally provide the requirements for institutional oversight by the Institutional Biosafety Committees (IBC) and the Recombinant DNA Advisory Committee (RAC). The NIH Guidelines also provide extensive guidance to researchers on the standards and procedures for the conduct of their clinical trials.¹⁶⁷

Researchers submit their materials to NIH’s Office of Biotechnology Affairs (OBA). These materials include a cover letter that, among other things, identifies the Intentional Biosafety Committees and IRB at the proposed clinical trial site; acknowledges that no research participant will be enrolled until RAC review is complete and IBC, IRB, and other regulatory approvals have been obtained; a scientific abstract; non-technical abstract; the proposed clinical protocol, including tables, figures, and relevant manuscripts; the proposed informed consent forms; and the curriculum vitae of the principal investigator. Additionally, researchers must respond to a series of questions listed in the NIH Guidelines about the objective and rationale of the proposed project, and questions relating to informed consent and privacy. An important characteristic of NIH oversight is that the materials submitted to OBA are generally considered to be in the public domain. This is a key difference from the FDA, which by law must safeguard proprietary information from public access.

Once it has received the aforementioned information, OBA forwards the application for preliminary consideration by the RAC. The RAC is a panel of experts including scientists, physicians, lawyers, ethicists, and laypersons that advises the NIH Director and the OBA on recombinant DNA research. In addition to reviewing specific research proposals involving gene transfer, RAC recommends changes to NIH Guidelines. While RAC has no formal authority to accept or reject research proposals, submission to the RAC is a compulsory aspect of the NIH review process. Thus, RAC’s current refusal to “entertain proposals for germ line alterations” effectively assures that no such protocols will receive NIH funding.

Following its review of a given proposal, the RAC determines whether the protocol “raises important scientific, safety, medical, ethical, or social issues that warrant in-depth discussion at the RAC’s quarterly public meeting.”¹⁶⁹ Any protocols that present “unique applications of gene transfer research, the use of new or otherwise salient vector or gene delivery systems, special clinical concerns, or important social or ethical issues”¹⁷⁰ are singled out for further review.

If the RAC selects a protocol for further review, the researcher must make a brief presentation and take questions about the protocol from RAC members and possibly outside experts at a RAC meeting. This process is open to the public. Following the presentation, the RAC makes a recommendation to the Director and the OBA that the researcher “should carefully consider ... as part of optimizing the safe and ethical conduct of the trial.” The recommendations are memorialized in a letter that is sent to the researcher, along with the institutional IRB and IBC overseeing the protocol, and the FDA.

Within twenty days of enrollment and obtaining consent from the first research subject, the researcher must submit to the OBA a number of items, including: a copy of the informed consent form approved by the IRB, a copy of the protocol approved by the IBC and IRB, a copy of final IBC approval from the clinical trial site, a copy of final IRB approval, the applicable NIH grant numbers, the FDA IND number, and the date of the initiation of the trial. Additionally, the researcher must provide a “brief written report that includes ... (1) how the investigator(s) responded to each of the RAC’s recommendations on the protocol (if applicable); and (2) any modifications to the protocol as required by FDA.”¹⁷¹ During the course of the clinical trial, researchers have an ongoing obligation to inform OBA, the IRBs, IBCs, FDA, and the sponsoring NIH institutions within fifteen days of serious adverse events that are unexpected that might be associated with the gene transfer project. If such adverse events involve death or risk of death, the must be reported within seven days. Additionally, researchers must provide OBA with an annual report.

Tort Litigation as a Regulatory Mechanism

In addition to the federal system of oversight described above, individuals have recently begun to use tort litigation as a way to regulate those engaged in gene transfer research. Because there have been no instances of human embryonic gene transfer, there are no decisional authorities that address the viability of a claim on behalf of a person, born or unborn, for harm done in the course of such a protocol. Still, it may be useful briefly to discuss the extant decisional authority bearing on legal claims available to an individual harmed during a clinical trial.

Claimants in clinical-trial cases have sued researchers for negligence in the conduct of the clinical trial. Such a claim requires the plaintiff to demonstrate that the researcher owed a duty of care to the subject, which he breached, resulting in cognizable injury. The question of whether a duty is owed by a researcher in this context has been the subject of some debate. Most courts that have considered the issue have found that a duty exists, by virtue of special relationship between researcher and subject, the quasi-contract formed by the informed consent agreement , or implied by the federal guidelines for human subject protections. The standard of care owed under these circumstances—a question analytically separate from whether a duty exists—has also been the subject of some discussion. Most courts addressing the question have held that the standards for informed consent set forth by the Common Rule and FDA’s human subject protections constitute the relevant standard of care, the breach of which may be considered actionable. Two courts have gone farther one holding that the researcher must disclose any conflicts of interest,¹⁷² and another holding that parents are legally incapable of subjecting their children to any risks in nontherapeutic research.^{xxxiv 173} In addition to the standards for informed consent in the federal guidelines, some commentators have suggested that courts should import medical malpractice jurisprudence to determine the standard of care. They argue that the researcher owes the subject “implementation of knowledge, skill and care ordinarily possessed and employed by members of the profession in good standing.”¹⁷⁴ Deviation from this standard, under this analysis, would constitute actionable breach. Claimants could prove the contours of this standard of care through the introduction of extrinsic evidence at trial, as through expert witness testimony. This might be problematic in the gene transfer context; it is such a new technique, “custom” might be hard to establish.

To recover, the claimant must also demonstrate that the researcher’s breach caused the relevant injury. Again, this might be difficult in the context of gene transfer research, given the complexity and novelty of the procedure. Moreover, even if the claimant could show that, but for the researcher’s conduct, the harm would not have occurred, the court may not be willing, on grounds of public policy, to impose liability. Courts have sometimes been hesitant to impose such liability on researchers for fear that to do so would have a chilling effect on scientific experimentation that is socially beneficial.¹⁷⁵

Proving harm might also be very difficult in the context of gene transfer research, particularly when the individual harmed is unborn or, as in the case of germ line gene transfer, unconceived. Courts have been hesitant to impose liability on harm to future generations.¹⁷⁶

In addition to negligence claims, individuals can bring actions for assault and battery on the theory that their informed consent was defective or not meaningful.

Nongovernmental Regulation

Various professional societies have issue statements providing guidance and reflection on the ethics of genetic engineering and gene transfer. For example, the American Medical Association has issued ethics opinions on each of these subjects. The AMA’s statement on genetic engineering makes it clear that if and when this practice becomes ready for clinical application, the AMA standards on clinical investigation, medical practice, and informed consent apply. Moreover, the AMA holds: genetic engineering should be safely conducted; there should be no unwanted virus employed; and the safety and effectiveness of any such procedure should be evaluated as well as possible.

The AMA’s statement on gene transfer asserts that there should be no germ line modification at this time because of the “welfare of future generations and its association with risks and potential for unpredictable and irreversible results.” Nontherapeutic applications of gene transfer are “contrary to the ethical traditions of medicine and against the egalitarian values of society.” Such uses of gene transfer can be undertaken only if the following three conditions are satisfied: (1) there is a clear and meaningful benefit; (2) there is no “trade off” with other characteristics or traits; and (3) “all citizens would have equal access to the technology, irrespective of income or other socioeconomic characteristics.”

Conclusion

The power to modify human traits and characteristics is not on the immediate horizon, but does appear to be approaching. Gene transfer, though still experimental, may be perfected sooner than artificial chromosomes and similar high-tech approaches. Federal regulation of research (NIH) and clinical trials (FDA) is fairly strong in this area, and tort litigation may provide additional strength to ensure safety fears are not realized. The regulations are chiefly aimed at safety of human subjects, and at the safety and efficacy of the gene therapy products themselves. While it does not have formal approval authority, the NIH’s RAC publicly discusses and explores the ethical concerns implicated by innovations in this area. The states have not been active in legislating in this area.

IV. POWER TO OBSERVE AND MANIPULATE NASCENT HUMAN LIFE
IN VITRO FOR PURPOSES OF SCIENTIFIC RESEARCH

Research using human embryos is inextricably intertwined with the biotechnologies that touch the beginnings of human life. It provides the groundwork for many of the techniques and practices, and it also relies on such techniques and practices—most notably, assisted reproduction—as a source for embryos for research. Thus, a comprehensive understanding of the current practices, ethical concerns, and present regulation of the new powers over nascent human life requires a treatment of human embryo research.

Before entering the discussion, however we need to define with some particularity its scope. Many activities could fairly be deemed to be human embryo research, depending on the purpose and nature of the activity. If construed broadly, “embryo research” might include novel or experimental in utero or ex utero interventions for therapeutic purposes, intended to benefit mother, child-to-be, or both, for example, novel assisted reproductive technologies, preimplantation genetic diagnosis, and embryonic gene transfer—subjects discussed elsewhere in this document. Or “embryo research” might be construed to include research performed on aborted fetuses, fetal tissue, or non-living embryos or embryonic tissue. We opt for a narrower definition, in keeping with our focus on current regulation of the biotechnologies that touch the beginnings of human life. Thus, for present purposes the following discussion will be limited to a treatment of basic research on ex utero living embryos not intended for transfer into a woman’s uterus.

Techniques and Practices

Present Applications of Human Embryo Research

Much of basic embryo research is aimed at improving infertility treatment. Additional research protocols involving human embryos seek general knowledge on early embryonic development, including morphology, biochemical and biophysical properties, and genetic expression. Some embryo researchers seek to enhance basic knowledge about the origin of birth defects. Others seek the development of contraceptives. Still others study cell division in early embryos looking for clues relevant to understanding cancer development and metastasis (particularly cancers affecting reproductive organs). Embryo research is also undertaken to increase understanding of somatic cell nuclear transfer and parthenogenesis. Finally, embryo research is undertaken with the aim of deriving and studying human embryonic stem cells.

Sources of Embryos

Researchers typically procure embryos for research purposes from assisted reproduction clinics —generally, embryos that remain following completion of IVF treatment (so-called “spare” embryos). Such researchers submit requests to clinics for embryos that have specifically been donated for research. As mentioned in Section I, the recent study by ASRM and Rand on the number of cryopreserved embryos in the United States found that of the nearly 400,000 embryos currently in cryostorage. Only 2.8 percent (11,000) have been designated for donation to research. Couples make an initial designation at the outset of their services for disposition of embryos in the event of death, divorce, or abandonment. After couples have completed their treatment, they are approached by researchers who make a specific request for embryo donation. Typically, these are researchers who have a pre-existing relationship with the ART clinic. In some instances, the couple’s fertility specialist is also the principal researcher making such requests.

A less common means of acquiring embryos for research is to create the embryos expressly for the purposes of research. In July 2001, the Jones Institute in Norfolk, Virginia, reportedly created more than one hundred embryos in this manner from the gametes of volunteer donors. (Subsequent reports suggest this program has been stopped).

Ethics

The chief ethical concerns raised by the practice of human embryo research arise from the fact that nontherapeutic embryo research necessarily involves the use and destruction of nascent human life. Even among people who do not assign the embryo “full-person” status, intentional destruction of nascent human life is cause for ethical concern. Moreover, in embryo research—unlike in assisted reproduction, where each embryo is created and used with the intention to conceive a live-born child—embryos are treated purely instrumentally; they become a mere natural resource for gaining knowledge. Regarding and treating nascent human life as a mere means—even to noble ends, such as alleviation of suffering—is a moral issue, with potentially serious consequences, and not only for the embryos. It could coarsen sensibilities and lead to a devaluation of life in other contexts, opening the door to moral hazards both in the context of research and beyond.

In addition to concerns about the use and destruction of nascent human life, ethical hazards in this context include potential commercialization of embryos, and subtle or overt coercion of couples undergoing fertility treatment to donate embryos to research against their will, and the attendant increased risks to their physical and emotional well being.

Regulation

Federal

The federal regulation of human embryo research has a long and somewhat tortured history. In the 1970s, the regulations governing the protection of human subjects involved in federally funded research provided that “no application or proposal involving human in vitro fertilization may be funded by the Department [until it] has been reviewed by the Ethical Advisory Board and the Board has rendered advice as to its acceptability from an ethical standpoint.”¹⁷⁷ In 1979, the EAB concluded that federal funding of IVF research was ethically acceptable, subject to certain conditions.^xxxv The Secretary of HHS did not act on this recommendation, and with the change in administrations, the EAB was dissolved in 1980. No subsequent EAB was appointed thereafter. This created a de facto moratorium on federal funding for embryo research until 1993. Acting on the advice of newly elected President Clinton, Congress passed the NIH Revitalization Act of 1993 nullifying the EAB requirement for federal funding. Thereafter, NIH Director Harold Varmus convened an advisory body to consider which types of embryo research, as an ethical matter, should be entitled to federal funding. The NIH Human Embryo Panel issued a report in 1994 concluding that certain species of embryo research were acceptable for federal funding, others may be acceptable under certain specified conditions, and others were unacceptable.^xxxvi One of the most controversial aspects of the NIH Panel’s conclusions was a qualified endorsement of the creation of embryos solely for purposes of research.^xxxvii The Embryo Panel submitted its conclusions to the Advisory Committee to the Director, which then forwarded them to the NIH Director. Before the Director could act on the recommendations, however, President Clinton directed NIH not to approve funds for the creation of human embryos solely for research purposes. Director Varmus accepted the remaining recommendations and began to plan for their implementation as a predicate to the funding of embryo research.

