Contemporary problem essay

Genetic Modification of Preimplantation Embryos: Toward Adequate Human Research Policies

Author(s): Rebecca Dresser

Source: The Milbank Quarterly , 2004, Vol. 82, No. 1 (2004), pp. 195-214

Published by: Wiley on behalf of Milbank Memorial Fund

Stable URL: https://www.jstor.org/stable/4149080

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Genetic Modification of Preimplantation Embryos: Toward Adequate Human Research Policies

REBECCA DRESSER

Washington University

Citing advances in transgenic animal research and setbacks in human trials of

somatic cell genetic interventions, some scientists and others want to begin planning for research involving the genetic modification of human embryos. Because this form of genetic modification could affect later-born children and

their offspring, the protection of human subjects should be a priority in decisions

about whether to proceed with such research. Yet because of gaps in existing federal policies, embryo modification proposals might not receive adequate scientific and ethical scrutiny. This article describes current policy shortcomings

and recommends policy actions designed to ensure that the investigational genetic modification of embryos meets accepted standards for research on human

subjects.

N THE LATE I990S, A GROUP OF SCIENTISTS-INCLUDING James Watson, codiscoverer of the structure of DNA; Daniel Koshland, former editor in chief of Science; and Leroy Hood, a lead-

ing molecular biologist-participated in a symposium on human genetic

engineering (Stock and Campbell 1998). Citing advances in transgenic animal research and the disappointing results of human somatic cell genetic interventions, these scientists joined several other symposium participants in arguing that the genetic modification of early embryos

offers great promise for advancing human health and welfare (Stock and Campbell 2000b). Accordingly, they called on researchers, scholars, and

Address correspondence to: Rebecca Dresser, Washington University School of Law, One Brookings Drive, Box 1120, St. Louis, MO 63130 (e-mail: [email protected] .edu).

The Milbank Quarterly, Vol. 82, No. 1, 2004 (pp. 195-214) @ 2004 Milbank Memorial Fund. Published by Blackwell Publishing.

'95

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196 Rebecca Dresser

policy officials to consider when and how to study this form of human

genetic modification. Those taking a positive view of preimplantation embryo genetic mod-

ification (PGM) emphasize its possible future benefits. For example, they say, the approach could enable someone with two copies of the gene for

Huntington's disease to have a biological child unaffected by the dis- ease. It also could allow parents to "enhance" their children by promoting

resistance to HIV infection or cancer (Capecchi 2000). Besides extensive animal and other laboratory studies, human trials

would be required to evaluate whether genetic modifications in embryos were safe and effective for clinical use. In such trials, embryos created

through in vitro fertilization would be genetically modified and then transferred to a woman's uterus for gestation. Thus, the health and welfare

of later-born children would be a major ethical and policy concern.

Studies involving the genetic modification of preimplantation em- bryos would raise significant human subjects issues requiring extensive

expert and public deliberation. If investigators were to propose a human

PGM study, however, the current oversight system would be ill prepared

to respond. Because of the gaps in the current federal policies protecting

human subjects, PGM studies might not receive adequate scientific and ethical scrutiny.

In this article, I examine PGM studies in light of U.S. oversight poli-

cies designed to protect human subjects. First, I discuss the relevant scientific developments and argue that scholarly analyses have not de-

voted enough attention to the human research phase of PGM. Second, I

describe current policies governing research involving human gene trans-

fer, research involving human embryos, and research involving human

subjects. Third, I point to policy omissions and uncertainties that could

contribute to the inadequate oversight of PGM research. I conclude with

recommendations for policy action. My goals are to alert scholars and policy officials to regulatory deficiencies and to create an opportunity to remedy the problems before PGM studies are undertaken.

Research Developments

The current research efforts to modify human genes incorporate somatic

cell gene transfer interventions. This form of investigational intervention

is designed to modify somatic (nonreproductive) cells in the subject's

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Genetic Modification of Preimplantation Embryos 197

body. Researchers conducting somatic cell gene transfer studies try to

deliver properly functioning genes to children and adults, with the most common techniques using genetically modified viruses. In a successful intervention, the virus infects the appropriate target cells; the normal

genes are integrated into the cell's genome; and the normal genes assume their correct function (Walters and Palmer 1997). Although numerous studies have been conducted since 1990, the approach has fallen short of

earlier expectations. To date, no somatic cell intervention has produced

sufficient evidence of safety and efficacy to gain approval for clinical use (FDA 2000).

