Reproduction and Responsibility:
The Regulation of New Biotechnologies
The President's Council on Bioethics
Washington, D.C.
March 2004 www.bioethics.gov
Chapter Five Research Involving In Vitro
Human Embryos
The biotechnologies of human reproductionare inextricably
entangled withresearch that uses or involves early-stage
human embryos. Such research provides the experimental groundwork
for many of the techniques of assisted reproduction, and it
relies on assisted reproduction techniques to produce the
ex vivo embryos it uses when it studies disease models and
seeks treatments and cures for the sick. Thus, a comprehensive
understanding of the current practices, ethical issues, and
regulation of reproductive biotechnology requires a consideration
of human embryo research.
Before entering the discussion, however, we need to define
its scope. Many activities could reasonably be deemed "human
embryo research," based 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, embryo, or both. This
might include 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
the current regulation of those biotechnologies that touch
on human reproduction. We will therefore limit ourselves,
in what follows, to considering basic research on early-stage
ex utero living embryos not intended for transfer into a woman's
uterus.
I. Techniques and Practices
A. 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 about early embryonic development,
including morphology, biochemical and biophysical properties,
and genetic expression. Some embryo researchers seek to enhance
basic knowledge about the origins 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, embryos are
used for deriving and studying human embryonic stem cells.
B. Sources of Embryos
Researchers typically procure embryos for research purposes
from assisted reproduction clinics-generally, embryos that
remain following completion of in vitro fertilization (IVF)
treatment and that are no longer wanted for transfer by those
who produced them (so-called "spare" embryos). Such researchers
submit requests to clinics for embryos that have been explicitly
donated for research. As mentioned in Chapter 2, the recent
study by the American Society for Reproductive Medicine (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 (roughly 11,000) have been
designated for donation to research. At the outset of fertility
treatment, couples designate what should be done with their
embryos in the event of their deaths, divorce, or abandonment.
After couples have completed their treatment, they are approached
by researchers who make specific requests for embryo donations.
Typically, these are researchers who have pre-existing relationships
with the assisted reproductive technologies (ART) clinic.
In some cases the couple's fertility specialist may also be
the principal researcher requesting donation.
Less often, embryos are created expressly for research.
In July 2001, the Jones Institute in Norfolk, Virginia, publicized
the fact that its scientists had created more than one hundred
embryos in this manner from the gametes of volunteer donors.
(Subsequent reports suggest this program has been stopped.)
There are no reliable data on the number of researchers now
producing embryos solely for research or the number of embryos
that have been produced solely for research.
C. Projected Techniques/Recent Experiments
While most embryo research is conducted with embryos produced
through IVF using sperm and ova, a range of recent developments
in experimental embryology is noteworthy. In July 2003, it
was announced that male human cells had been transplanted
into a three-day-old female human embryo. Researchers grew
the resulting human embryo hybrid (dubbed a "she-male" in
the press) for six days before destroying it.1
The purpose of the experiment, according to the head of the
research team that conducted it, was to show that cells from
a sibling might be transplanted into an embryo in order to
prevent the development of certain genetic diseases.2
This experiment was conducted in the United States, with embryos
that were donated specifically for the purpose of such experimentation.
Advanced techniques in embryological experimentation have
also allowed researchers to create "hybrid" cloned embryos
made from human and animal cells. For instance, in August
and September of 2003 it was announced that cloned embryos
had been created by fusing human skin cells with enucleated
eggs from rabbits3
and by fusing female human cells with enucleated oocytes from
cows.4
Researchers in South Korea recently produced 30 cloned human
embryos (via somatic cell nuclear transfer using the egg donors'
own cumulus cells), grew them to the blastocyst stage (five
to six days), and successfully derived a pluripotent embryonic
human stem cell line from them.5
This marks the first verified successful cloning of human
embryos, and their successful growth to the stage at which
embryonic stem cells may be obtained. Although the researchers
who accomplished this express no interest in using their technique
for procreative purposes, the cloned embryos they produced
were cultivated past the developmental stage at which in vitro
embryos are typically transferred to a woman's uterus in an
effort to produce a child.