Before NIH had the opportunity to approve any embryo research protocols, however, Congress implemented a statutory ban on federal funding that remains in effect to the present day. According to the “Dickey-Wicker Amendment” to the Department of Health and Human Services (DHHS) appropriations bill for Fiscal Year 1996,¹⁷⁸ which has been re-enacted each year since, no federal funds may be used for: the creation of a human embryo or embryos for research purposes; or research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero “under 45 CFR 46.208(a)(2) and section 498(b) of the Public Health Service Act (42 USC. 289g(b)).”^xxxviii The first referenced statute provides that no fetus in utero can be involved as a subject in any activity covered by Subpart B of Part 46 of Title 45 (federal human subjects protections, described below) unless the risk to the fetus imposed by the research was minimal and the purpose of the activity was the development of important biomedical knowledge which could not be obtained by other means. The second statute (section 498(b) of the Public Health Service Act) requires that the research risk standard be the same for fetuses which are intended to be aborted and fetuses which are intended to be carried to term. “Human embryo” is defined broadly as “any organism, not protected as a human subject under 45 CFR 46 ... that is derived by fertilization, parthenogenesis, cloning, or any other means from one or more human gametes or human diploid cells.”

In light of the legislative restriction on federal funding, in 1998 the National Institutes of Health (NIH) sought a legal opinion from the DHHS Office of the General Counsel on whether NIH funds may be used for research using embryonic stem cells. DHHS concluded that the Dickey-Wicker Amendment did not prohibit the federal funding of research “utilizing” (but not deriving) human embryonic stem cells because such cells are not embryos. However, before DHHS allocated any funding for such research, there was an intervening election in which the White House switched from Democratic to Republican control. One of newly elected President Bush’s first actions was to review the former administration’s policy for the federal funding of embryonic stem cell research.

On August 9, 2001, President Bush announced his decision to allow federal funds to be used for research only on existing human embryonic stem cell lines, as long as, prior to August 9, 2001: (1) the stem cell line had already been developed, and (2) the embryo from which the stem cell line was derived no longer had the possibility of development as a human being. In addition, the President established the following criteria that must be met for federally funded stem cell research: the stem cells must have been derived from an embryo that was created for reproductive purposes; the embryo was no longer needed for these purposes; informed consent must have been obtained for the donation of the embryo; and no financial inducements were provided for donation of the embryo. Because of President Bush's statement, on November 7, 2001, the NIH rescinded a November 21, 2000, guidance on NIH-funded stem cell research insofar as that guidance applied to research on stem cells derived from human embryos.^xxxix In order to facilitate research using human embryonic stem cells, the NIH has created a Human Embryonic Stem Cell Registry that lists the human embryonic stem cell lines that meet the eligibility criteria.^xl

There are currently no federal laws or regulations directly applicable to the use of embryos in privately funded research.

FDA does not regulate bench research on embryos that is not aimed at the development of a “product” subject to its approval.

Embryo research using cloned human embryos—embryos created by somatic cell nuclear transfer—have been the subject of separate legislative activity. In July 2001 and again on February 27, 2003, the House of Representatives passed a bill^xli that would ban all human cloning. It would also make illegal the shipment or receipt “for any purpose an embryo produced by human cloning or any product derived from such embryo.” If enacted, this bill would prohibit research on cloned embryos and on stem cells extracted from such embryos. As of this writing, the Senate has not acted on the bill.

Secretary's Advisory Council on Human Research Protections (SACHRP). The charter of SACHRP, which recently replaced the National Human Research Protections Advisory Committee, requires SACHRP to “provide advice relating to the responsible conduct of research involving human subjects” with special emphasis on various special populations, including embryos. Thus, for purposes of the charter of this federal advisory committee, human embryos are human subjects.

Human Subjects Protections

Entities and individuals that conduct human-subjects research are regulated under federal and state laws and regulations, as well as the policies and procedures of the institutions at which federally funded research is conducted. There are several regulatory structures that form the basis of the federal government’s jurisdiction over human subjects research. The two major sources of regulation are the Office of Human Research Protections (OHRP) and the Food and Drug Administration (FDA), both housed in the Department of Health and Human Services (DHHS). Additionally, the National Institutes of Health (NIH), a main source of funding for research, has regulations and policies that must be followed to the extent a research project is funded by the NIH. DHHS regulations, at 45 CFR Part 46, govern federally funded or supported research on human subjects. Subpart A of the regulations, known as the “Common Rule,” has been adopted and separately codified by fourteen agencies other than DHHS. Subparts B, C, and D, govern research on vulnerable populations, namely, Subpart B governs research on pregnant women, human fetuses and neonates, Subpart C governs research on prisoners, and Subpart D governs research on children. OHRP is the office that is charged with developing guidance interpreting the Common Rule and enforcing its requirements. OHRP determination letters are issued to institutions determined by OHRP to be out of compliance with DHHS regulations and provide an additional source of guidance regarding the meaning of the regulations and the government’s enforcement focus. The Common Rule applies to “all research involving human subjects conducted, supported or otherwise subject to regulation by any Federal Department or Agency” which has adopted its provisions. As a practical matter, the reach of the Common Rule extends beyond federally funded or supported human-subjects research to cover all research done at a given institution. This is because all institutions that receive federal funds to conduct human subjects research are required to enter into an “assurance” with the federal government, under which the institution promises to abide by applicable federal regulations and ethical principles in the conduct of human-subjects research. The terms of an assurance often apply the ethical principles outlined in the Belmont Report¹⁷⁹ and the requirements of the Common Rule, including Subparts B, C, and D, to all research conducted at the institution, regardless of the funding source. Historically, there were several forms of assurances, depending on the sort of project involved, and the terms of each assurance would vary depending upon its negotiation. Recently, OHRP instituted the “Federalwide Assurance,” a uniform assurance document that will be required as of December 31, 2003, for all institutions receiving federal research funds, regardless of what kind of assurance the institution was previously operating under. Although many institutions conducting research receive some form of federal funding requiring them to execute a Federalwide Assurance, there are institutions or other private companies that conduct research solely with private funds and which will therefore not be required to execute an assurance. Although these privately funded research entities may be governed by FDA or state law requirements, or both, they will not be subject to the requirements of 45 CFR 46. In addition to being limited to institutions that receive federal funds, the scope of the Common Rule’s requirements are further limited by the definition of human subjects research (see discussion on research versus practice, below) and the regulatory exemptions within the Common Rule that expressly carve out certain types of research from its requirements.¹⁸⁰ For example, research that involves the collection or study of existing data, that is, a retrospective chart review, will not be subject to the Common Rule’s requirements if the sources of data are publicly available or the investigator records the data in such a manner that the subjects cannot be identified, directly or through a code linked to the subjects.¹⁸¹ If human-subjects research falls within one of the six categories of exempt research, there is no requirement for institutional review board (IRB) review, approval, and continued oversight of the research; nor is there a federal requirement for obtaining the written informed consent of the subject. Although exempt research falls outside of the requirements of the Common Rule by definition, OHRP has counseled institutions to implement a process whereby investigators are required to apply to the institution or IRB for a determination that their research qualifies as being exempt from IRB review, approval, and oversight. Alternatively, institutions may elect to review exempt research in an “expedited” manner according to 45 CFR 46.110, or under some other administrative review procedure to ensure that the research’s exempt status does not change during the course of the project.

One of the main protections of human subjects afforded by the Common Rule is the requirement that human-subjects research be reviewed, approved, and monitored by an IRB, an independent ethical body constituted in accordance with the requirements of 45 CFR 46.107. An IRB may approve only such research as meets the criteria in 45 CFR 46.111, and any additional applicable requirements for the special populations governed by Subparts B, C, and D. Specifically, to approve research on human subjects under 45 CFR 46.111, an IRB must find the following:

Risks to subjects are minimized.
Risks to subjects are reasonable in relation to anticipated benefits, if any, and the importance of the knowledge that may reasonably be expected to result.
Selection of subjects is equitable (e.g. no one population bears the burden of research without direct benefit; adult subjects should be used for research where possible before children are enrolled, etc.).
Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with and to the extent required by 45 CFR 46.116.
Informed consent will be appropriately documented, in accordance with and to the extent required by 45 CFR 46.117.
When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.

Research approved by an IRB is also subject to continuing review, at intervals appropriate to the degree of risk presented by the study but at least once a year.¹⁸² OHRP has issued detailed guidance regarding the continuing review process, when it should occur, and what materials should be reviewed.¹⁸³

The NIH guidelines on human subjects do not directly cover ex utero embryos, but may touch other participants in such research. For purposes of 45 CFR 46, a “human subject” is a living individual about whom an investigator conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. If the identity of the embryo donor(s) can be readily ascertained by the investigator—either because the research is conducted in vivo or because donor identifiers are associated with the embryo—the donor(s) could be “human subjects” within the meaning of 45 CFR 46. Ex utero embryos have never been treated as “human subjects” for purposes of this section. However, for purposes of the additional safeguards required under Subpart B, a “fetus” is defined as “the product of conception from implantation until delivery.” This legal definition differs from the standard medical definition, which uses the term “embryo” to name the product of conception up to eight weeks (well after implantation, which usually occurs before the end of the first week), and reserves the term “fetus” for products of conception eight weeks old and beyond. Thus, if the research is conducted in vivo, what might be considered research on an “embryo” by most scientists could be considered research on a “fetus” for purposes of 45 CFR 46 (and therefore subject to Subpart B).

Implanted embryos are covered by the protections under the Common Rule applicable to research on pregnant women and fetuses. Pregnant women or fetuses may only be involved in research if the following conditions are met: (i) where scientifically appropriate, preclinical studies and clinical studies have been conducted and provide data for assessing potential risks to pregnant women and fetuses; (ii) the risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit to the woman or the fetus; or, if there is no prospect of direct benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means; (iii) any risk is the least possible for achieving the objectives of the research; (iv) the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means and the woman’s informed consent is obtained; (v) if the research holds out the prospect of direct benefit solely to the fetus and the informed consent of the pregnant woman and the father is obtained, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest; (vi) each individual providing consent to the research is fully informed regarding the reasonably foreseeable impact of the research on the fetus or the neonate; (vii) if the pregnant individual is a child, as that term is defined under 45 CFR 46.402(a), assent and permission are obtained in accord with the provisions of Subpart D of the regulations governing research on children; (vii) no inducements, monetary or otherwise, will be offered to terminate a pregnancy; (ix) the individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and (x) the individuals engaged in the research will have no part in determining the viability of a neonate.

The FDA has never officially adopted the Common Rule. But FDA regulations governing research on human subjects are identical in many respects to the Common Rule. FDA’s jurisdiction to regulate research is based primarily on its ability to regulate the interstate shipment of investigational drugs and devices governed by the Federal Food Drug and Cosmetic Act. Although the protection of human subjects is one goal of FDA’s regulatory structure, the primary goal is the integrity of the data collected during a clinical investigation of an FDA-regulated product. The FDA’s requirements for human subjects research apply regardless of federal funding, assuming that the product being studied in the clinical investigation is subject to FDA regulation (that is, the study of an investigational drug, biologic, device, or other regulated product), or the clinical investigation is intended to gather data used to support an application to the FDA for a research or marketing permit.¹⁸⁴ The primary FDA regulations relating to research include the following, found in title 21 of the Code of Federal Regulations:

Part 312: Procedures for conduct of clinical studies with investigational drugs.
Part 812: Procedures for conduct of clinical studies with investigational devices.
Part 50: Requirements and general elements of informed consent.
Part 54: Disclosure of financial interests by clinical investigators.
Part 56: Procedures and responsibilities for IRBs.

Parts 50 and 56 apply IRB oversight and informed consent requirements to FDA-governed research, similar to those under the Common Rule. One noticeable distinction is that whereas the Common Rule provides for IRB waiver of informed consent for certain types of minimal risk research,¹⁸⁵ waiver of informed consent is limited under FDA regulations to emergency use of an investigational drug or device or research intended to be conducted in an emergency setting, because the use of an investigational device or drug is automatically considered to present at least a minimal risk to the subjects.¹⁸⁶

As mentioned previously, investigational drugs and devices may not be shipped interstate or used to conduct a clinical investigation unless the sponsor of the research has applied for and obtained an “investigational new drug application” (IND) or “investigational device exemption” (IDE).¹⁸⁷ Some exemptions apply, for example, the clinical investigation of a legally marketed drug is permissible without an IND where the results will not be submitted to the FDA and the investigation does not increase the risks to the subjects. Similarly, the investigation of a non-significant risk device is deemed to have an approved IDE, and no application to the FDA is necessary, if an IRB approved the investigator’s non-significant risk determination. These kinds of exempt investigations must nonetheless be conducted in accordance with FDA’s IRB oversight and informed-consent requirements, according to the terms of Parts 50 and 56. FDA regulations governing clinical investigations do not apply to the off-label use of an investigational drug or device in the practice of medicine.¹⁸⁸

State Laws

States are the principal sources of direct regulation for embryo research. Currently, twenty-six states have laws that apply to research involving embryos, fetuses, and their tissue.¹⁸⁹ These laws vary widely in their application and content. Some states, in an effort to disincentivize abortion, regulate research on aborted fetuses and embryos,^xlii matters beyond the scope of this document. Additionally, many states define “embryo research” broadly so as to reach experimental practices such as cryopreservation, preimplantation genetic diagnosis, and perhaps gene transfer. Such statutes are discussed in the sections of this document addressing these specific subjects. The following discussion will focus only on regulations that may govern the use of in vitro embryos in the context of nontherapeutic scientific research.