Somatic cell intervention is distinguished from a second approach, called germ line genetic intervention, which involves modifying genes in

germ (sperm or egg) cells. Such modifications become part of the genetic

material that may be inherited by the initial subject's descendants. Most discussions of germ line modification stress its potential effects on future

generations. On the one hand, if a germ line genetic modification had adverse effects, the burdens could fall not only on direct subjects but on their descendants as well. On the other hand, successful germ line interventions could enable a direct subject's descendants to avoid genetic

disease, to avoid being a carrier of genetic disease, or to benefit from mental and physical enhancements (Walters and Palmer 1997).

Because PGM would be performed in the cells of very early embryos, the modification would be maintained as the cells differentiated and

thus would be present in the germ cells of later-born individuals (Resnik,

Steinkraus, and Langer 1999). The effects on the descendants of geneti-

cally altered individuals are, however, of only secondary interest to PGM

supporters. Instead, they see interventions in the early embryo as the

most efficient way to alter genes in a later-born child. They contend that genetic alterations at the embryonic stage are more likely to have the desired functional effects than are somatic cell interventions per-

formed after birth. In response to concerns about adverse effects in later

generations, they suggest that future research will produce methods of blocking the transmission of germ line alterations to the direct subjects'

offspring (Capecchi 2000). Although the enthusiasm about PGM rests in part on some promising

results in animal studies involving the genetic modification of embryos,

the current techniques are unacceptable for humans. The existing meth-

ods of producing transgenic animals cause extensive damage to many embryos and surviving animals. Because most methods produce animals

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198 Rebecca Dresser

with different levels of foreign gene expression, further breeding is re-

quired to produce animals with stable and properly functioning foreign

genes (Frankel and Chapman 2000; Friedmann 2003). The use of artifi- cial chromosomes, embryonic stem cells, cloning, and other innovations

could improve the outcomes in animals, but these techniques may not be

suitable for human application (Friedmann 2003; Willard 2000). Fur- thermore, the disappointing results in human somatic cell gene transfer

show that what makes sense in theory may not be successful in prac- tice. In sum, it is difficult to reconcile the optimism regarding human PGM with the state of the science. At the same time, the rosy predic-

tions about PGM support the need for an adequate oversight system to

prevent premature human applications.

Inadequate Attention to Human Research Issues

Scholarly discussions of modifying inheritable genes have focused on the ethical and policy issues that would ensue if modifications were widely

available. For the most part, those who contend that such modifica- tions are desirable and inevitable and those who challenge this view emphasize the technology's broad ethical and social implications, often overlooking the ethical issues that would arise earlier in the technol- ogy's development. For example, the editors of a recent book asked the

contributors to discuss whether genetic modifications "no more risky in humans than natural conception" would be acceptable and desirable (Stock and Campbell 2000a, 97). Another recent discussion analyzed the major ethical arguments for and against such modifications on the

"optimistic assumption that the methods will gradually be refined until

they reach the point where gene replacement or gene repair is technically

feasible and able to be accomplished in more than 95 % of attempted gene

transfer procedures" (Walters and Palmer 1997, 80).

Although some analysts have voiced concern about the ethics of hu-

man testing, they have not examined the research issues in detail. For

instance, a working group convened by the American Association for the Advancement of Science (Frankel and Chapman 2000) described the

preclinical research advances that would be necessary before human trials

should be considered. The group did not, however, evaluate inheritable genetic modifications in light of the federal policies governing human

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Genetic Modification of Preimplantation Embryos 199

subjects research. In the same vein, a recent philosophical analysis ac- knowledged that human trials of germ line genetic interventions would

present serious risks and uncertainties but nonetheless simply called for

"careful scrutiny of any protocols for experiments involving those inter- ventions" (Buchanan et al. 2000, 194).

The ethics and policy literature has neglected the human research stage

of technology development. Scholars and other writers have not devoted enough attention to the human research that would be necessary to ascertain whether PGM would be an acceptable health intervention. In turn, policymakers have not devoted enough attention to the oversight

that would be appropriate for PGM research.