II. Ethical Considerations
The ethical questions connected with embryo research have
been discussed in detail in two previous Council reports:
Human Cloning and Human Dignity (July 2002) and Monitoring
Stem Cell Research (January 2004). We present here the
briefest outline of the relevant issues; readers seeking further
elaboration should consult Chapter 6 of the cloning report
and Chapter 3 of the stem cell report.
First, human embryo research has the potential to do great
good, both for infertile couples seeking to conceive children
and for countless sick and suffering patients whose diseases
or disabilities might be cured or ameliorated by regenerative
medicine that made use of embryonic stem cells. Although the
promise of such research for human therapies remains speculative,
many researchers believe it will offer great benefits to perhaps
millions of patients.
The chief ethical concerns raised by the practice of human
embryo research arise from the fact that such research generally
necessitates the use and destruction of human embryos. Many
people regard embryos as human beings at the earliest stage
of life, and thus worthy of the same respect and protections
that we afford all human persons. Even among many who do not
assign human embryos the moral standing of "full persons,"
intentional destruction of developing human life is a cause
for some ethical disquiet. To regard developing human life
as a mere means-even a means to a noble end, such as the alleviation
of suffering-presents a moral problem with potentially serious
consequences for society as a whole. It might lead to the
coarsening of sensibilities in the general culture. It might
make respect for human life conditional on the possession
of certain capacities, and thus open the door to moral hazards
both in research and beyond.
The creation of human embryos solely for research raises
additional concerns. Unlike in assisted reproduction, where
each embryo is created with a view to conceiving a live-born
child, embryos produced solely for research are treated purely
instrumentally. They become a "natural resource" for gaining
scientific and medical knowledge and, in the process, the
techniques of assisted reproduction are severed entirely from
the aspiration to produce a human child.
Other ethical hazards include the potential for embryos
to be commercialized and the danger that couples undergoing
fertility treatment might be subtly or overtly pressured to
donate embryos to research against their will. The first concern
focuses not so much on the destruction of embryos but on their
treatment in the marketplace and the laboratory; the second
concern focuses on the treatment of persons involved in creating
such embryos-namely, gamete donors and fertility patients.
These concerns have been expressed by individuals on all sides
of the debate about the moral standing of human embryos.
III. Regulation
A. Federal Law
The federal regulation of human embryo research has a long
and complicated history, and public policy debate on embryo
research has centered largely on the question of federal funding,
not the regulation of embryo research as such. 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 Departmenti
[until it] has been reviewed by the Ethics Advisory Board
(EAB) and the Board has rendered advice as to its acceptability
from an ethical standpoint."6
In 1979, the EAB concluded that federal funding of IVF research
was ethically acceptable, subject to certain conditions.ii
The secretary of the Department of HEW did not act on this
recommendation; the EAB was dissolved in 1980. No subsequent
EAB was appointed thereafter. The result was a de facto moratorium
on federal funding for embryo research until 1993. Acting
on the advice of newly elected President Clinton, Congress
passed the National Institutes of Health (NIH) Revitalization
Act of 1993, nullifying the requirement that there be an EAB
review before an application can be federally funded. Thereafter,
NIH Director Harold Varmus convened an advisory panel to consider
which types of embryo research, as an ethical matter, should
be entitled to federal funding. The NIH Human Embryo Research
Panel issued a report in 1994 concluding that certain kinds
of embryo research were acceptable for federal funding, others
might be acceptable under certain specified conditions, and
still others were unacceptable.iii
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.iv
The Embryo Research Panel submitted its conclusions to the
Advisory Committee, 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 proposals
for embryo research protocols, however, Congress implemented
a statutory ban on federal funding that remains in effect.
According to the Dickey-Wicker Amendment to the Department
of Health and Human Services (HHS) appropriations bill for
fiscal year 1996,7
which has been re-enacted each year since, no federal funds
may be used for the following: 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 C.F.R. 46.208(a)(2) and section
498b of the Public Health Service Act (42 U.S.C. 289g[b])."v
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 is minimal and the purpose of the activity is the
development of important biomedical knowledge which could
not be obtained by other means. The second statute (section
498b of the Public Health Service Act) requires that the research
risk standard be the same for fetuses that are intended to
be aborted and fetuses that are intended to be carried to
term. "Human embryo" is defined broadly as "any organism,
not protected as a human-subject under 45 C.F.R. 46 . .