A number of states have regulations potentially applicable to research on in vitro embryos. New Hampshire expressly permits research on in vitro embryos up to fourteen days of development, but prohibits implantation of these embryos. Additional states prohibit to various extents nontherapeutic research on in vitro embryos.^xliii Most of these proscribe such research if not beneficial to the embryo itself. Illinois, New Mexico, and Utah have statutes that proscribe research on fetuses that might be construed to reach in vitro embryos. Recently there has been a groundswell of legislation introduced at the state level in response to developments in embryonic stem cell research and cloning. In Massachusetts, efforts are currently under way to amend the fetal-research statute (which presently prohibits experimentation on embryos and fetuses unless it is incident to the study of the human fetus while it is in its mother’s womb) to exempt embryos from its definition of “fetus.” California has recently passed legislation that expressly permits and encourages research involving the derivation of human embryonic stem cells—including research involving cloning techniques.

It bears noting that some of the above mentioned embryo research statutes have come under judicial scrutiny. Indeed, statutes in Utah, Illinois, and Louisiana have been held to be unconstitutionally vague, on the grounds that “experimentation” is not clearly defined so as to put practitioners on notice that certain activities may be criminal. One court in Illinois went further, striking down a portion of an older statute on the additional grounds that it could reach certain practices and techniques of assisted reproduction, thus infringing upon a woman’s constitutional right to make reproductive decisions.

Professional Self Regulation

A number of professional organizations and societies have published guidelines and opinions on embryo research. In the main, these guidelines are substantially similar to the NIH embryo research guidelines proposed by the Clinton administration (discussed below). Two that are worthy of note are statements from ASRM and the American Academy of Pediatrics.

ASRM’s 1994 report entitled “Research on Preembryos: Justifications and Limits” notes what it considers the great benefits of embryo research, and concludes that it is a permissible activity. ASRM further concludes that it is not “prudent at this time” to maintain embryos in vitro beyond fourteen days. The opinion does not seem to take a position on the creation of embryos expressly for research.

ASRM sets forth guidelines on donation of embryos in two ethics opinions: “Donating Spare Embryos for Embryonic Stem Cell Research”¹⁹⁰ and “Informed Consent and the Use of Gametes and Embryos.”¹⁹¹ These include a discussion of the risks and benefits, a description of the purpose and nature of research, and the potential for commercial value of the research (and the donors’ lack of entitlement to such value), and the special character of embryonic cell lines. Additionally, couples are to be told that their decision does not affect their status as patients, that no research embryos will be transferred, and that they may change their minds at any point up until the point the protocol begins. ASRM advises that clinics should have a policy on privacy and confidentiality. Both members of a couple seeking treatment must agree on donation to research—if they disagree, then no embryos shall be donated. Final consent (confirming the couple’s initially stated preferences for embryo disposition) is obtained only after the couple has decided not to continue storing their embryos. ASRM’s opinion on the disposition of abandoned embryos precludes the use of such embryos in research. An embryo is deemed “abandoned” if the couple “has not given written instruction for disposition, has not been in contact with the program for a substantial period of time, and has not provided a current address and telephone number.” ASRM notes that it is preferable (though not compulsory) that an individual other than the couple’s fertility specialist be the one to request donation for research. ASRM concludes that there should be no buying and selling of embryos, though reasonable fees (defined by the contracting parties) may be paid for efforts and costs incurred.

The American Academy of Pediatrics issued a statement on human embryo research in September 2001 concluding that embryonic stem cell research is sufficiently valuable that it should be funded by NIH and regulated by DHHS. The Academy took the position that federally funded embryo research should be approved by IRBs subject to the following conditions:

The embryos are already frozen and are no longer clinically needed.
There is a clear separation in the donor decision process between the decision by the donors to create embryos for infertility treatment and the decision to donate frozen embryos for research purposes after they are no longer clinically needed.
The decision to donate is strictly voluntary and without monetary inducements.
The physician responsible for fertility treatments is not to be the person performing the research on the same frozen embryos, and there should be no monetary relationship, i.e., transfer of funds in the research project to the physician responsible for the fertility treatments.
There are to be no personal identifiers associated with the embryos used for research.
There are to be no restrictions placed by the donor on the type of research performed.
The research performed on these frozen embryos can be of no direct benefit to the original donors.
The embryo research does not involve research in reproductive cloning, transferring an altered embryo to a woman's uterus, or use of a human embryo in combination with other human or animal embryos.

The Academy also provided guidelines for informed consent. Specifically, informed consent should advise donors that:

All identifiers associated with the frozen embryos will be removed.
The donors will not receive any future information regarding subsequent testing or research on these embryos.
Cells or tissue developed from the embryos may be used at some future time for human transplantation research.
Cells or tissues derived from the embryos may be kept indefinitely.
The donated frozen embryos may be of commercial value, but the donors will not receive any financial or other benefits from any such commercial development.
The research performed on these frozen embryos is not intended to provide direct medical benefit to the donor.
The research will not involve the transfer of these embryos to a woman's uterus or involve reproductive cloning or combination of the embryo with any other embryo of human or animal origin.

The American Medical Association has similarly issued guidance on human embryo research, supporting the conclusions of the 1994 NIH Human Embryo Research Panel and recommending the creation of a RAC-like body to provide oversight for cloning experiments. Additionally, the AMA has signaled its support for federal funding of early stage embryo research.

While its conclusions do not have the force of law and were never fully adopted, the principles articulated by the NIH Embryo Panel have been widely echoed in the policies and ethical opinions of a number of professional societies and organizations. Thus, it is worthwhile to summarize briefly the key conclusions of the Embryo Panel. The Panel agreed that federal funding of embryo research in certain areas is permissible for three reasons: (i) the scientific promise of such research is significant; (ii) the embryo does not, in the Panel’s view, enjoy the same moral status as a person; and (iii) the absence of federal funding (and thus oversight) leads to a status quo in which there is no consistent scientific or ethical review of research protocols. ¹⁹²

The Panel identified and distinguished the categories of research that should receive funding. The first category was research deemed by the Panel to be “acceptable for federal funding,” provided it was conducted in accordance with certain guidelines. These guidelines included requirements that the research be conducted by qualified researchers, according to a valid research design, under the direction of an IRB, with a minimum number of embryos necessary, with adequate informed consent, etc. Additionally, the Panel advised that there should be no purchase or sale of gametes or embryos (though reasonable compensation for expenses and efforts should be permitted), and there should be equitable selection of gamete and embryo donors to prevent discrimination. Finally, the Panel noted that, subject to certain exceptions, embryos should not be maintained in vitro for more than fourteen days following fertilization.

Types of research deemed “acceptable for funding” include research aimed at improving successful outcome of pregnancy, research on the process of fertilization, the genetics of embryonic development, the effects of cryopreservation on the development of oocytes, preimplantation genetic diagnosis, embryonic stem cells (using excess IVF embryos with appropriate informed consent) and oocyte nuclear transfer (in protocols were there is no transfer to a uterus or functional equivalent). Within the category of “acceptable research,” the Panel singled out a subcategory of projects that is acceptable for federal funding, but deserving “very careful scrutiny” during the ad hoc review process (recommended by the Panel for research protocols). Such projects include research involving existing embryos were “one of the progenitors received monetary compensation,^xliv“ and projects of outstanding merit requiring fertilization of ova as part of the protocol. As stated previously, this latter recommendation was quite controversial, and was explicitly rejected by the Clinton administration.

The Panel identified a second category, namely, research “that warrants additional review.” Such research would be presumptively ineligible for federal funding, but this presumption could be overcome by a showing of outstanding merit, and following “explicit consideration of the ethical issues and social consequences.” Research in this category includes: cloning by blastomere separation or blastocyst splitting (without transfer), “research between the appearance of the primitive streak and the beginning of closure of the neural tube” (occurring between Days 17 and 21 of embryonic development), research using fetal oocytes for fertilization or parthenogenesis (without transfer), research on oocyte nuclear transfer (with subsequent transfer to a woman’s uterus), and embryonic stem cell research involving embryos fertilized exclusively for such research.

The third and final category of research identified by the Panel was projects “considered unacceptable for funding.” These projects were deemed unacceptable on ethical grounds including concerns for adverse effects on the well being of children, women and men involved in such research; the “special respect” due to the in vitro embryo; concern for “public sensitivities on highly controversial research proposals”; and “concern for the meaning of humanness, parenthood, and the succession of generations.”¹⁹³ Research that is “unacceptable for federal funding” included the cloning of embryos via blastomere separation or blastocyst splitting (with transfer to a woman’s uterus); PGD for non-medically indicated sex selection; development of chimeras (with or without transfer); cross-species fertilization (except for clinical protocols exploring “the ability of sperm to penetrate eggs”); research involving transfer of parthenotes to a woman’s uterus; research involving the transfer of human embryos into nonhuman animals, or “for extrauterine or abdominal pregnancy.”¹⁹⁴

Conclusion

There is effectively no federal regulation of research on in vitro embryos. States have widely varying approaches to the subject, ranging from silence (and thus permission) to prohibition of such research. The private sector’s guidance on this point is largely driven by the principles articulated by the NIH Human Embryo Panel, namely, that the embryo is entitled to “special respect,” but may be used and destroyed in “worthwhile” research protocols. Additionally, there seems to be some agreement among scientific professional societies that embryos should not be cultivated beyond fourteen days development.


V. COMMERCE AND COMMODIFICATION

With advances and innovations in assisted reproduction, embryo research, genetic screening, and genetic modification, there have arisen new markets for the articles and services associated with these technologies and practices, including gametes and embryos. Developments in patent law, meanwhile, have raised issues of ownership of human genes, tissues, and even embryos. Such developments have significant implications for society’s understanding of property in the human body. This section discusses: markets in gametes and embryos; marketing of ART services; commercialization in research; and patenting of living organisms and human beings.

Markets in Gametes and Embryos

Current Practices

The vast majority of gametes and embryos are procured or conceived in the context of assisted reproduction. There has long been a market for sperm donation in this country.¹⁹⁵ In the early 1980s, multimillionaire Robert Graham established the “Repository for Germinal Choice,” offering infertile couples the opportunity to purchase sperm from Nobel laureates.¹⁹⁶ One commentator notes that today there are “thousands of sperm banks … in this country offering modest, yet significant remuneration.”¹⁹⁷ In 2000, the average payment to sperm donors was between $60 and $70 per donation.¹⁹⁸ Some sperm donors have marketed themselves aggressively, with one individual seeking to sell his sperm for $4,000 a vial. ¹⁹⁹

The market for ova is a more recent development. Donated ova are generally procured by one of the following means: informally, from an intimate relation; indirectly, through a pooled brokerage; or directly, from an individual seller or from the ART clinic itself.²⁰⁰

IVF clinics, brokers, and infertile couples solicit gamete donors through advertising.²⁰¹ The structure of the transactions vary; the typical convention is that donors are compensated for their time, efforts, and reasonable expenses, rather than for the gametes themselves. While there do not seem to be any definitive studies on the subject, it appears that most donors provide gametes on an anonymous basis without regard to specifically desired traits. There is, however, anecdotal evidence that there are exceptions to this rule.

For example, some pooled brokerages solicit a pool of potential donors, create individual profiles (including photograph, biographical data, information on physical characteristics, medical history, etc.), and create a database. One such brokerage, Egg Donation, Inc., seeks in a donor someone who is “bright and attractive, between the ages of 21 years to 30 years, of any ethnic background, preferably who has completed a college degree or is presently pursuing a college degree and is in excellent health.”²⁰² Another brokerage, Tiny Treasures, specializes in Ivy League ovum donors. Its database includes photographs, SAT scores, grade point averages, and compensation requests. Compensation for ovum donors from pooled brokerage varies. Egg Donation, Inc., advises potential donors that the donor fee “will range from $3,500 to $12,000.” As to which variables drive cost, the website explains: “Asian and Jewish ovum donors are always in demand. A tall, attractive donor with a masters or doctorate degree will always receive higher compensation than most other donors.” Ivy League donors from Tiny Treasures seek anywhere from $8,000 to $20,000 compensation for an ova retrieval episode.

Pooled brokerages charge potential recipients a fee to browse their database of donors. Once a donor is selected, the brokerage begins the “matching process” which includes psychological screening, medical screening, and legal consultation. Thereafter, a contract is executed between the parties, and the process of stimulation and retrieval is initiated.

Some couples solicit ovum donors directly with targeted advertisements. Many place advertisements in school newspapers at prestigious colleges and universities. One such advertisement at Vassar College offered $25,000 in exchange for the ova of a “healthy, intelligent college student or college graduate, age 21-33 with blue eyes and blonde or light brown hair.”²⁰³ Another advertisement in the Stanford Daily offered $50,000.²⁰⁴

An alternative means of acquiring ova is through so-called “oocyte sharing,” by which women undergoing infertility treatment are given a price discount in exchange for agreeing to share their ova with other patients. According to ASRM, few details are published on how these transactions are structured, but “[i]t seems that IVF patients in these sharing programs generally donate up to half the oocytes retrieved in a single cycle to another patient, in return for a 50%-60% reduction in the total costs of the IVF cycle.”²⁰⁵

There does not seem to be a market for human embryos. There is no evidence that early extracorporeal embryos are bought or sold in the United States. As discussed in Section I, individuals and couples may donate to researchers and to other infertile couples any “excess” embryos that remain after the completion of infertility treatment.