Although federal research policies contain rules and guidance rele- vant to designing acceptable PGM studies, significant policy gaps exist

as well. This inconsistent coverage reflects the limits of federal poli- cies governing gene transfer research, human embryo research, and the

protection of human research participants. A second set of policy issues

concerns the appropriate interpretation of the current regulations. Re-

view bodies would confront many questions in applying the existing policy provisions to PGM proposals.

Federal Policies Governing Human Genetic Research

National Institutes of Health

Some proposals to study PGM in humans would be subject to federal oversight systems governing gene transfer research. The Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health (NIH) reviews proposals to conduct gene transfer research in institu- tions receiving federal funds for any type of recombinant DNA research.

Privately funded studies need not be reviewed by the RAC, although officials encourage sponsors to submit such studies for RAC evaluation. Strictly speaking, the RAC lacks the authority to prevent even feder-

ally funded gene transfer proposals from being implemented. However,

federal officials may require a full RAC review and discussion of pro- posals raising "important scientific, safety, medical, ethical, or social issues" (Recombinant DNA Advisory Committee 2002, 7). Because the review and discussion are open to the public, investigators and sponsors

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200 Rebecca Dresser

disregarding the RAC's recommendations could face severe criticism. The RAC's recommendations are also distributed to NIH officials, who

may invoke their funding authority to induce compliance. Finally, RAC materials are available to institutional review boards (IRBs), which can

refuse to approve research proposals that disregard the RAC's recom- mendations for protecting human subjects (King 2002). Investigators submitting gene transfer research proposals to the RAC

must respond to a series of questions in the NIH's Guidelines for Research

Involving Recombinant DNA Molecules (NIH 2002). These questions seek general information pertinent to human subjects protection, such as

the study intervention's expected risks and benefits, facts to be disclosed

to prospective participants, and criteria for subject selection. But the guidelines do not cover other topics relevant to human subjects protec- tion in PGM studies.

This omission is due in part to the RAC's current stance on human studies of germ line modification. The RAC's official position is that it

"will not at present entertain proposals for germ line alterations" (NIH 2002, 94). But the RAC's definition of germ line studies would not nec-

essarily encompass PGM research. According to the NIH's guidelines, a germ line alteration "involves a specific attempt to introduce genetic

changes into the germ ... cells with the aim of changing the set of genes

passed on to the individual's offspring" (NIH 2002, 94). As noted ear- lier, supporters today stress PGM's potential benefits for the children

who are expected to develop from genetically modified embryos. These

researchers see changes in the genes of the direct subjects' offspring as an unavoidable side effect of PGM rather than its aim. Thus, the RAC's

refusal to review germ line studies might not apply to PGM proposals whose primary objective is to change the genes in direct subjects. At the

same time, the NIH's current guidelines leave the RAC unprepared to conduct a thorough review of PGM proposals.

Recent developments could lead the RAC to revise its policies. In the

late 1990s, researchers asked the RAC to consider preliminary protocols

for in utero gene transfer in humans. They argued that genetic alterations

at the fetal stage were needed to mitigate the harm produced by certain mutations. The RAC, however, determined that its approval would be premature, due to inadequate preclinical data regarding the risks and po- tential benefits to the fetuses (and ultimately the children) who would

be the study's subjects. The RAC also expressed concern about possi- ble germ line effects, because the genetic modifications would occur

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Genetic Modification of Preimplantation Embryos 201

relatively early in the subjects' development (Recombinant DNA Advi- sory Committee 2000). Despite this concern, the RAC has said it would

be willing to consider future proposals for in utero gene transfer research

(NIH 2002). If the RAC does review such proposals, it will have to de- velop a systematic approach to evaluating potential germ line effects in

this form of genetic modification research.

In 2001, a second event highlighted the need for the RAC to pay closer

attention to potential germ line alterations. At that time, the RAC was

shown evidence that foreign DNA was present in the seminal fluid of men participating in a somatic cell gene transfer study. Although there

was no indication that the foreign DNA had been incorporated into the men's sperm cells, officials acknowledged that certain somatic cell

gene transfer approaches might cause germ line alterations (National Human Genome Research Institute 2002). This incident put pressure on the RAC to scrutinize more carefully the potential germ line effects in somatic cell gene transfer studies.