. that is derived by fertilization, parthenogenesis, cloning,
or any other means from one or more human gametes or human
diploid cells."
In light of the legislative restriction on federal funding,
in 1998 NIH sought a legal opinion from the HHS Office of
the General Counsel on whether NIH funds may be used for research
using embryonic stem cells. HHS concluded that the Dickey-Wicker
Amendment did not prohibit the federal funding of research
"utilizing" (as opposed to deriving) human embryonic stem
cells taken from embryos that have already been destroyed
using private funding. However, before HHS allocated any funding
for such research, the newly elected Bush administration initiated
a review of the former administration's policy for the federal
funding of embryonic stem cell research and halted the consideration
of research proposals.
On August 9, 2001, President Bush announced his decision
to allow federal funds to be used for research on existing
human embryonic stem cell lines, so long as the following
conditions were met: (1) the derivation process had been initiated
prior to August 9, 2001, thus creating no public incentive
for future embryo destruction; (2) the embryo from which the
stem cell line was derived had already been destroyed and
thus had no potential for further development. In addition,
the President established the following additional criteria
in order for a stem cell line to be eligible for federal funding:
the stem cells must have been derived from an embryo that
was initially created for reproductive purposes and no longer
needed for these purposes, informed consent must have been
obtained for the donation of the embryo, and no financial
inducements had been 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.vi
As part of the implementation of this funding policy, the
NIH has created a Human Embryonic Stem Cell Registry that
lists the human embryonic stem cell lines that meet the eligibility
criteria.vii
There are currently no federal laws or regulations directly
applicable to the use of embryos in privately funded research.
The FDA does not regulate human embryo research unless it
is aimed at the development of a "product" subject to its
approval.
Embryo research using cloned human embryos-embryos created
by somatic cell nuclear transfer-has been the subject of separate
legislative activity. On July 31, 2001, and again on February
27, 2003, the House of Representatives passed a bill that
would ban the creation of cloned human embryos for any purpose.
It would also make illegal the shipment or receipt "for any
purpose of an embryo produced by human cloning or any product
derived from such embryo." If enacted, this bill would prohibit
research on cloned human embryos and on stem cells extracted
from such embryos. As of this writing, the Senate has not
acted on the bill.
In addition to specific federal legislation directly addressed
to embryo research, there are a number of other federal activities
that, less directly, do or might touch embryo research.
1. 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.
2. Human-Subjects Protections.
Entities and individuals that conduct human subjects research
are regulated under federal regulations, as well as by the
policies and procedures of the institutions at which federally
funded research is conducted. (Ex vivo embryos, however, are
not considered "human subjects" for these purposes.) 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 HHS. Additionally, NIH, a main source
of funding for research, has regulations and policies that
must be followed to the extent a research project (or institution)
is funded by the NIH. HHS regulations, at 45 C.F.R. 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 HHS.viii
Subparts B, C, and D govern research on vulnerable populations:
specifically, 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 guidelines interpreting
the Common Rule and enforcing its requirements. OHRP determination
letters are issued to institutions determined by OHRP to be
out of compliance with HHS 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" that 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 institutions that receive
any federal funding. All institutions receiving 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 all human
subjects research undertaken at the institution.ix
The terms of an assurance often apply the ethical principles
outlined in the Belmont Report8
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.
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
and the regulatory exemptions within the Common Rule that
expressly exclude certain types of research from its requirements.9
For example, research that involves the collection or study
of existing data-for example, 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.10
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.
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 C.F.R. 46.107. An IRB may approve only such research
as meets the criteria in 45 C.F.R. 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 C.F.R. 46.111, an IRB must conclude
that a number of safeguards relating to risks to the subjects,
selection of subjects, informed consent, monitoring of subjects,
and privacy, are satisfied.x
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.11
OHRP has issued detailed guidance regarding the continuing
review process, specifying when it should occur and what materials
should be reviewed.12
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 C.F.R. 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 C.F.R. 46. Ex utero embryos, as such, have never been
treated as "human subjects" for purposes of this section.