Ethical Concerns

The buying and selling of gametes raises several ethical concerns. Some argue that the commodification and commercialization of reproductive tissues might diminish respect for procreation. Others additionally claim that it may taint the otherwise altruistic motivations that lead individuals to donate their gametes.

Ovum sales raise additional ethical concerns. The process of ova retrieval is onerous and potentially risky for donors. The high fees paid to ovum donors—typically from financially vulnerable populations, such as full-time students—can create pressure to undergo these invasive procedures. Oocyte sharing somewhat reduces the probability of successful pregnancy, because by definition it reduces the number of ova available for transfer during a given ART cycle. An additional concern is that a free market in ova can lead to discrimination and greater inequality. The 1994 NIH Human Embryo Panel speculated that an open market for ova would lead to a two-tiered system in which wealthy white ovum donors would receive high payments primarily from IVF patients, whereas poor minority women would receive substantially lower payments primarily from researchers.²⁰⁶

Finally, financial incentives for donation encourage individuals to become biological parents—sometimes many times over—to children with whom they will have no relationship. With the advent of laws providing children with a right to know their biological parentage, such donors may become involved in these children, regardless of their choice to remain anonymous.
There are ethical concerns, however, implicated by the prospect of not compensating individuals for the donation of gametes. For example, if there is no such payment, some couples will remain without children because the supply of egg and sperm will be sharply reduced.

Regulation

There are currently no federal laws touching the sale of gametes. The National Organ Transplantation Act “makes it unlawful for any person to knowingly acquire, receive, or otherwise transfer any human organ for valuable consideration for use in human transplantation if the transfer affects interstate commerce.”²⁰⁷ While the term “organ” in this statute has been construed to include fetal organs, it has never been extended to include sperm, ova, or embryos. A number of states ban or otherwise restrict the sale of embryos.^xlv Only Louisiana explicitly bans the sale of ova. Virginia, on the other hand, explicitly exempts ova from its prohibition on the sale of body parts. California bans the sale of ova for use in cloning. Some states broadly prohibit or limit the sales of organs or nonrenewable tissues, but it is an open question whether ova fall within the ambit of such prohibitions.^xlvi

ASRM has issued ethical guidelines for its members on financial incentives for oocyte donation. Following a discussion of the ethical concerns implicated in payment or oocyte sharing programs, it concludes that these transactions are acceptable, subject to certain limitations. First, ASRM calculates a “reasonable” payment for oocyte donation by taking the average fee for sperm donation ($60 to $75 for one hour) and multiplying it by the number of hours spent in a medical setting during oocyte donation (fifty-six hours). Thus, ASRM concludes that the reasonable fee for an oocyte donor is $3,360 to $4,200. But since this calculus might not account for the more onerous nature of oocyte donation, ASRM concludes that “at this time sums of $5,000 or more require justification and sums above $10,000 go beyond what is appropriate.”²⁰⁸

ASRM concludes that oocyte sharing is permissible provided that programs “formulate and disclose clear policies on how oocytes are allocated, especially if a low number of oocytes or oocytes of varying quality are produced.” The Society advises that the reduction in fees resulting from oocyte donation should not be contingent on the number or quality of ova retrieved. Additionally, ASRM advises its members to: ensure that there is a physician assigned to the oocyte donor (preferably not the fertility specialist for the ova recipient); disclose policies regarding medical coverage for any complications experienced by the oocyte donor; ensure advertising is accurate and responsible; avoid donors from recruiting agencies who have been paid exorbitant fees; and limit the number of times a woman undergoes retrieval procedures “purely to provide oocytes to others.”²⁰⁹

In a separate Practice Committee Report, ASRM advises its members to limit the number of stimulated cycles per oocyte donor to six, in light of health risks attending the procedure. In the same document, ASRM advises its members to “strive to limit successful donations from a single donor to no more than 25 families per population of 800,000, given concerns regarding inadvertent consanguinity in offspring.”²¹⁰

Sale of ART Services

Current Practices

Assisted reproduction is a booming industry, with gross revenues of four billion dollars per year, serving one in six infertile couples in the United States.²¹¹ The costs of assisted reproduction services are variable, depending on the particular procedures undertaken. For example, at one prominent clinic, the cost of an initial consultation is $370, one IVF cycle using never-frozen embryos is $9,345 (while transfer of cryopreserved embryos is only $4,000 per transfer), PGD (for sex selection or disease screening) is $4,000, and ICSI (frequently a prerequisite for PGD) is $2,000. Preconception sex selection (as by sperm sorting) adds another $2,000. Most couples must undergo more than one cycle to achieve a successful result—the most recently reported percentage of live births per cycle (using never-frozen, self-provided embryos) was 25.4 percent.²¹² ART clinics actively engage in advertising and marketing efforts to solicit potential business, emphasizing the range of procedures available to the infertile couple.

Most infertility patients pay for these services out-of-pocket, for reasons discussed below. Thus, some clinics offer alternative means of offsetting expenses. One means of reducing the costs of fertility treatment, discussed above, is oocyte sharing. Another means offered by some clinics is “shared risk” or “refund” programs, in which infertile patients pay a higher fee, with the understanding that if they achieve an “ongoing pregnancy or delivery, the provider keeps the entire fee.”²¹³ However, if treatment results in failure, “90%-100% of the fee is returned.”²¹⁴

Ethical Concerns

The intense commercialization of ART services raises ethical concerns similar, though not identical, to those raised by ARTs themselves. For example, it may diminish the dignity of human procreation and reduce respect for nascent human life by promoting the notion that these are reducible to articles of commerce. Unethical clinicians may exploit the vulnerability and despair of the infertile population with misleading advertisements and solicitations. As discussed in Section I, commercial competition may induce IVF clinics to try boost their success rates by adopting risky procedures (such as transfer of an excessive number of embryos per cycle) or by selectively excluding certain types of patients (such as older patients or those who otherwise have a lower probability of success). Finally, given that infertility treatment is expensive and that in the United States insurance coverage for such services is rare, there is the problem of inequality, with ART being a luxury enjoyed only by the rich. Ethical questions may also be raised regarding ova sharing and shared-risk programs as alternative means of structuring payment. Ova-sharing programs can induce women to undergo risks in superovulation to harvest as many ova as possible, and may reduce a woman’s ultimate chances for success, given that fewer ova are available for her own use. Shared-risk programs may have the potential to be exploitative, to promote unrealistic expectations for success, to induce patients and clinicians to undertake unnecessary risks, or to create a conflict of interest between doctor and patient.

Current Regulation

Although the majority of states have no specific laws mandating the coverage of assisted reproduction services, an insurance company’s failure to cover such services may in some cases be challenged by patients as a violation of the terms of the particular contract. For example, if the contract provides coverage for “illness” or “medically necessary procedures”—as most do—and does not specifically exclude infertility services, patients may argue that infertility falls into these categories and must be covered. Courts are divided on such questions. For example, in Kinzie v. Physician’s Liability Insurance Co., an Oklahoma appellate court held as a matter of law that IVF is not medically necessary but rather elective. In Egert v. Connecticut General Life Insurance Co., the court rejected the defendant insurance company’s claim that infertility is not an illness but rather the result of an illness, holding such a claim to be an improper construction of the insurance contract’s provisions and the insurance company’s internal guidelines. Some insurance companies have refused to cover IVF on the grounds that it is experimental, citing its less than 50 percent rate of success.²¹⁵

Fourteen states currently regulate the coverage of infertility treatment.^xlvii Some of these states mandate the coverage of IVF, subject to certain conditions, for example, by requiring that the treatment be provided in conformity with guidelines of the American College of Obstetricians and Gynecologists and ASRM.²¹⁶ Certain states require coverage only of fertilization of a donor’s own ova with her spouse’s sperm.^xlviii

The Federal Trade Commission has the authority to investigate deceptive claims in advertising by health care providers, including ART clinics, engaged in interstate commerce. It has jurisdiction, for example, to investigate claims of pregnancy success rates. FTC has the specific authority to investigate claims made in promotional materials, advertisements, contracts, consent forms, and other point of sale materials. To prove deception, FTC must show that there has been a “representation, omission, or practice that is likely to mislead the consumer” and that such deception is likely to affect the consumer’s choice regarding the purchase of a service or product. For those clinics or individuals found to be engaged in deceptive advertising or unfair competition, FTC can impose civil penalties and cease and desist orders.^{xlix 217}

ASRM has issued guidelines on the subjects of advertising and shared-risk or refund programs. ASRM enumerates eight principles for advertising that must be followed by members: (i) advertising must comply with FTC guidelines; (ii) claims must be supported by reliable data; (iii) clinics should not rank or compare success rates; (iv) advertisements should not unreasonably inflate expectations about success; (v) advertisements including references to outcomes may not selectively omit unfavorable data; (vi) the method used to calculate success must be clear; (vii) the Practice Director is ultimately responsible for all advertising content; and (viii) when quoting statistics, the following statement must be included: “A comparison of clinic success rates may not be meaningful because patient medical characteristics and treatment approaches may vary from clinic to clinic.”²¹⁸

In a separate ethics opinion, ASRM sets forth the ethical concerns raised by “shared-risk” or “refund” programs, whereby patients pay a higher initial fee that is refunded if the treatment fails to result in success. Such concerns include the risks of exploitation, unreasonable expectations, overly aggressive and unsafe efforts to maximize chances for success, and conflict of interest. Following this discussion, ASRM concludes that shared risk transactions may be ethically offered to patients lacking health insurance coverage for treatment, provided certain conditions are satisfied, namely, “that the criterion for success is clearly specified, that patients are fully informed of the financial costs and advantages and disadvantages of such programs, that informed consent materials clearly inform patients of their chances of success if found eligible for the shared risk program, and that the program is not guaranteeing pregnancy and delivery.” Additionally, ASRM advises its members to clearly inform patients that “they will be paying a higher cost for IVF if they in fact succeed on the first or second cycle than if they had not chosen the shared risk program, and that, in any event, the costs of screening and drugs are not included.” To prevent the danger that shared risk programs may create incentives for clinicians to take actions that might harm patients in pursuit of success (and to avoid a refund), ASRM advises that patients be informed of the potential conflicts of interest. Moreover, such patients should not be overstimulated, and should be advised of the risks of multifetal gestation.²¹⁹ As with all other ASRM guidelines, these are suggestions rather than directives.

Commercialization in Research

Many academic researchers and scientists have extensive commercial interests bound up in their particular fields of inquiry.²²⁰ Indeed, some academic institutions have license agreements with biotechnology companies entitling such schools to company profits growing out of such research.²²¹ These arrangements have given rise to a host of questions beyond the scope of the present inquiry, including those concerning the possible deleterious consequences for free and open scientific research and collaboration.^l

Patenting of Living Organisms and Human Beings

Current Practices

The Constitution confers upon Congress the authority to regulate patent rights: Article I, Section 8, provides in part that Congress shall have the power “To promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive right to their respective Writings and Discoveries.” Although the concept of patents (and intellectual property more generally) pre-dates the Constitution, the patent is a form of property right expressly permitted by the Constitution.

A patent is an exclusive property right granted to an inventor for a limited time (currently, in most cases, twenty years from the filing date of the application). A patent grants an inventor the right to exclude all others from making, using, offering to sell or selling within, or importing into, the United States the process or article that is the subject of the patent.²²² The holder of a patent has a right to bring an enforcement action in court against others who infringe the patent.²²³ A patent is a right to exclude others, not necessarily a right to practice, make, or own the invention. Patents do not grant the inventor a right to the tangible product that is the product of a patented process. As a general matter, Congress may define and restrict what is patentable, and otherwise restrict patent rights by statute (for example, to promote national security²²⁴).

The Patent Act, which has changed little since it was authored by Thomas Jefferson and enacted in 1793, provides patent rights for three types of patents: plant patents, design patents, and utility patents. Perhaps 95 percent of all patents issued are utility patents.²²⁵ A utility patent may be claimed by whoever “invents or discovers any new and useful process, machine, manufacture or composition of matter, or any new and useful improvement thereof.”²²⁶

To receive a patent, an invention must be novel, nonobvious, and useful. A rich body of law, precedent, and agency practice defines these terms; but in general the bar for meeting them is not terribly high. Although traditionally, the inquiry into a proposed invention’s “usefulness” might have considered the moral value of the invention, current U.S. patent practices do not take such matters into account.

Ethical Concerns

The prospect of patenting human tissues and organisms, as well as the current reality of patenting human DNA, raise several categories of ethical concerns. First, patents create a quasi property right, and of course the idea of one person or entity owning another, or part of another, as property raises deep worries. Second, patents exist to encourage production for profit, and so we must be sure that those things which are patented are things we wish to see produced, and used as sources of profit. Third, patents imply a seal of state sanction, so we should wish to be careful what processes and products we choose to make patentable. Finally, there is the practical concern that patents on genes and the like create a property right in a limited resource with wide utility. Patents, in this way, erect a great obstacle to the use of such resources for the benefits of many. A powerful counterpoint to these claims, however, is that patents are a crucial mechanism to encourage the research and development of enormously useful advances in biomedical science and biotechnology. By permitting researchers to protect the fruits of their labors for a limited time, patents, as Lincoln famously said, “add the fuel of interest to the fire of genius.”

