This discussion document—which is not a report
of the Council—was prepared for use at the Council's June
2003 meeting. It was prepared solely to aid discussion and does
not represent the official views of the Council or of the United States
U.S. Public Policy and the Biotechnologies
That Touch the Beginnings of Human Life:
A Detailed Overview
I. Power to Initiate Human
Life by Artificial Means
II. Power to Screen and Select
for Genetic Conditions
III. Power to Modify Traits
IV. Power to Observe and Manipulate
Life In Vitro for Purposes of Scientific Research
V. Commerce and Commodification
Summary and Conclusion
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
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
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
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
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
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
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
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
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
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
for reasons discussed elsewhere in this document this technique
is not currently approved for use in clinical practice in the United
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
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
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
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
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
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.
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).
In 2000, for never-frozen self-provided ova or embryos, the overall
rate of live births per cyclexi
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).
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
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
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
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
urological defects, retinoblastoma,49
neural tube defects,50
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
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
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
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
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
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,
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.
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
(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
The final version of the program, incorporating comments received
by the CDC, was published in the Federal Register on July
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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 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
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
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
(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
(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
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
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.
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
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
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
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
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
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.
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
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
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
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
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
At present, PGD can identify genetic markers associated with more
than one hundred diseases, including diseases such as early onset
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
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
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
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
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.
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.
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.
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.
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.
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
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)
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
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
Currently, there are more than 500 gene transfer research protocols
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
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.
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
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
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.
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
These are products subject to the licensing, false labeling, and
misbranding provisions for biologics (under PHSA161
) and drugs under the (FDCAxxxiii
). 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
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
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
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
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
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
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
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
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.
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.”
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
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).
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
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
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 billxli
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
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
Part 812: Procedures for conduct of clinical studies with investigational
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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.
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
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
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
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
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.
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
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
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
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
Patenting of Living Organisms and
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
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.”
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
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
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
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.
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
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.
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.
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
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
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
18. Until recently, no federal money was budgeted
for validation. Instead, SART underwrote the costs of validation
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
25. This is in contrast to the ethical opinion
of the American Academy of Pediatrics (1994), which deems PGD an
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
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
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
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
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
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.
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:
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.
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.
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,
43. See generally Ibid, especially ref.
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.
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,
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
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,
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,
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.
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. 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,
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,
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,”
(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.
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:
81. Pub. L. No. 102-493, 42 USC 263a-1 et
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.
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
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,
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
129. 21 USC.A. 801 et. seq.
130. 42 USC §11101-11152.
131. See 42 USC §§1395x(e)
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,
(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.
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
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).
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
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.
169. See note 166, above.
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:
191. Ethics Committee of the American Society
for Reproductive Medicine, “Informed Consent and the Use of
Gametes and Embryos.” Fertility and Sterility, 68:
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,
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
(3 June 2003). Note: the Repository closed its doors for good in
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,
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
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.
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.
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).
215. “In Vitro Fertilization: Insurance
and Consumer Protection,” Harvard Law Review, 109:
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
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
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.
240. 55 BNA Patent, Trademark and Copyright
J. 1371 (April 9, 1998).
241. 58 BNA Patent, Trademark and Copyright
J. 1430 (June 17, 1999).