Guidelines addressing possible germ line effects in in utero and so- matic cell gene transfer studies could form the foundation for guidelines

addressing such effects in PGM studies. All three forms of research would require attention to similar matters, such as appropriate long- term follow-up procedures for direct subjects and their offspring. But

PGM would also raise a distinct set of questions about human subjects. For example, unlike the other two types of research, PGM studies would

raise questions about the storage, disposition, and control of genetically

modified embryos. Until the RAC completes a focused inquiry into the

protection of PGM subjects, it will not be prepared to review proposals

to modify genes in embryos expected to develop into children.

Food and Drug Administration

The Food and Drug Administration (FDA) operates a second federal oversight system for human gene transfer studies. The agency requires that human tests of "products containing genetic material. .. to alter the

biological properties of living cells" conform to the same standards that

govern drug tests (FDA 1984; FDA 1993, 53, 249). Research sponsors must secure an investigational new drug (IND) exemption before test- ing genetic material in humans. The IND application must describe the

investigator's plans for protecting human subjects and include a com- mitment to submit the study for an IRB evaluation (FDA 2003a). In

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202 Rebecca Dresser

contrast to the RAC, the FDA has the authority to block human tests,

including industry-sponsored proposals.

Like the RAC, the FDA has not explicitly addressed human subjects protection in germ line modification research. In a guidance statement

for industry sponsors, the FDA presents its standards for human testing

of interventions involving genetically modified cells. But the document

does not cover product tests involving "genetic modification aimed at the modification of germ cells" (FDA 1998, 3). Again, the exclusion of germ line modification would not necessarily apply to PGM tests aimed at modifying the genes of direct subjects. But the FDA's failure

to consider human subjects protection in PGM means that the agency is

not prepared to evaluate PGM product testing.

Recent developments could generate revisions in the FDA's policy. Because of the possible germ line effects produced by somatic cell gene

transfer techniques and by certain interventions aimed at enhancing women's fertility, the FDA is considering policies that address germ line risks in these contexts (FDA 2002). Although this response might signal the beginning of a policy approach to PGM research, an ex- panded inquiry would be needed to develop a robust oversight system for human PGM (Palmer and Cook-Deegan 2003). The policy would have to address matters unique to PGM, such as the control of genet- ically modified embryos. For the agency to exercise adequate human subjects oversight, its policies must be more closely tailored to PGM research.

U.S. Policies Governing Human Embryo Research

For the past two decades, policy discussions of human embryo research have focused on laboratory studies that require the destruction of early embryos. But when novel interventions, such as genetic modification, target embryos expected to be transferred for gestation, the interventions could affect the health and welfare of later-born children. As a result,

the interventions should be evaluated according to regulatory policies governing research involving human subjects.

Advisory groups have recognized this dimension of embryo research.

In 1979, the Ethics Advisory Board of the U.S. Department of Health, Education and Welfare issued a report on research involving human

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Genetic Modification of Preimplantation Embryos 203

in vitro fertilization (IVF) and embryo transfer (U.S. DHEW 1979). Department officials had asked the board to consider whether such re-

search was ethically acceptable and could be eligible for federal fund- ing. In its report, the board expressed concern about the safety of IVF and urged researchers and clinicians to collect data that could shed light on the procedure's possible risks to children. But human subjects policies were never established in response to the board's report.

In the early 1990s, the NIH's director asked another group, the Human Embryo Research Panel, to consider the ethics of embryo re- search. The panel determined that preimplantation embryos should be regarded as human research subjects when investigators intend to trans-

fer them to a woman's uterus. The panel then recommended that research

interventions affecting such embryos be permitted only if "there is rea-

sonable confidence that any child born as a result of the procedures has

not been harmed by them" (NIH 1994, 41). Again, however, the ad- visory group's recommendations never became official human subjects policy.

Partly because of the absence of federal oversight, rigorous data on the

safety and efficacy of IVF and related interventions are lacking (Schultz and Williams 2002; Sutcliffe 2002). At this point, only one federal law explicitly addresses experimental interventions on embryos expected to

become children. This is the provision that prohibits the NIH from funding research that involves the destruction of human embryos (U.S.

Congress 1996). The provision also bans NIH funds for research in which

embryos are "knowingly subjected to risk of injury or death greater than

that allowed" by the regulations of the U.S. Department of Health and

Human Services (DHHS) governing research on fetuses in utero (discussed

later). The provision sets a level of acceptable risk for PGM studies but

says nothing about other human subjects issues raised by such studies. Moreover, the law applies solely to studies seeking the NIH's support.