Current Regulation

I. Patenting Living Things. The foregoing analysis presupposes that the claimed invention consists of patentable subject matter. The test for determining this question is quite broad, with some limitations. The Supreme Court has relied on the assertion that the statutory subject matter for a patent includes “anything under the sun that is made by man.”²²⁷ The Court recognized that “laws of nature, physical phenomena, and abstract ideas” are not proper subject matter for patents.²²⁸ For example, minerals found in the earth, plants found naturally occurring, and physical laws such as E=mc² are not patentable subject matter.²²⁹ With respect, however, to those compositions of matter and manufactures that are not naturally occurring (made by man), the Court has established in principle that the nature of the subject—including whether or not the subject consists of a living organism—is irrelevant to the issue of patentability. Congress, of course, retains its unquestioned authority to exclude certain subject matter from patentability.

For about the first one hundred ninety years of its existence, the PTO declined to grant patents for inventions that were “products of nature,” including living organisms.^{li 230} With a few possible exceptions, such as Pasteur’s 1873 patent for a form of yeast, the “product of nature” doctrine prevailed. In 1980, the Supreme Court departed from the “rule of nature” doctrine in the landmark case, Diamond v. Chakrabarty. The applicant sought protection for a form of bacteria that had been genetically engineered to break down multiple components of crude oil, useful, for example, to clean up oil spills.²³¹ The patent examiner rejected the patent on two grounds: first, the bacterium was a “product of nature,” and, second, as a living thing, the bacterium was not patentable. PTO’s Board of Appeals upheld the rejection on the basis that the bacterium was a living thing. ²³²

The Supreme Court had to consider whether living organisms could constitute a “new and useful process, machine, manufacture, or composition of matter” within the meaning of the Patent Act. Reviewing the history of the Act and relevant case law, the Court embraced the notion that “anything under the sun that is made by man”—whether a chemical compound, a machine, a process, or a living organism—is proper subject matter for a patent.²³³ The Court held that the nature of the subject matter for the patent—even if a living thing—was not a proper basis on which to deny an application. It concluded by noting that Congress was free to amend the law either to expressly exclude living organisms from coverage under the Act, or to add special provisions similar to those that exist for plants.

In 1988, the Court of Appeals for the Federal Circuit extended Chakrabarty’s holding beyond microbial organism to multicellular organisms (in this case, oysters), confirming that higher life forms may constitute “anything under the sun that is made by man” for purposes of patentability.²³⁴ PTO has adopted the position that “nonnaturally occurring, nonhuman multicellular living organisms, including animals, [are] patentable subject matter within the scope of 35 USC 101.”²³⁵ Shortly after the Allen decision, the PTO issued the first patent granted on a higher animal, a transgenic mouse modified to be susceptible to cancer (the “Harvard Mouse”).²³⁶

II. Patenting of Human Organisms. Can a human organism (whether of the zygote, blastocyst, embryonic, or fetal stage) be the subject of a patent? Currently, the only express limitation on patents that cover human organisms is an interpretative ruling of PTO, which states that the agency will not grant a patent if “the broadest reasonable interpretation of the claimed invention encompasses a human being.”²³⁷

It is not clear, however, what precisely the PTO means by “human being.” The PTO has issued at least one patent, US 6,211,429, which includes a “method for producing a cloned mammal” that also covers “the living, cloned products produced by each of the methods described.” This patent lacks the “nonhuman” disclaimer that has previously been required for approval under the relevant provisions of the Manual of Patent Examination Procedure. While it is not clear how this broad patent squares with the PTO’s policy of refusing to issue patents that “encompass a human being,” a spokesperson for the PTO has reiterated that this policy remains in force, and there will be no “patent claims drawn to humans.”²³⁸ A spokesman the University of Missouri (the patent holder) has asserted that no human reproductive cloning would be permitted in connection with this particular patent.²³⁹

In 1997, a team of inventors sought to obtain a patent for an invention that covers the production of human-animal chimeras that could be up to 50 percent human.^lii Two years later, the PTO rejected the application, at one point during the process issuing a “media advisory” suggesting that a “morals” requirement still exists with respect to measurement of utility.²⁴⁰ The PTO ultimately rejected the application on the grounds that a claimed invention that “encompasses a human being” is not patentable.²⁴¹ Then-PTO Commissioner Bruce Lehman declared: “There will be no patents on monsters, at least not while I’m commissioner.” But the PTO did not explain why, given that the application sought to cover only those organisms that would be less than 50 percent human, the application “encompassed” a human being. The agency has given no guidance about whether there is a minimum threshold at which such a patent could be obtained (for example, organisms that are up to 10 percent human, or 5 percent human, or 1 percent human). Nor is it clear why patents may be granted on portions of human DNA, but not on an organism that incorporates portions of human DNA.

For now the PTO’s position on patenting human organisms remains merely administrative; it has not been confirmed either judicially or by Congress.^liii The only constitutional provision suggested to have any bearing on this question is the 13th Amendment, which prohibits slavery and involuntary servitude; but it is possible this provision could be found by the courts to apply only to live-born humans. Therefore, the current state of the law with respect to the patentability of human organisms is unclear.

The PTO’s exclusion from patentability of any invention that covers a human may conflict with the United States’ obligations under the Agreement on Trade-Related Aspects of Intellectual Property Rights Agreement (TRIPs), which is obligatory upon the United States by virtue of its participation in the World Trade Organization. Article 27(l) of TRIPs prohibits member states from discriminating in their patent systems against any field of technology. If PTO’s interpretative ruling is grounded only in the Patent Act and not in the Constitution, then TRIPs, being the later statute, would presumably trump. But if PTO’s position is required by the 13th Amendment (or any other part of the Constitution), then the conflict must be resolved in favor of the Constitution, because treaties may not alter constitutional requirements.

Conclusion
Innovations in the biotechnologies and practices that touch the beginnings of human life have given rise to new markets and opportunities for commercialization. There are currently no governmental regulatory mechanisms that explicitly govern the sale of gametes. Very few states have laws that speak to this issue. There are voluntary professional standards that provide guidance relating to gamete donor protections and financial incentives for gamete donation. The assisted reproduction industry is subject to governmental regulations that relate to insurance coverage and truth in advertising. Professional societies have issued voluntary statements providing guidance on advertising and various approaches to the payment for services. Finally, while patents have been issued for living organisms, and even for certain processes for creating human organisms, it seems that by virtue of a policy statement of the PTO, it is not yet possible to patent a human being as a product. It is unclear what the contours of this prohibition are, or whether it will be modified in the future.

SUMMARY AND CONCLUSION

Summary

The foregoing was an effort to present in some detail the current regulatory activities governing the biotechnologies that touch the beginnings of human life. It seems that the present constellation of regulatory mechanisms is broad but not uniform or systematic in its objectives, scope, or enforcement.

The power to initiate life by artificial means is subject to oversight by a host of sources, governmental and nongovernmental. The values underlying governmental regulation are concerns for consumer protection, quality assurance in laboratory procedures, safety and efficacy of products according to their intended use, and the delivery of medical care according to accepted standards of practice. Nongovernmental oversight is aimed fundamentally at ensuring the satisfaction and privacy of those who seek ART services. These standards, while extensive, are hortatory in nature. What seems to be missing from both governmental and nongovernmental regulations, independently or in the aggregate, are meaningful, enforceable safeguards for the well being of the children who come to be born with the aid of these new powers. Moreover, there does not seem to be even oversight activity, much less effective guidelines that aim at concerns relating to the enhanced control over procreation with their resulting impact on the meaning of family, children, and human dignity. Finally, the system of regulation currently in place does not reflect the concerns many people have about the use and destruction of nascent human life that attends the exercise of these new powers over procreation. And there is little knowledge and less guidance regarding the storage and disposition of embryos left over after attempts at procreation.

New powers to screen and select for specific traits and characteristics are not regulated by government, as such. Generally the technologies and practices giving rise to these new powers are regulated according to the context in which they are undertaken—in the course of the practice of medicine or in the course of embryo research. There are presently no authorities—public or private—charged with safeguarding the well-being of children born following PGD. There are no authorities responsible for evaluating the impact PGD may have on the way such children come to be regarded, or the ultimate effects on the meaning of human procreation. There do not seem to be any authorities or regulatory efforts to comprehensively monitor the uses, applications, or long-term effects of PGD on children born after its use. At the nongovernmental level, there are guidelines that the use of PGD for elective sex selection “should be strongly discouraged” on ethical grounds, but these are not binding, and in fact, are not followed by at least one prominent practitioner of assisted reproduction. There are also no guidelines regarding the boundary between using PGD for producing a disease-free child and using it for so-called enhancement purposes or to produce siblings for children needing transplant donors.

Potential new powers to modify and engineer developing human beings, if they are ever realized, would likely be regulated in the larger context of the federal regulation of gene transfer research, done on existing patients. Current regulations in this regard include stringent protections for human subjects and rigorous standards requiring practitioners to demonstrate and document the safety and efficacy of such procedures. Moreover, most (if not all) such research is subject to federal guidelines that require submission of prospective research protocols to a body that publicly discusses the ethical implications of projects raising novel or important issues. Thus, safety, efficacy, and public deliberation are the chief animating principles of regulation in this regard. Officially, it is the safety of the participants in such research that drives the federal regulation of genetic modification, but these regulations seem also to be informed by a regard for as yet unconceived future generations who may be affected (unintentionally) by such modification. That being said, there is no positive authority that empowers the federal government to consider the safety of such future individuals. This absence of positive authority might prove to be an obstacle to meaningful regulation of germ line gene transfer, should it ever be undertaken; yet intentional germ line modification is not now being pursued due to concerns for safety and efficacy.

New powers to observe and manipulate in vitro nascent human life for purposes of scientific research are not regulated in a meaningful way by the federal government. The federal government neither promotes nor prohibits such research. State regulation varies widely, ranging from permissive approaches (no regulation at all) to strict prohibition. There is thus no uniformity in governmental regulation of embryo research. The nongovernmental regulation of this power takes the form of ethical opinions and practice guidelines issued by professional societies. Subject to certain limitations discussed above, these authorities, in the main, endorse and promote such research based on their view that the embryo’s moral status permits its use and destruction for certain scientific ends.

Commercialization and commodification growing out of the biotechnologies touching the beginnings of human life are subject to some degree of regulation, but they are largely left to the market. There is very little controlling law on the sale of gametes. Professional societies provide some detailed yet hortatory guidelines regarding financial incentives and donor protections. The ART industry is subject to external regulation for purposes of consumer protection, particularly with regard to truth in advertising and reporting success rates. As for access, there is some state statutory authority relating to the provision of insurance coverage, but this varies widely in scope and substance. Professional societies offer some guidance as to how to structure compensation and truth in advertising. Regarding intellectual property protections, there is currently no federal statutory or judge made authority that precludes patents on human beings, but there is a policy statement that directs PTO examiners not to issue patents that “encompass human beings.” It is unclear precisely what this means in practice.

Conclusion

While the document is intentionally neutral regarding what changes, if any, should be made in the present system, it may be possible at this point to make a few general observations about the regulatory landscape as a whole.

Taken as a whole, the present system advances a number of goods and values. It promotes the safety and efficacy of products for their intended uses, and provides an extensive system of protections for human subjects participating in clinical trials. It seems to allow for the robust and innovative practice of medicine, permitting physicians wide latitude to employ novel approaches in their efforts to help patients overcome infertility. Scientists are generally uninhibited (though not federally funded) by the present system of regulation from pursuing research on matters relating to human health, and in many cases can secure patents to protect the fruits of their labors. The present system accords prospective parents a great deal of freedom to choose from a variety of approaches to assisted reproduction, and similarly confers upon them maximal freedom to make choices on behalf of their children-to-be. Finally, present governance of commerce growing out of the biotechnologies that touch the beginnings of human life is largely left to the market, with all the attendant benefits of the freedom to contract and free enterprise.

The weaknesses of the present system in some ways grow out of its strengths. Practitioners and parents have such wide latitude to pursue the benefits of the new biotechnologies touching the beginnings of human life precisely because there are no governmental authorities or professional bodies charged with ensuring the well-being of such children-to-be, and tort liability is a crude and merely after the fact substitute for recommended guidelines. As with their treatment in other branches of medicine, the interests of such children are solely the province of parents. There are strong reasons to believe, however, that assisted reproduction—especially in light of the advent of the new genetic technologies—is, for reasons discussed extensively above, unique and perhaps deserving of special oversight in this regard. There are presently no governmental bodies with the responsibility to monitor or discuss the broader ethical implications of these new biotechnologies. Scientists currently enjoy unbounded freedom regarding what they can and cannot do with human embryos because the current system of federal regulation neither officially promotes nor prohibits such research. This approach withholds the endorsement of the federal government for such research, but also leaves privately funded research unregulated and unbounded, to the extent that states are silent on the matter. Finally, as to commerce and commodification, the present system lacks a uniform approach to questions of access and does not include safeguards or oversight mechanisms for deleterious effects on human dignity that may result from the increasing commercialization of human procreation or the buying and selling of gametes and embryos.