Embryos inside a woman's uterus are covered by the protections
under the Common Rule applicable to research on pregnant women
and fetuses.xi
Pregnant women or fetuses may only be involved in research
if the following conditions are met: (1) where scientifically
appropriate, preclinical studies and clinical studies have
been conducted and provide data for assessing potential risks
to pregnant women and fetuses; (2) 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
that cannot be obtained by any other means; (3) any risk is
the least possible for achieving the objectives of the research;
(4) 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; (5) 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;
(6) each individual providing consent to the research is fully
informed regarding the reasonably foreseeable impact of the
research on the fetus or the neonate; (7) if the pregnant
individual is a child, as that term is defined under title
45 C.F.R. 46.402(a), assent and permission are obtained in
accord with the provisions of Subpart D of the regulations
governing research on children; (8) no inducements, monetary
or otherwise, will be offered to terminate a pregnancy; (9)
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 (10) the individuals engaged
in the research will have no part in determining the viability
of a neonate.
B. State Law
States are the principal sources for the direct regulation
of embryo research. State laws vary widely in their application
and content. Some states, in an effort to disincentivize abortion,
regulate research on aborted fetuses and embryos,xii
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 parts of this document that address those specific
subjects. The following discussion will focus only on regulations
that may govern direct research on early-stage in vitro embryos
not intended for transfer, and where the aim of the research
is to further scientific knowledge and medicine in a general
way (unrelated to the specific embryos themselves).
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 once they undergo
such experimentation. Additional states also prohibit research
on in vitro embryos to various extents.xiii
For example, Pennsylvania proscribes any type of "nontherapeutic
experimentation" or "nontherapeutic medical procedure" upon
any "unborn child," defined as "an individual organism of
the species homo sapiens from fertilization until live birth."13
Most of these states proscribe such research if not beneficial
to the embryo itself. For example, Michigan prohibits research
on live human embryos, fetuses, or neonates, if such research
substantially jeopardizes the subject's life or health.14
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 human cloning. In Massachusetts, efforts
are currently under way to amend the fetal research statute
(which now prohibits experimentation on embryos and fetuses
unless it is incidental 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
the creation and use of cloned embryos. A law recently passed
in New Jersey similarly declares that research "involving
the derivation and use of human embryonic stem cells and human
embryonic germ cells" is permitted, including "somatic cell
nuclear transplantation."15
A related New Jersey law purports to outlaw "cloning," defined
as "replication of a human individual by cultivating a cell
with genetic material through the egg, embryo, fetal, and
newborn stages into a new human individual."16
This would seem to be the most permissive of all such state
laws that proscribe cloning for reproductive purposes while
permitting cloning for biomedical research. Most such laws
(like the federal bill recently proposed by Senators Orrin
Hatch, Dianne Feinstein, and Arlen Specter17)
prohibit the transfer of a cloned embryo to a woman's uterus.
The New Jersey law, by contrast, defines "cloning" in a way
that seems to allow the transfer of a cloned embryo to a woman's
uterus, as well as the cultivation of the cloned embryo up
to the "newborn" stage.
It bears noting that some of the above-mentioned embryo
research statutes have come under judicial scrutiny. Statutes
in Illinois, Louisiana, and Utah have been held to be unconstitutionally
vague, on the grounds that "experimentation" is not defined
clearly enough for practitioners to understand that certain
of their activities may be criminal. One court in Illinois
went further, striking down a portion of an older statute
on the grounds that it could reach certain practices and techniques
of assisted reproduction, thus infringing upon a woman's constitutional
right to make reproductive decisions.
C. Professional Self-Regulation
A number of professional organizations and societies have
published guidelines and opinions on human embryo research.
These are substantially similar to the guidelines proposed
by the 1994 NIH Human Embryo Research Panel (discussed elsewhere
in this chapter and summarized below). Two that are worth
noting are statements from ASRM and the American Academy of
Pediatrics (AAP).