At this time, the federal regulations governing research involving human subjects do not explicitly cover investigational interventions in human embryos expected to be transferred for further development. The

Federal Policy for the Protection of Human Subjects (also known as the Common Rule) defines a "human subject" as "a living individual" (Federal Policy 1991, 28,013). Although the language is sufficiently general to encompass preimplantation embryos when the intent is to transfer for gestation, it has not been interpreted in this way. The DHHS

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204 Rebecca Dresser

regulations governing research involving fetuses apply only after embryo

implantation. A new group, the DHHS Secretary's Advisory Committee on Human

Research Protections, could possibly respond to this policy problem. The committee was directed to "provide advice on the responsible conduct of research involving human subjects," including "pregnant women, embryos, and fetuses" (U.S. DHHS 2002b, 1). It remains to be seen whether committee members will propose policies for studies involving

interventions in embryos expected to develop into children.

Federal Policies Governing Research Involving Human Subjects

Federal policies to protect human subjects would apply to PGM stud- ies after modified embryos were transferred to a woman's uterus. The basic federal policy is contained in the Common Rule, which governs proposals supported by or performed at institutions funded by the NIH and most other federal agencies. The Common Rule requires investiga-

tors to submit human study proposals to multidisciplinary IRBs, which

determine whether the proposals meet the regulatory demands for a reasonable balance of risks and anticipated benefits. Institutional re- view boards also evaluate the research team's plans for explaining the study to prospective participants and for ensuring that a study's poten- tial burdens and benefits will be equitably distributed (Federal Policy 1991).

Studies conducted by employees of institutions receiving funds from

the NIH and other DHHS agencies must also comply with regulations governing vulnerable populations that would be included in PGM re- search. These regulations include Subpart B: Additional DHHS Protec- tions for Pregnant Women, Human Fetuses and Neonates Involved in Research (U.S. DHHS 2001), and Subpart D: Additional DHHS Protec- tions for Children Involved as Subjects in Research (U.S. DHHS 2002a). The regulations require IRBs and investigators to pay special attention to the complexities of decision making when pregnant women and cou-

ples consider enrolling in studies that will affect an expected or existing child. The regulations also limit the acceptable research risks to fetuses

and children and give sufficiently mature children a role in deciding whether to enter or remain in a study.

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Genetic Modification of Prenimplantation Embryos 205

Certain human subjects protections would also apply to PGM stud- ies in private settings not explicitly covered by the Common Rule. The

Food and Drug Administration's regulations cover the investigational uses of new biological products in humans, requiring such proposals to be reviewed by an IRB applying the Common Rule's substantive provisions on acceptable risk-expected benefit ratios, informed decision making, and subject selection (FDA 2003b). Since 2001, the FDA has applied the DHHS's pediatric research rules to privately sponsored re- search that the agency regulates (FDA 2001), but it has not adopted the

DHHS's provisions governing research involving pregnant women and fetuses.

Although the federal regulations governing human subjects research

offer guidance on the appropriate conduct of PGM studies, the guidance is incomplete. The existing policies offer a framework for protecting many of the rights and interests of prospective parents participating in research but leave later-born children vulnerable to harm. Both the

DHHS and the FDA lack policies explicitly addressing situations in which investigational modifications in the genome of an embryo could

have health consequences for a later-born child. As noted earlier, the fed-

eral embryo research statute limits the permissible risk in such situations,

but it does not address parental decision making and other ethical consid-

erations relevant to this form of investigational intervention. Moreover, the federal embryo research statute applies solely to NIH-funded studies.

These gaps in federal oversight leave human subjects without adequate

protection in certain settings. Some fertility specialists, particularly those

working in clinics not affiliated with academic medical centers, are unaccustomed to submitting study proposals for FDA and IRB review (Frankel and Chapman 2001). In 2001, for example, infertility specialists

published the results of a study using a technique called ooplasm transfer,

which produces embryos with a mixture of mitochondrial DNA from two women (Parens and Juengst 2001). The infertility researchers had

not obtained an investigational new drug (IND) exemption for this work. After the results were published, FDA officials notified researchers that

an IND exemption would be required. But this was four years after the first pregnancy involving an ooplasm transfer. Meanwhile, FDA officials expressed concern about the procedure's safety (FDA 2002). To prevent similar unauthorized investigations, clear human subjects rules

are needed governing novel interventions in embryos expected to be transferred for gestation.