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Footnotes

1. There are a number of adjunct screening procedures that may be performed at this stage of assisted reproduction that are discussed extensively in Section II below.
2. The number of ova collected depends on a number of variables, including the donor’s age, health, etc. In some cases, ten or more ova are fertilized.
3. ICSI is also indicated when the sperm is acquired by artificial means through assisted sperm retrieval. ICSI is also used in the course of a normal IVF cycle for oocytes that have been mixed with sperm but have not yet fertilized. Some ART clinics require ICSI if patients desire to use preimplantation genetic diagnosis, discussed further in Section II below.
4. Specific concerns regarding the possible health effects of ICSI on the child-to-be are discussed under “ethical concerns,” below.
5. There is currently research underway on a procedure that would help women with defective ova to conceive. The procedure, called “ovarian nuclear transfer,” involves transplantation of the nucleus of the mother’s ova into an enucleated donor ovum. The resulting child would thus receive genetic information from three sources, the ovum donor, the nucleus donor, and the sperm donor.
6. There is not yet a reliable method of freezing unfertilized ova. This is perhaps due to their large size and high water content. Additionally, it seems that freezing an ovum toughens the zona pellucida in a way that can inhibit sperm penetration.
7. Gestational surrogates were used in 1.2 percent of the cycles undertaken in the United States in 2000.
8. This statistic is for never-frozen, self-provided ova or embryos—the most common approach in 2000.
9. 28.4 percent were twins, 7.7 percent were triplets or more. In 5.8 percent of ART pregnancies, the pregnancy ended in miscarriage where the number of fetuses was impossible to determine. The rate of multiple-fetus pregnancies from ART cycles using never-frozen donor ova was 42.5 percent. (CDC Report, p. 20.)
10. It should be noted, however, that progress is being made toward single embryo transfer with retention and pregnancy in about 34 percent of the transfers. See DeSutter, P., et al., “Single Embryo Transfer and Multiple Pregnancy Rate Reduction in IVF/ISCI: A Five Year Appraisal,” Reproductive BioMedicine Online, 6: 2003, http://www.rbmonline.com/Article/836 (30 May 2003).
11. A “cycle” is initiated when a woman begins the process of superovulation and monitoring (CDC Report at 4.) Not all cycles result in successful ova collection, fertilization, transfer, pregnancy, or birth.
12. There seems to be a negative association between cryopreservation and implantation. For all pregnancies initiated using frozen self-provided embryos, the success rate was 20.3 percent live births per transfer (19.5 percent per thaw) (CDC Report, p. 44). For cycles using never-frozen donated embryos, 43.4 percent of transfers resulted in live births (CDC Report, p. 49). For frozen donated embryos, the success rate was 23.5 percent per transfer (CDC Report, p. 49).
13. Of the 2,313 live births using frozen, self-provided embryos, 25.6 percent resulted in multiple births (CDC Report, p. 45). Of the 2,922 live births using never-frozen donated embryos, 40.3 percent resulted in multiple births (CDC Report, p. 48). There are no such statistics for cycles using frozen, donated embryos.
14. The U.S. national average for prematurity among children born by natural means is approximately 12 percent. (March of Dimes Survey, 2000).
15. Researchers at Johns Hopkins University noted that among the patients listed in the 1994 Beckwith-Wiedemann registry, IVF conception was six times more common than in the general population. That is, 4.6 percent of the patients in the registry were conceived through IVF, as compared with 0.8 percent of the national population. BWS sufferers are predisposed to Wilms’ tumor, hepatoblastoma, neuroblastoma and other cancers. Despite their findings, JHU researchers suggested that parents should not alter their plans to use IVF.
16. The discussion of one such adjunct, preimplantation genetic diagnosis, will be deferred to Section II below.
17. In 2000, approximately 69 percent of all transfers failed to result in birth. It bears noting, however, that there is in the course of natural reproduction, a very high degree of embryo loss, likely due to natural defects. Because the causes of failure in both natural and assisted reproduction are not fully understood, it is difficult to compare the two phenomena in a meaningful way.
18. Until recently, no federal money was budgeted for validation. Instead, SART underwrote the costs of validation itself.
19. It bears noting that these HCT/Ps are not “drugs” and thus do not require FDA approval as such. If they did, it would effectively require pre-market approval (including clinical trials) for all HCT/Ps before any could be distributed to human beings. This would effectively put all tissue banks (including blood and sperm banks) and clinicians working with such products out of business.
20. As of June 2003 the effective date of these regulations had been delayed.
21. Indeed there are specific regulations governing devices used in ART. See 21 CFR 884.6100 et seq.
22. The Model Medical Practice Act defines “practice of medicine” as: advertising, holding out to the public or representing in any manner that one is authorized to practice medicine in the jurisdiction; offering or undertaking to prescribe, order, give or administer any drug or medicine for the use of any other person; offering or undertaking to prevent or to diagnose, correct or treat in any manner or by any means, methods, or devices any disease, illness, pain, wound, fracture, infirmity, defect or abnormal physical or mental condition of any person, including the management of pregnancy and parturition; offering or undertaking to perform any surgical operation upon any person; rendering a written or otherwise documented medical opinion concerning the diagnosis or treatment of a patient or the actual rendering of treatment to a patient within a state by a physician located outside the state as a result of transmission of individual patient data by electronic or other means from within a state to such physician or his or her agent; rendering a determination of medical necessity or a decision affecting the diagnosis or treatment of a patient; and using the designation Doctor, Doctor of Medicine, Doctor of Osteopathy, Physician, Surgeon, Physician and Surgeon, Dr., M.D., D.O. or any combination thereof in the conduct of any occupation or profession pertaining to the prevention, diagnosis or treatment of human disease or condition unless such a designation additionally contains the description of another branch of the healing arts for which one holds a valid license in the jurisdiction.
23. This guideline is currently being re-evaluated.
24. During his presentation to the Council in December 2002, Dr. Collins speculated that one such application of PGD would be to screen for genetic markers correlated with higher IQ levels. While he expressed skepticism that such tests would be effective or reliable, he did think the demand for such tests would be high.
25. This is in contrast to the ethical opinion of the American Academy of Pediatrics (1994), which deems PGD an “experimental” procedure.
26. ICSI is the preferred technique for insemination in this context. PGD following ICSI yields the most accurate results, because there are no excess sperm imbedded in zona pellucida of the fertilized ovum that might contaminate or otherwise affect the accuracy of the analysis of the biopsied cells.
27. When used for therapeutic indications, PGD is regulated within the larger regulatory framework for assisted reproduction (discussed in Section I). When used for purely research purposes, the regulation of PGD is subsumed under the framework for regulating embryo research, discussed in Section IV below.
28. There is demographic evidence that choosing sex of children is increasing in the U.S.—largely using sonography and abortion. No governmental or private institution to the best of our knowledge is monitoring such uses or such demographic effects.
29. Some commentators prefer the term “inheritable genetic modification” rather than “germ line” modification, because there are means of effecting heritable genetic change that do not involve gene transfer into the reproductive cells. Such alternatives include ooplasm transfer or ovum nuclear transplantation, both of which can result in inheritance of the mitochondrial DNA from the donor of the ooplasm or ovum.
30. ewman, Stuart A., Department of Cell Biology and Anatomy, New York Medical College, written comments to the President’s Council on Bioethics, April 2003. (“Laboratory experience shows that insertion of foreign DNA into inopportune sites in an embryo’s chromosomes can lead to extensive perturbation of development. For example, the disruption of a normal gene by insertion of foreign DNA in a mouse caused abnormal circling behavior when present in one copy, lack of eye development, lack of development of the semicircular canals of the inner ear and anomalies of the olfactory epithelium (the tissue that mediates the sense of smell), when mice were inbred so that mutation appeared in the homozygous form (i.e., on both copies of the relevant chromosome). Another such “insertional mutagenesis” event led to a strain of mice that exhibited limb, brain and craniofacial malformations, as well as displacement of the heart to the right side of the chest, in the homozygous state. Each of these developmental anomaly syndromes were previously unknown. From current, or even anticipated models for the relationship between genes and organismal forms and functions, the prediction of complex phenotypes on the basis of knowledge of the gene sequence inserted or disrupted is likely to remain elusive. ... During [embryonic] development, [gene alteration] is much more complicated [than in a developed individual]. Tissues and organs are taking form during this period, and the activity of genes is anything but modular. During development many, if not most, gene products can have multiple effects on the architecture of organs and the wiring of the nervous system, including the brain. Individuals produced by developmental intervention (particularly as it comes to extend beyond the single gene, to chromosomes or groups of chromosomes) could turn out to be “experimental artifacts,” in the sense that their bodies and mentalities could be quite different from those of anyone generated by natural processes using standard starting materials (including by IVF)”).
31. Unlike an already existing embryo, ovum and sperm cannot be said to constitute an existing individual whose genetic abnormalities issue in a putative claim for treatment; hence, there is no compelling imperative to treat that might conceivably justify running such risks.
32. Because all gene therapy is currently understood as experimental, recipients of gene therapy are considered human subjects with all the attendant protections of the Common Rule and FDA safeguards. An embryo, however, is not a “human subject” for purposes of these protections, though parents (certainly the mother) would qualify as a subject in the context of ex utero gene modification. Human subjects protections only reach embryos once they are implanted in vivo, as discussed in Section IV below.
33. Recall that an article may be regulated both as a drug and a biologic, if it satisfies both definitions—which are very expansive, as discussed in Section I, above.
34. The Grimes Court seems to qualify this view somewhat later in the opinion, stating that parents may not authorize the exposure of their children to more than minimal risk in studies that offer no prospect of benefit to such children. This view more closely tracks the federal guidelines.
35. Such conditions included informed consent for use of gametes, the purposes of the research was important and “not reasonably attainable by other means,” and embryos would not be maintained outside the body beyond fourteen days after fertilization. (DHEW EAB 1979, 106, 107 (quoted in NBAC report at 34).)
36. The specific conclusions of the NIH Embryo Panel are discussed further, infra.
37. “The Panel believes that the use of oocytes fertilized expressly for research should be allowed only under two conditions. The first condition is when the research by its very nature cannot otherwise be validly conducted. The second condition . . . is when a compelling case can be made that this is necessary for the validity of a study that is potentially of outstanding scientific and therapeutic value.” (Report of the Human Embryo Research Panel, September 1994).
38. A minor technical matter: 45 CFR 46.208 no longer exists, although the Dickey-Wicker reference to it exists as recently as the Fiscal Year 2003 Consolidated Appropriations Resolution (P.L. 108-07, signed February 20, 2003) and in NIH's March 18, 2003, explanation of the appropriations resolution (Notice NOT-OD-03-035). 45 CFR 46.208(a)(2) is currently expressed at 45 CFR 46.204(b)).
39. The guidance was issued following a decision by NIH that the Dickey-Wicker amendment did not prohibit federally funded research preceding or following the destruction of human embryos. Thus, NIH concluded that it could fund research projects on human embryonic stem cell lines that had been previously derived. The November 21, 2000, guidance remains effective with respect to NIH funding of research using germ cells derived from fetal tissue.
40. The registry is available at http://escr.nih.gov/.
41. H.R. 534
42. See, for example, Arizona, Arkansas, California, Florida, Indiana, Kentucky, Missouri, Nebraska, Ohio, Oklahoma, Tennessee, and Wyoming.
43. See, for example, Louisiana, Maine, Massachusetts, Michigan, Minnesota, New Hampshire, New Mexico, North Dakota, Pennsylvania, Rhode Island, and South Dakota.
44. The Panel concluded that federal funding is acceptable only for research involving embryos acquired by these means prior to September 1994.
45. See, for example, Florida, Illinois, Louisiana, Michigan, South Dakota, and Utah.
46. Eggs, while technically “nonrenewable” (since women are born with a finite number of them), could be said to be so numerous as to constitute renewable tissue.
47. Arkansas, California, Connecticut, Hawaii, Illinois, Maryland, Massachusetts, Montana, New Jersey, New York, Ohio, Rhode Island, Texas, and West Virginia. (Source: ASRM web site.)
48. See, for example, Arkansas.
49. FTC has initiated disciplinary actions against fertility clinics for misrepresentation of reproductive service successes. For example, in October 1991 FTC charged Reproductive Genetics In Vitro, P.C., of Denver, Colorado, with making false and unsubstantiated claims about the success of its IVF program. The company claimed in its promotional brochure that women who make a single attempt at conception have a 25 percent chance of becoming pregnant and that the clinic’s success rate was two and a half times higher than the national average of 10 percent. FTC alleged that these claims were unsubstantiated and that the company was failing to disclose that it excluded from its success rate statistics those women who began the IVF program but did not become pregnant because they never reached the stage where a fertilized ovum was transferred into their uterus. The allegations were settled by consent agreement on January 15, 1992. In February 1992 FTC testified before Congress in favor of a success-rate formula that “takes into account all significant negative results.”
50. For an extensive discussion of commercialization in research, see the two-volume report recently issued by the Association of American Medical Colleges Task Force on Financial Conflicts of Interest in Clinical Research entitled “Protecting Subjects, Preserving Trust, Promoting Progress.” Volume I is entitled “Policy and Guidelines for the Oversight of Individual Financial Interests in Human Subjects Research” (December 2001); and Volume II is entitled “Principles and Recommendations for Oversight of an Institution’s Financial Interests in Human Subjects Research” (October 2002).
51. The PTO did grant patents in 1967 and 1968 that covered micro-organisms (Chakrabarty, 444 U.S. at 314, n.9).
52. See Thomas A. Magnani, The Patentability of Human-Animal Chimeras, 14 Berkley Tech. L.J. 443, 443 (1999). The inventors—Dr. Stuart Newman and Jeremy Rifkin—claim to have sought the patent for use in the purest form of the patent; that is, they stated that their intention was to prevent anyone from producing human-animal chimeras during the life of the patent, for the purpose of allowing greater policy discussions to occur before such creatures would be created.
53. “[PTO] lacks substantive rule making authority. … A challenge to the non-patentability of human beings would be a case of first impression to the Court.” Hauda, Karen, U.S. Patent and Trademark Organization, testimony before the President’s Council on Bioethics, Washington, D.C., June 20, 2002.