ASRM's 1994 report, entitled "Research on Pre-embryos: 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 offers guidelines for the donation of embryos in two
ethics opinions: "Donating Spare Embryos for Embryonic Stem
Cell Research"18
and "Informed Consent and the Use of Gametes and Embryos."19
These guidelines specify the importance of making sure that
potential embryo donors understand the risks and benefits,
as well as the purpose and nature of the research and its
potential commercial value (and their own lack of entitlement
to such value). 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 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 to be 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 mandatory) that
an individual other than the couple's fertility specialist
be the person who requests 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 AAP 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
HHS. The Academy took the position that federally funded embryo
research should be approved by IRBs subject to the following
conditions (which are similar to those set out by a panel
of the NIH in the late 1990s):
- The embryos are already frozen and are no longer clinically
needed.
- There is a clear separation in the donor decision process
between the decision by the donors to create embryos for
infertility treatment and the decision to donate frozen
embryos for research purposes after they are no longer clinically
needed.
- The decision to donate is strictly voluntary and without
monetary inducements.
- The physician responsible for fertility treatments is
not to be the person performing the research on the same
frozen embryos, and there should be no monetary relationship,
that is, transfer of funds in the research project to the
physician responsible for the fertility treatments.
- There are to be no personal identifiers associated with
the embryos used for research.
- There are to be no restrictions placed by the donor on
the type of research performed.
- The research performed on these frozen embryos can be
of no direct benefit to the original donors.
- The embryo research does not involve research in reproductive
cloning, transferring an altered embryo to a woman's
uterus, or use of a human embryo in combination with other
human or animal embryos.
The Academy also provided guidelines for informed consent.
Specifically, informed consent should advise donors that:
- All identifiers associated with the frozen embryos will
be removed.
- The donors will not receive any future information regarding
subsequent testing or research on these embryos.
- Cells or tissue developed from the embryos may be used
at some future time for human transplantation research.
- Cells or tissues derived from the embryos may be kept
indefinitely.
- The donated frozen embryos may be of commercial value,
but the donors will not receive any financial or other benefits
from any such commercial development.
- The research performed on these frozen embryos is not
intended to provide direct medical benefit to the donor.
- The research will not involve the transfer of these embryos
to a woman's uterus or involve reproductive cloning
or combination of the embryo with any other embryo of human
or animal origin.
The American Medical Association (AMA) 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 experiments
that involve cloned embryos or cloning techniques. Additionally,
the AMA has signaled its support for federal funding of research
using early-stage human embryos.
While its conclusions do not have the force of law and were
never fully adopted, the principles articulated by the NIH
Embryo Research Panel in 1994 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 Research Panel.
The Panel agreed that federal funding of embryo research in
certain areas is permissible for three reasons: (1) the scientific
promise of such research is significant; (2) the embryo does
not, in the Panel's view, enjoy the same moral status as a
person; and (3) 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.20
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, and with adequate
informed consent. Additionally, the Panel advised that there
should be no purchase or sale of gametes or embryos (though
reasonable compensation for expenses and efforts should be
permitted), and there should be equitable selection of gamete
and embryo donors to prevent discrimination. Finally, the
Panel noted that, subject to certain exceptions, embryos should
not be maintained in vitro for more than fourteen days following
fertilization.
Types of research deemed "acceptable for funding" include
research aimed at improving the outcome of pregnancy and 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 where
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 was acceptable to them
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 where "one of the progenitors received monetary
compensation,"xiv
and "projects of outstanding merit requiring fertilization
of ova as part of the protocol." As we noted earlier, this
latter recommendation was quite controversial and was not
accepted by the Clinton administration.
The Panel identified a second category, namely, research
"that warrants additional review." Such research would be
presumptively ineligible for federal funding, but this presumption
could be overcome by a showing of outstanding merit, and following
"explicit consideration of the ethical issues and social consequences."
Research in this category includes cloning by blastomere separation
or blastocyst splitting (without transfer), "research between
the appearance of the primitive streak and the beginning of
closure of the neural tube" (occurring between days 17 and
21 of embryonic development), research using fetal oocytes
for fertilization or parthenogenesis (without transfer), research
on oocyte nuclear transfer (with subsequent transfer to a
woman's uterus), and embryonic stem cell research involving
embryos fertilized exclusively for such research.