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206 Rebecca Dresser

Uncertainties in Interpreting Current Human Research Rules

The existing human subjects policies cover investigational interventions involving adults, children, and fetuses in utero. Researchers and review-

ers, however, would encounter numerous questions when applying the

Common Rule and DHHS requirements to PGM studies. The following is a survey of the major issues that they would encounter.

The Common Rule

The Common Rule establishes three basic requirements for human stud- ies. First, the risks to the subjects must be minimized, and any remaining

risks must be "reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be

expected to result" (Federal Policy 1991, 28,015). For PGM studies, the reasonableness of risks to the subjects depends largely on the seriousness of the target condition, the available alternatives to PGM, and the social

value of the anticipated research data.

Whether PGM studies present reasonable risks could be a point of contention. Studies aimed at avoiding genetic diseases in children could provoke disagreement because of the available alternatives to PGM. In most cases, for instance, preimplantation genetic diagnosis (PGD) of- fers prospective parents a better chance of having a healthy child. In this technique, early embryos are genetically tested, and those testing positive for disease are not transferred for gestation (Botkin 1998). The

PGD technique raises ethical concerns because it results in discarding embryos. But because PGM also would result in discarding embryos (experts expect that some embryos would be damaged or the mutations would not be corrected), it would not be a morally preferable alternative to PGD. The PGD alternative is not available in the relatively rare case in which both members of a couple have two copies of recessive disease genes or one member has two copies of a dominant disease gene. Yet even

these couples have other reproductive options, such as adoption or the use of donor gametes. Because PGD and other alternatives present fewer risks to later-born children, reviewers could find that PGM studies pre-

sented unreasonable risks to subjects. It could also be difficult to enroll

enough subjects in a PGM study to produce generalizable knowledge, which would reduce the study's value to society.

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Genetic Modification of Preimplantation Embryos 207

Studies to improve normal characteristics would present an additional

source of controversy. Some members of society may see the benefits of ge-

netic interventions for enhancement as sufficiently important to justify

the risks. As Buchanan and his colleagues observed, "If individuals-or groups of individuals-value some enhancements very highly, they may

well be willing to take significant risks to produce it . . in their chil- dren" (2000, 195). The question is whether the Common Rule's demand for reasonable research risks permits studies exposing to harm embryos

expected to develop into healthy children in exchange for the uncertain

possibility of physical or mental enhancement.

Investigators and review groups must also develop a principled ap- proach to evaluating PGM's potential consequences to future genera- tions. In some medical and research contexts, individuals are exposed to radiation, chemotherapy, and other interventions that may cause mu- tations in germ line cells (Blaese 2003). In these situations, the bene- fits to the recipients are regarded as sufficiently valuable and probable

to justify potential harms to their offspring. In the context of PGM research, however, the potential benefits to direct subjects would not be as clear. Evaluating PGM's possible consequences to descendants would be further complicated by the need to rely initially on nonhuman

and other preclinical data. Review groups would also have to consider the possibility that future techniques could prevent the transmission of germ line changes or reduce adverse effects in descendants (Resnik 2002).

Fulfilling the Common Rule's second basic directive could be chal- lenging, too. This directive requires investigators to help prospective participants or their representatives make informed and voluntary deci-

sions about enrolling and remaining in research. The duration of PGM studies would introduce a special complexity. Because genetic alterations could affect the subjects later in life, as well as their offspring, many years

of data collection would presumably be necessary. Thus, research discus- sions would begin with the prospective parents considering PGM and would occur later with the parents of the genetically modified children. Eventually, investigators would have to discuss the research with child subjects mature enough to understand basic study information. When these children turned eighteen, they would be free to decide whether to participate in the research. Those subjects who bore children would also be responsible for deciding whether to allow their offspring to be followed. Research teams would have to ensure that prospective subjects

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2 08 Rebecca Dresser

in each of these groups were given an opportunity to choose both to begin and to continue participating in the study.

The Common Rule's third major requirement mandates equitable sub-

ject selection. This provision is designed to ensure that the harms and benefits of the research are fairly distributed among groups and indi-

viduals. Although pregnant women would participate in PGM studies, the subjects at greatest risk would be their later-born children. In the

early phase of PGM studies, a vulnerable population would be exposed to

relatively high risk, primarily to advance knowledge that could benefit others. Review groups would have to decide whether PGM's potential benefits justified exposing vulnerable subjects to this level of risk.