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ENDNOTES

1. President’s Council on Bioethics, Human Cloning and Human Dignity: An Ethical Inquiry, p. 211, Washington, DC: Government Printing Office, 2002.
2. Centers for Disease Control and Prevention (CDC), 2000 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports, p. 14, Atlanta, GA, Government Printing Office, 2002.
3. Ibid, p. 64.
4. Ibid, p. 64.
5. Ibid, p. 64.
6. Ibid, p. 37.
7. Ibid, p. 37.
8. Ibid, pp. 37, 73.
9. Ibid, p. 39.
10. Depypere, H.T., et al., “Intracellular pH Changes During Zona Drilling,” Fertility and Sterility, 61: 319, 1994.
11. Tarín, J.J., “Subzonal Insemination, Partial Zona Dissection or Intracytoplasmic Sperm Injection? An Easy Decision?” Human Reproduction, 10: 165, 1995.
12. Catt, J., et al., “Subzonal Insertion of Multiple Sperm Is a Treatment for Male Factor Infertility,” Fertility and Sterility, 61: 123, 1994.
13. Barritt, J., et al., “Cytoplasmic Transfer in Assisted Reproduction,” Human Reproduction Update 7: 428-435, 2001.
14. Edwards, R.G., et al., “Destruction of Cryopreserved Embryos: UK Law Dictated the Destruction of 5000 Cryopreserved Human Embryos,” Human Reproduction 12: 3, 1997.
15. Hoffman, D.I., et al., “Cryopreserved Embryos in the United States and Their Availability for Research,” Fertility and Sterility, 79: 1063-1069, 2003.
16. See CDC Report, note 2, above, p. 44.
17. Ibid, p. 44.
18. See note 15, above.
19. Van Voorhis, B.J., et al., “The Efficacy and Cost Effectiveness of Embryo Cryopreservation Compared with Other Assisted Reproductive Techniques,” Fertility and Sterility, 64: 647, 1995.
20. Gardner, D. K., et al., “Culture and Transfer of Human Blastocysts Increases Implantation Rates and Reduces the Nee for Multiple Embryo Transfers,” presentation at the October 1997 annual meeting of the American Society for Reproductive Medicine, Cincinnati, OH.
21. Scott, R.T., et al., “Embryo Quality and Pregnancy Rates in Patients Attempting Pregnancy Through In Vitro Fertilization,” Fertility and Sterility, 55: 426, 1991.
22. American Society for Reproductive Medicine, Practice Committee Report, “The Role of Assisted Hatching in IVF: A Review of the Literature,” August 2000, http://www.asm.org/Media/Practice/assistedhatching.pdf (4 June 2003).
23. Macaluso, M., Senior Research Scientist and Chief of Women’s Health and Fertility Branch, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, email comments to the President’s Council on Bioethics, 29 May 2003.
24. See CDC Report, note 2, above, p. 73.
25. Ibid, p. 34.
26. New York State Task Force on Life and the Law, Assisted Reproductive Technologies: Analysis and Recommendations for Public Policy, p. 63, New York: New York State Task Force on Life and the Law, 1998.
27. See CDC Report, note 2, above, p. 37.
28. Ibid, p. 73.
29. See NYSTF Report, note 26, above, p. 69.
30. See CDC Report, note 2, above, p. 20.
31. Ibid, p. 17.
32. Ibid, p. 19.
33. Ibid, p. 20.
34. McElrath, T.F., et al., “Fertility Therapy and the Risk of Very Low Birth Weight,” Obstetrics and Gynecology, 90: 600, 1997; Mullen, M. A., “Medically Assisted Reproductive Technologies: A Review,” Research Studies of the Royal Commission on New Reproductive Technologies, 9: 47, 1993.
35. Rufat, P., et al., “Task Force Report on the Outcome of Pregnancies and Children Conceived by In Vitro Fertilization (France: 1987 to 1989),” Fertility and Sterility, 61: 324, 1994.
36. See NYSTF Report, note 26, above, p. 70.
37. Edwards, R.G., et al., “Current Status of In-Vitro Fertilisation and Implantation of Human Embryos,” Lancet, 2: 1265-9, 1983.
38. Gould, K.G., “Ovum Recovery and In Vitro Fertilization in the Chimpanzee,” Fertility and Sterility, 40: 378-83, 1983.
39. Van Steirteghem, A.C., et al., “High Fertilization and Implantation Rates After Intracytoplasmic Sperm Injection,” Human Reproduction, 8: 1061-6, 1993.
40. Hewitson, L., et al., “Unique Checkpoints During the First Cell Cycle of Fertilization After Intracytoplasmic Sperm Injection in Rhesus Monkeys,” Nature Medicine, 5: 431-3, 1999.
41. Kimura, Y., et al., “Intracytoplasmic Sperm Injection in the Mouse,” Biology of Reproduction, 52: 709-20, 1995.
42. Schatten, G. P., “Safeguarding ART,” Nature Cell Biology & Nature Medicine, S19—S22, 2002.
43. See generally Ibid, especially ref. 47.
44. Winston, R., et al., “Are We Ignoring Potential Dangers of In Vitro Fertilization and Related Treatments?” Nature Cell Biology & Nature Medicine, S14-S18, 2002.
45. Ibid.
46. American Society for Reproductive Medicine press release, “Highlights from ASRM 2002: The 58th Annual Meeting of the American Society for Reproductive Medicine, October 12-17, 2002—Seattle, Washington; 170,000 Babies Born in USA from ART since 1985: Success Rate More Than Doubled in That Time,” October 14, 2002, http://www.asrm.org/Meida/Press/170000babies.html (1 June 2003).
47. Hansen, M., et al., “The Risk of Major Birth Defects After Intracytoplasmic Sperm Injection and In Vitro Fertilization,” The New England Journal of Medicine, 346: 725, 2002.
48. Bonduelle, M., et al., “Neonatal Data on a Cohort of 2889 Infants Born After ISCI (1991-1999) and of 2995 Infants Born After IVF (1983-1999),” Human Reproduction, 17: 671, 2002; see also Bergh, T., et al., “Deliveries and Children Born After In-Vitro Fertilisation in Sweden 1982-1985,” Lancet, 354: 1579-85, 1999.
49. Moll, A.C., et al., “Incidence of Retinoblastoma in Children Born After In-Vitro Fertilisation,” Lancet, 361: 309-10, 2003.
50. See Bergh, note 48, above.
51. Mestel, R., “Some Studies See Ills for In Vitro Children: Evidence of Increases in Eye Cancer and Mental Retardation Needs to be Verified,” 24 January 2003, p. A1.
52. Strain, L., et al., “A True Hermaphrodite Chimera Resulting from Embryo Amalgamation After In Vitro Fertilization,” New England Journal of Medicine, 338: 166, 1998.
53. Johns Hopkins Medical Institutions press release, In Vitro Fertilization May be Linked to Bladder Defects, 18 March 2003, http://www.hopkinsmedicine.org/press/2003/March/030318A.htm (28 April 2003), quoting the study’s senior author, John P. Gearhart, M.D.: “These defects are extremely rare, and our preliminary findings should not alone discourage couples from undergoing IVF”.
54. See notes 47 and 48, above.
55. See note 44, above.
56. See Mestel, note 51 above; see also Schatten, note 42, above.
57. See note 42, above, esp. ref. 17.
58. See note 44, above.
59. See note 42, above.
60. Slotnick, R.N., Ortega, J.E., “Monoamniotic Twinning and Zona Manipulation: A survey of U.S. IVF Centers Correlating Zona Manipulation Procedures and High-Risk Twinning Frequency,” Journal of Assisted Reproduction and Genetics, 13: 381, 1996.
61. See CDC Report, note 2, above, p. 20; Wilcox, L.S., et al., “Assisted Reproductive Technologies: Estimates of Their Contribution to Multiple Births and Newborn Hospital Days in the United States,” Fertility and Sterility, 65: 361, 1996.
62. See CDC Report, note 2, above, p. 20.
63. American Society for Reproductive Medicine, Patient’s Fact Sheet “Complications of Multiple Gestation,” August, 2001, http://www.asrm.org/Patients/FactSheets/complications-multi.pdf (3 June 2003).
64. Haning, R.V., et al., “Effects of Fetal Number and Multifetal Reduction on Length of In Vitro Fertilization Pregnancies,” Obstetrics and Gynecology, 87: 964, 1996.
65. Martin, J.A., et al., “Triplet Births: Trends and Outcomes, 1971-1994,” Vital and Health Statistics. Series 21, Data from the National Vital Statistics System, 21: 1-20, 1997.
66. See NYSTF Report, note 26, above, p. 74.
67. Barker, D.J., “The Wellcome Foundation Lecture, 1994: The Fetal Origins of Adult Disease,” Proceedings of the Royal Society of London. Series B. Biological Sciences. 262: 37-43, 1995.
68. Schieve, L.A., et al., “Low and Very Low Birth Weight in Infants Conceived with Use of Assisted Reproductive Technology,” The New England Journal of Medicine, 346: 731-737, 2002.
69. Evans, M.I., et al., “Efficacy of Transabdominal Multifetal Pregnancy Reduction: Collaborative Experience Among the World’s Largest Centers,” Obstetrics and Gynecology, 82: 61, 1993.
70. See NYSTF Report, note 26, above, p. 71.
71. Haning, R.V., et al., “Effects of Fetal Number and Multifetal Reduction on Length of In Vitro Fertilization Pregnancies,” Obstetrics and Gynecology, 87: 964, 966, 1996; Lee, J.P., et al., “Obstetric Outcomes of Twin Pregnancy after Multifetal Pregnancy Reduction (MFPR) Are Affected by Initial Number of the Fetuses,” presentation at the October, 1997 annual meeting for the American Society for Reproductive Medicine, Cincinnati, OH.
72. E. Geva et al., “Multifetal Pregnancy Reduction: A Possible Risk Factor for Periventricular Leukomalacia in Premature Newborn,” Presentation at the October 1997 annual meeting of the American Society for Reproductive Medicine, Cincinnati, OH.
73. Delvigne, A., et al., “Systematic Review of Data Concerning Etiopathology of Ovarian Hyperstimulation Syndrome,” International Journal of Fertility and Women’s Medicine, 47: 211-26, 2002.
74. See American Society for Reproductive Medicine, Practice Committee Report, “Induction of Ovarian Follicle Development and Ovulation with Exogenous Gonadotropins,” 1998, http://www.asrm.org/Media/Practice/ovulation.html (2 June 2003); Millican, Lynn, R.N., B.S.N., Paralegal, Testimony before the Senate Health, Education, Labor, and Pensions Committee, April 24, 2002.
75. See Millican, note 74, above.
76. Verlaenen, H., et al., “Singleton Pregnancy After In Vitro Fertilization: Expectations and Outcome,” Obstetrics and Gynecology, 86: 906, 1995.
77. See NYSTF Report, note 26, above, p. 70.
78. Ibid.
79. Collins, J.A., “A couple with Infertility,” Journal of the American Medical Association, 274: 1159, 1995.
80. Hübner, K., et al., “Derivation of Oocytes from Mouse Embryonic Stem Cells,” Science, 300: 1251-1256, 2003.
81. Pub. L. No. 102-493, 42 USC 263a-1 et seq.
82. 42 USC 263a-1(a).
83. 42 USC. 263a-7(1).
84. 65 FR 53312.
85. 42 USC. 263a-7(2).
86. 64 FR 39374-01.
87. 42 USCA 263a-1 § 3(i)(1), (2).
88. See, for example, Fl. St. § 63.212 et seq.; La R.S. 40:32; Va. St. § 20-156; Wa. St. 26.26.011.
89. N.H. Rev. Stat. S. 168-B:13.
90. Ibid.
91. Ibid.
92. 18 Pa.C.S.A. § 3213.
93. NM St. §24-9A et seq.; La. R.S. 9:131 et seq.; SD St. §34-14-17.
94. NM Stat. Ann. 24-9A-S.
95. NM Stat Ann 24-9A-1.
96. Reilly, C., “Constitutional Limits on New Mexico’s In Vitro Fertilization Law,” New Mexico Law Review, 24: 125-144, 1994.
97. See generally Lifchez v. Hartigan, 735 F.Supp. 1361 (N.D. Il., 1990); Margaret S. v. Edwards, 794 F.2d 994 (5th Cir. 1986); Jane L. v. Bangerter, 102 F.3d 1112 (10th Cir. 1996).
98. Lifchez v. Hartigan, 735 F.Supp 1361, 1377 (N.D. Il. 1990).
99. See generally, 21 USC. 301 et seq. (“Federal Food, Drug and Cosmetic Act”); 42 USC. 201 et seq. (“Public Health Services Act”).
100. 42 USC. 264 (known as “Section 361” of the Public Health Services Act).
101. See 21 USC. 321(g)(1).
102. 21 USC. 355(a).