The third and final category of research identified by the
Panel was projects "considered unacceptable for funding."
These projects were deemed unacceptable on ethical grounds,
including concerns for adverse effects on the well-being of
children, women, and men involved in such research; the "special
respect" due to the in vitro embryo; concern for "public sensitivities
on highly controversial research proposals"; and "concern
for the meaning of humanness, parenthood, and the succession
of generations."21
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); preimplantation
genetic diagnosis (PGD) for non-medically indicated sex selection;
development of human-animal 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; and
research involving the transfer of human embryos into nonhuman
animals, or "for extrauterine or abdominal pregnancy."22
IV. Conclusion
There has been significant policy debate and direct legislative
action on the question of federal funding for embryo research-culminating
in the current policy of funding research that employs a limited
number of specifically eligible embryonic stem cell lines.
There is no federal regulation of research on in vitro embryos
when such research is privately funded and supported. States
have widely varying approaches to the subject, ranging from
active support and endorsement, to silence (and thus permission),
to prohibition of such research. The private sector's practices
on this point seem to reflect the principles articulated by
the NIH Human Embryo Research Panel in 1994, 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-a limit that has been proposed by a number
of bodies, both governmental and nongovernmental.
_________________
Footnotes
i.
The Department of Health, Education, and Welfare (DHEW),
now called the Department of Health and Human Services
(HHS).
ii.
These conditions included: informed consent for the use
of gametes, the research had to be important and "not
reasonably attainable by other means," and that embryos
must not be maintained outside the body beyond fourteen
days after fertilization. (DHEW EAB 1979, 106, 107.)
iii.
The specific conclusions of the NIH Embryo Research Panel
are discussed further, below.
iv.
"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, pp. 44-45.)
v.
A minor technical matter: 45 C.F.R. § 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 C.F.R. § 46.208(a)(2)
is currently expressed at 45 C.F.R. § 46.204(b).
vi.
The guidance was issued following a decision by NIH that
the Dickey-Wicker amendment did not prohibit federally
funded research preceding or following the
destruction of human embryos. Thus, NIH concluded that
it could fund research projects on human embryonic stem
cell lines that had been previously derived. The November
21, 2000, guidance remains effective with respect to NIH
funding of research using germ cells derived from fetal
tissue.
vii.
The registry is available at escr.nih.gov. For a more
complete discussion of the federal legislation and policy
developments pertaining to stem cell research, see the
Council's report, Monitoring Stem Cell Research
(January 2004), especially Chapter 2, available at www.bioethics.gov.
viii.
The FDA has never officially adopted the Common Rule.
But FDA regulations governing research on human subjects
include requirements that are functionally identical to
the Common Rule. Unlike the Common Rule, however, the
FDA's requirements for human subjects research apply regardless
of whether the research is federally funded, provided
that the prospective product being studied in the
clinical investigation is subject to FDA regulation generally
(21 C.F.R. §§ 50.1, 56.101). Even clinical investigations
that are exempt from the IND requirements (for example,
where the results will not be submitted to the FDA and
the investigation does not increase the risks to the subjects)
must nonetheless be conducted in accordance with FDA's
IRB oversight and informed consent requirements. It is
important to note, however, that FDA regulations governing
clinical investigations do not apply to the off-label
use of an investigational drug or device in the practice
of medicine. (See 21 C.F.R. § 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].)
The FDA requirements for IRB oversight
and informed consent are similar to those under the Common
Rule. One distinction is noticeable. Whereas the Common
Rule provides for IRB waiver of informed consent for certain
types of minimal risk research (see 45 C.F.R. §
46.116), 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 (see 21 C.F.R. §§
50.23, 50.24).
ix.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 is now 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 that 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 C.F.R. § 46.
x.