DHHS Policies Governing Research Involving Vulnerable Populations

The DHHS provisions governing research involving vulnerable popula- tions would raise more questions for groups considering PGM proposals.

These provisions, and the ethical principles they incorporate, would raise

serious questions about the acceptability of initial human studies. Ini- tial human tests of drugs and biological products are designed mainly to

obtain information about dosage and toxicity. Such studies also seek, "if

possible, to gain early evidence on effectiveness" (FDA 2003c, 62). A cru- cial regulatory issue would be whether the reviewers classified the initial

PGM studies as offering a potential benefit to later-born child subjects. Their decision would turn on whether the data from animal and other

preclinical investigations furnished a reasonable basis for predicting a direct benefit to child subjects.

The DHHS's regulations restrict the level of permissible risk when study interventions do not offer subjects the prospect of a direct benefit.

In this situation, Subpart B permits only minimal risk to fetuses (U.S. DHHS 2001). According to the Common Rule, minimal risk "means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily

encountered in daily life or during the performance of routine physical or psychological examinations or tests" (Federal Policy 1991, 28,013-4).

Although federal regulations do not include a specific definition of minimal risk to fetuses, the National Commission for the Protection of

Human Subjects of Biomedical and Behavioral Research considered this matter extensively (1974). The commission members concluded that

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Genetic Modification of Preimplantation Embryos 209

minimal research risks are those that are similar to the risks of normal

fetal development and routine obstetric tests. They also concluded that

the pregnant woman's ability to terminate her pregnancy should not affect the level of fetal risk permitted in research. Congress incorporated

this latter conclusion into the law governing federally funded research

involving fetuses (U.S. Congress 2003). In a similar approach, Subpart D limits the risks to children from

research interventions that do not offer a direct benefit. Institutional

review boards may approve a study intervention offering child subjects no direct benefit if the intervention presents no more than minimal risk. Alternatively, such interventions may be approved if they present

"a minor increase over minimal risk," involve "experiences to subjects that are reasonably commensurate with those inherent in their actual or

expected medical... situations," and are "likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance" (U.S. DHHS 2002a, 121).

It is unclear whether initial human PGM studies could be approved under the regulations governing research interventions that present no

prospect of direct benefit. To support their approval, compelling animal and other preclinical data demonstrating the probable safety for humans would be necessary. A related issue is whether the concepts of "mini- mal risk" and "minor increase over minimal risk" should be evaluated

against the usual risks faced by healthy children or by children with the genetic condition being studied. The latter approach could permit certain higher-risk research procedures to be classified as minimal risk,

because the usual risks faced by children with serious genetic diseases are much higher than those faced by healthy children (Kopelman 2000).

Different issues would be raised if the initial PGM studies were clas-

sified as offering fetuses and children the prospect of a direct benefit.

The federal regulations permit fetuses and children to be exposed to research interventions presenting greater than minimal risk if the inter-

ventions also offer them the prospect of a direct benefit. The pediatric

research regulations deem as acceptable those interventions offering a direct benefit if the "relation of the anticipated benefit to the risk is at

least as favorable to the subjects as that presented by available alternative

approaches" (U.S. DHHS 2002a, 121). Investigators seeking to perform PGM to avoid genetic disease thus would have to show that existing therapies offered a similar or less satisfactory balance of risks and poten-

tial benefits. Investigators proposing PGM to produce disease resistance

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2 I0 Rebecca Dresser

or other enhancements would need to establish that the possible benefits

were significant enough to justify the risks to healthy children, taking

into account the available alternatives to achieving such enhancements.

It is possible that federal officials would permit PGM studies that do

not conform to these DHHS requirements. The regulations governing research involving pregnant women and fetuses establish a national re-

view process for permitting research not otherwise approvable. In this process, the local IRB, the DHHS secretary, and a national panel of experts must determine that the research offers "a reasonable opportu-

nity to further the understanding, prevention, or alleviation of a serious

problem affecting the health or welfare of pregnant women [or] fetuses."

The secretary and national panel must also conclude (following a public

meeting and an opportunity for public comment) that the study will be

consistent with "sound ethical principles" and satisfy the usual require- ments for informed choice (U.S. DHHS 2001, 56,780). The pediatric research regulations establish a similar process (U.S. DHHS 2002a). Al- though the requirements for a national review would ensure that such

proposals received public scrutiny, the policies' substantive standards are

sufficiently vague that PGM interventions might qualify for approval

through this process.