103. Merrill, R.A., “Human Tissues and Reproductive Cloning: New Technologies Challenge FDA” Houston Journal Health Law and Policy, 3: 1-86, 2002, citing 21 USC. 355(b). The specific FDA protections for human subjects involved in clinical trials are discussed extensively in Section II, infra.
104. Ibid.
105. 21 USC 355(i).
106. 42 USC. 262(i).
107. 42 USC 262(a)(1)(A).
108. 42 USC 262(a)(2)(B)(i).
109. 21 CFR 601.2.
110. 42 USC 262(j).
111. 42 USC 264.
112. 63 FR 26,744.
113. 63 FR 26,745.
114. 63 FR 26,748.
115. 21 CFR 1271.15.
116. 21 USC 321(h).
117. 21 USC 360(c).
118. 21 USC 360(k).
119. 42 USC 262(c).
120. 42 USC 262(a) and 21 USC 355(e).
121. 42 USC 262(d).
122. 42 USC 262(f) and 21 USC 332, 333, and 334.
123. 37 Fed. Reg. 16,503 (1972).
124. United States v. Evers, 643 F.2d. 1043 (5th Cir. 1981). See also United States v. Evers, 453 F. Supp. 1141 (M.D. Ala. 1978) (stating that Congress did not intend for the FDA to interfere with the practice of medicine).
125. For an exhaustive analysis of the FDA’s exercise of jurisdiction in the context of human cloning, see Merrill, note 102, above.
126. Zoon, Katherine C., Director, Center for Biologics Evaluation and Research, Food and Drug Administration, testimony before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, House of Representatives, March 28, 2001; see also Merrill, note 102, above.
127. 42 USC 263a.
128. See e.g., M.G.L.A. ch.111 §70E.
129. 21 USC.A. 801 et. seq.
130. 42 USC §11101-11152.
131. See 42 USC §§1395x(e) and 1395bb.
132. Del Zio v. Presbyterian Hospital, 74 Civ. 3588 (S.D.N.Y. April 12, 1978).
133. Rebar, R., American Society for Reproductive Medicine, written comments to the President’s Council on Bioethics, 15 April, 2003.
134. American Medical Association, Ethical Conduct in Assisted Reproductive Technology, 22 July 2002, http://www.ama-assn.org/ama/pub/category/8418.html (3 June 2003).
135. American Academy of Pediatrics, Fetal Therapy—Ethical Considerations, May 1999, http://www.aap.org/policy/re9817.html (3 June 2003).
136. Collins, F.S., Director, National Human Genome Research Institute (NHGRI), Presentation at the December 2002 meeting of the President’s Council on Bioethics, Washington, D.C. Transcript available on the Council’s web site at http://bioethics.gov/transcripts/dec02/session5.html.
137. American Society for Reproductive Medicine, Fact Sheet, “Preimplantation Genetic Diagnosis,” December 1996, http://www.asrm.org/Patients/FactSheets/PGD-Fact.pdf (3 June 2003).
138. Zitner, A., “A Girl or Boy, You Pick,” Los Angeles Times, 23 July 2002, p. A1.
139. American Society for Reproductive Medicine, Practice Committee Report, “Preimplantation Genetic Diagnosis,” June 2001, http://www.asrm.org/Media/Practice/preimplantation.pdf (3 June 2003).
140. International Center for Technology Assessment, written comments to the President’s Council on Bioethics, May 2003.
141. Ibid.
142. See note 136, above.
143. Schatten, Gerald P., Professor and Vice Chair, Obstetrics-Gynecology & Reproductive Sciences and Cell Biology-Physiology, University of Pittsburgh School of Medicine, and Director, Pittsburgh Development Center; and Deputy Director, Magee-Women’s Research Institute, Presentation at the December 2002 meeting of the President’s Council on Bioethics, Washington, DC. Transcript available on the Council’s web site at http://bioethics.gov/transcripts/dec02/session6.html.
144. See note 139, above.
145. S. Munne et al., “First Pregnancies after Polar Body Biopsy for Testing of Chromosome Translocations,” presentation at the ASRM annual meeting, Boston, MA, November 2-6, 1996; S.E. Smith et al., “Birth after Polar Body Biopsy Using Acidified Tyrode’s Medium Followed by ICSI,” presentation at the ASRM annual meeting, Cincinnati, OH, October 18-22, 1997.
146. See note 42, above.
147. No. 122555/00, 2003 WL 1922819 (N.Y. Sup.) (slip opinion).
148. Ethics Committee of the American Society for Reproductive Medicine, “Sex Selection and PGD,” Fertility and Sterility, 72: 595-598, 1999.
149. Ethics Committee of the American Society for Reproductive Medicine, “Preconception Gender Selection for Nonmedical Reasons,” Fertility and Sterility, 75: 861-684, 2001.
150. Blaese, R.M., et al., “T Lymphocyte-Directed Gene Therapy for ADA-SCID: Initial Trial Results After Four Years,” Science, 270: 475-480, 1995.
151. NIH Recombinant DNA Advisory Committee, “Human Gene Transfer Protocols,” February, 2003, http://www4.od.nih.gov/oba/rac/PROTOCOL.pdf (27 May 2003).
152. Newman, S.A., “Human Developmental Modification: Prospects and Perils,” submitted to the President’s Council on Bioethics by The Council for Responsible Genetics, April 2003.
153. Chan, A.W.S., et al., “Transgenic Monkeys Produced by Retroviral Gene Transform into Mature Oocytes,” Science, 291: 309-312, 2001.
154. Larin, Z., et al., “Advances in Human Artificial Chromosome Technology,” Trends in Genetics, 18: 313-319, 2002.
155. See note 136, above.
156. 49 FR 50878.
157. Food and Drug Administration, Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy, March 1998, http://www.fda.gov/cber/gdlns/somgene.pdf (4 June 2003).
158. Ibid.
159. 58 FR 53248.
160. 58 FR 53251.
161. 42 USC 262(a).
162. PHSA Section 351(a).
163. 42 USC 262(d)).
164. 21 CFR Part 312—drug reqs applicable to biologics.
165. Food and Drug Administration, “Human Gene Therapy and the Role of the Food and Drug Association,” September 2000, http://www.fda.gov/cber/infosheets/genezh.htm (13 May 2003).
166. Recombinant DNA Advisory Committee, “Frequently Asked Questions: Recombinant DNA and Gene Transfer,” 9 September 2002, http://www4.od.nih.gov/oba/RAC/RAC_FAQs.htm (13 May 2003).
167. National Institutes of Health, “NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines),” April 2002, Appendix M.
168. Ibid.
169. See note 166, above.
170. Ibid.
171. Ibid.
172. Moore v. Regents of the University of California, 793 P.2d 479, 486 (Ca. 1990).
173. Grimes v. Kennedy Krieger Institute, Inc., 782 A.2d 807, 846 (Md. 2001).
174. Keeton, W.P., et al., Prosser and Keeton on the Law of Torts, §32 at 187 (5th ed., 1984).
175. Enright v. Eli Lilly, 570 NE2d 198 (NY 1991).
176. Ibid, at 201-04.
177. 45 CFR 46.204(d) (later repealed).
178. P.L. 104-99, Section 128.
179. Belmont Report, The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Bethesda, MD: Government Printing Office, 1978.
180. See 45 CFR 46.101(b).
181. See 45 CFR 46.101(b)(4).
182. See 45 CFR 46.109(e).
183. See OHRP Guidance on Continuing Review, July 11, 2002. (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/contrev2002.htm).
184. See 21 CFR 50.1, 56.101.
185. See 45 CFR 46.116.
186. See 21 CFR 50.23, 50.24.
187. See 21 CFR Parts 312 (investigational drugs) and 812 (investigational devices).
188. See 21 CFR 312.2(d) (expressly carving out the off-label use of drugs in the practice of medicine); 812.2(a) (limiting the applicability of Part 812 to clinical investigations to determine the safety and efficacy of a device).
189. Andrews, L. B., “State Regulation of Embryo Stem Cell Research,” Commissioned Paper for National Bioethics Advisory Commission, Ethical Issues in Stem Cell Research, January 2000, http://www.georgetown.edu/research/nrcbl/nbac/stemcell2.pdf (4 June 2003).
190. Ethics Committee of the American Society for Reproductive Medicine, “Donating Spare Embryos for Embryonic Stem Cell Research,” Fertility and Sterility, 78: 957-960, 2002.
191. Ethics Committee of the American Society for Reproductive Medicine, “Informed Consent and the Use of Gametes and Embryos.” Fertility and Sterility, 68: 780-781, 1997.
192. National Institutes of Health, Ad Hoc Group of Consultants to the Advisory Committee to the Director, Report of the Human Embryo Research Panel, September 1994, p. x.
193. Ibid, p. 80.
194. Ibid, p. 83.
195. Alpers, A., et al., “Commodification and Commercialization in Human Embryo Research,” Stanford Law and Policy Review, 6: 39-45, 1995.
196. Plotz, D., “The ‘Genius Babies,’ and How They Grow,” Slate, 2 February 2001, http://slate.msn.com/id/100331/ (3 June 2003). Note: the Repository closed its doors for good in 1998.
197. Baum, K., “Golden Eggs: Towards the Rational Regulation of Oocyte Donation,” Brigham Young University Law Review, 107-166, 2001.
198. Ethics Committee, American Society for Reproductive Medicine, “Financial Incentives Recruitment of Oocyte Donors,” Fertility and Sterility, 74: 216-220, 2000.
199. Andrews, L. B., “Changing Conceptions: Governance Challenges in the Engineering of Human Life,” an unpublished draft paper, June 2003, cited with the author’s permission.
200. See note 197, above.
201. See note 198, above.
202. See generally http://www.eggdonor.com.
203. Shanley, M.L., “Collaboration and Commodification in Assisted Procreation: Reflections on an Open Market and Anonymous Donation in Human Sperm and Eggs,” Law and Society Review, 36: 257-280, 2002.
204. Healy, B., “Donors at Risk: The High Cost of Eggs,” US News & World Report, 13 January 2003.
205. See note 198, above.
206. See note 195, above.
207. 42 USC 274e.
208. See note 198, above.
209. Ibid.
210. American Society for Reproductive Medicine, Practice Committee Report, “Repetitive Oocyte Donation,” November 2000, http://www.asrm.org/Media/Practice/oocyte_donation.pdf (4 June 2003).
211. See note 199, above.
212. See CDC Report, note 2, above, p. 17.
213. Ethics Committee, American Society for Reproductive Medicine, “Shared-Risk or Refund Programs in Assisted Reproduction,” http://www.asrm.org/Media/Ethics/shared.html (16 May 2003).
214. Ibid.
215. “In Vitro Fertilization: Insurance and Consumer Protection,” Harvard Law Review, 109: 2092-2109, 1996.
216. See, for example, Arkansas Statutes Ann., Sections 23-85-137 and 23-86-118.
217. See generally 15 USC 45(a)(2).
218. American Society for Reproductive Medicine, Practice Committee Report, “Guidelines for Advertising by ART Programs,” October 1999, http://www.asrm.org/Media/Practice/ArtAdvertising.pdf (4 June 2003).
219. See note 213, above.
220. See generally, Munro, N., “Mixing Business with Stem Cells,” National Journal, 33: 21 July 2001.
221. Ibid, noting Johns Hopkins and U. Wisconsin’s agreements with Geron.
222. 35 USC 271(a) (2003).
223. 35 USC 281 et seq.
224. 42 USC 2181(a) (2003).
225. R.R. Donnelly & Sons, Co. v. U.S., 40 Fed. Cl. 277, 279 n.6 (Ct. Fed. Cl. 1998).
226. 35 USC § 101.
227. Supreme Court of the United States, Diamond v. Chakrabarty, 447 U.S. 303, 309 (1980) (quoting legislative history).
228. Ibid.
229. Ibid.
230. See, for example, Funk Bros. Seed Co. v. Kalo Innoculant Co., 333 U.S. 127, 130-131 (1948).
231. See Chakrabarty at 305, note 227, above.
232. Ibid at 305-306.
233. Ibid at 309-311.
234. 846 F.2d 77 (Fed. Cir. 1988).
235. U.S. Patent and Trademark Organization, Manual of Patent Examination Procedure, section 2105.
236. 55 BNA Patent, Trademark & Copyright J. 1371 (April 9, 1998).
237. Manual of Patent Examination Procedure, sec. 2105 (eighth ed., 2001).
238. Gillis, J., “A New Call for Cloning Policy; Group Says Patent Would Apply to Human Embryos,” Washington Post, 17 May 2002, p. A12.
239. Ibid.
240. 55 BNA Patent, Trademark and Copyright J. 1371 (April 9, 1998).
241. 58 BNA Patent, Trademark and Copyright J. 1430 (June 17, 1999).