The IRB must conclude that 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 (for example, no one population
bears the burden of research without direct benefit; adult
subjects should be used for research where possible before
children are enrolled, etc.); informed consent will be
sought from each prospective subject or the subject's
legally authorized representative, in accordance with
and to the extent required by 45 C.F.R. § 46.116; informed
consent will be appropriately documented, in accordance
with and to the extent required by 45 C.F.R. § 46.117;
when appropriate, the research plan makes adequate provision
for monitoring the data collected to ensure the safety
of subjects; and when appropriate, there are adequate
provisions to protect the privacy of subjects and to maintain
the confidentiality of data.
xi.
The regulation provides protection for "fetuses," 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 from the time of fertilization
up to eight weeks (well after implantation, which usually
occurs before the end of the first week). Thus, if the
research is conducted in vivo post-implantation, what
might be considered research on an "embryo" by most scientists
could be considered research on a "fetus" for purposes
of 45 C.F.R. § 46 (and therefore subject to Subpart B).
xii.
See, for example, Arizona, Arkansas, California, Florida,
Indiana, Kentucky, Missouri, Nebraska, Ohio, Oklahoma,
Tennessee, and Wyoming.
xiii.
See, for example, Louisiana, Michigan, Minnesota, New
Hampshire, New Mexico, Pennsylvania, and South Dakota.
Some states, including Maine, Massachusetts, North Dakota,
and Rhode Island, prohibit research on embryos or fetuses
"before or after expulsion from the mother's womb." It
is unclear whether these statutes govern research on in
vitro embryos.
xiv.
The Panel concluded that federal funding is acceptable
only for research involving embryos acquired by these
means prior to September 1994.
_________________
Endnotes
1.
Gleicher, N., et al., "Blastomere transplantation as a possible
treatment," presented at the 19th Annual Meeting
of the European Society of Human Reproduction and Embryology,
June 29 to July 2, 2003, Madrid, Spain (www.eshre.com).
2.
"Sex Cells," ScienCentral News, July 29, 2003, quoting
Dr. Norbert Gleicher, founder of the Center for Human Reproduction.
3.
Chen, Y. et al., "Embryonic stem cells generated by transfer
of human somatic nuclei into rabbit oocytes," Cell Research
12:251-264 (2003), reporting on experiments in Shanghai
Second Medical University in China, in which human cells
were fused with empty rabbit oocytes.
4.
"First human clone embryo ready for implantation," NewScientist.com,
September 15, 2003, reporting that fertility practitioner
Panayiotis Zavos created human cloned embryos by fusing
human cells with empty cow oocytes.
5.
See Hwang, W.S., et al., "Evidence of a Pluripotent
Human Embryonic Stem Cell Line Derived from a Cloned Human
Blastocyst," Science Express, doi:10.1126/science.1094515
(2004).
6.
45 C.F.R. § 46.204(d) (later repealed).
7.
Pub. L. No. 104-99, § 128, 110 Stat. 26.
8.
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, Maryland: Government
Printing Office, 1978.
9.
See 45 C.F.R. § 46.101(b).
10.
See 45 C.F.R. § 46.101(b)(4).
11.
See 45 C.F.R. § 46.109(e).
12.
See OHRP Guidance on Continuing Review, July 11,
2002 (http://ohrp.osophs.dhhs. gov/humansubjects/guidance/contrev2002.htm).
13.
18 Pa. Cons. Stat. Ann. §§ 3203, 3216.
14.
Mich. Comp. Laws Ann. § 333.2685.
15.
N.J. Stat. Ann. 26:2Z-2.
16.
N.J. Stat. Ann. 2C:11A-1.
17.
S. 303, 108th Congress.
18.
Ethics Committee of the American Society for Reproductive
Medicine, "Donating Spare Embryos for Embryonic Stem Cell
Research," Fertility and Sterility 78: 957-960 (2002).
19.
Ethics Committee of the American Society for Reproductive
Medicine, "Informed Consent and the Use of Gametes and Embryos,"
Fertility and Sterility 68: 780-781 (1997).
20.
National Institutes of Health, Ad Hoc Group of Consultants
to the Advisory Committee to the Director, Report of
the Human Embryo Research Panel, September 1994, p.
x.
22.
Ibid., p. 83.
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