Conclusion

This examination shows that U.S. policies offer limited protection to human subjects in research involving the genetic modification of em- bryos expected to develop into children. The inadequacies of current policies mean that officials are not fully prepared to respond to future

proposals for human PGM research and to the harmful consequences of

any objectionable PGM experiments that might be performed. Certain policy shortcomings are relevant not only to PGM research but also to

cloning and other investigational interventions affecting preimplanta- tion embryos expected to be transferred for gestation (Dresser 2003).

Three policy actions would go a long way to remedying this situa- tion. First, the RAC or another qualified interdisciplinary body should

begin work on a human subjects policy specifically for PGM studies. Officials from both the NIH and the FDA should help to formulate the

policy. Second, federal agencies should develop a human subjects policy to protect later-born children who might be affected by PGM and other

investigational interventions in preimplantation embryos. Third, the

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Genetic Modification of Preimnplantation Embryos 2 II

FDA should apply the DHHS's regulations protecting pregnant women and fetuses to privately funded studies of the products it regulates.

In addition, scholars and other analysts should respond to the policies'

inadequacies. Experts in relevant fields should develop ethically defen-

sible policies to guide PGM and related studies, and they should also develop defensible applications of existing policy provisions to PGM re- search. Without such efforts, the nation will remain unready to protect

human subjects in this emerging research area.

References

Blaese, R.M. 2003. Germ Line Modification in Clinical Medicine: Is There a Case for Intentional or Unintended Germ Line Changes? In Designing Our Descendants: The Promise and Perils of Genetic Modifica- tion, edited by A.R. Chapman and M.S. Frankel, 68-76. Baltimore: Johns Hopkins University Press.

Botkin, J. 1998. Ethical Issues and Practical Problems in Preimplanta- tion Genetic Diagnosis.Journal of Law, Medicine & Ethics 26:17-28.

Buchanan, A., D.W. Brock, N. Daniels, and D. Wikler. 2000. From Chance to Choice: Genetics andJustice. Cambridge, England: Cambridge University Press.

Capecchi, M. 2000. Human Germline Gene Therapy: How and Why. In Engineering the Human Germline, edited by G. Stock and J. Campbell, 31-42. New York: Oxford University Press.

Dresser, R. 2003. Human Cloning and the FDA. Hastings Center Report 3 3(3):7-8.

Federal Policy for the Protection of Human Subjects. 1991. Federal Reg- ister 56:28,013-8.

Food and Drug Administration (FDA). 1984. Statement of Policy for Regulatory Biotechnology Products. Federal Register 49:50, 878-80.

Food and Drug Administration (FDA). 1993. Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products. Federal Register 58:53, 248-51.

Food and Drug Administration (FDA). 1998. Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy. Available at http://www.fda.gov/cber/gdlins/somgene.pdf (accessed June 10, 2003).

Food and Drug Administration (FDA). 2000. Human Gene Therapy and the Role of the Food and Drug Administration. Available at http://www.fda.gov/cber/infosheets/genezn.htm (accessed June 6, 2003).

This content downloaded from ������������104.222.18.130 on Wed, 02 Dec 2020 03:54:09 UTC�������������

All use subject to https://about.jstor.org/terms

2 12 Rebecca Dresser

Food and Drug Administration (FDA). 2001. Additional Protections for Children in Clinical Investigations of FDA-Related Products. Federal Register 66:20, 589-600.

Food and Drug Administration (FDA). 2002. Meeting Documents, Bio- logical Response Modifiers Advisory Committee (May 9-10). Avail- able at http://www.fda.gov/ohrms/dockets/ac/cber02.htm (accessed July 18, 2003).

Food and Drug Administration (FDA). 2003a. IND Content and Format. Code of Federal Regulations 21:?312.23.

Food and Drug Administration (FDA). 2003b. Institutional Review Boards. Code of Federal Regulations 21: ?56.

Food and Drug Administration (FDA). 2003c. Phases of an Investiga- tion. Code of Federal Regulations 21: 3 12.21.

Frankel, M.S., and A.R. Chapman. 2000. Human Inheritable Genetic Modi- fications: Assessing Scientific, Ethical, Religious, and Policy Issues. Amer- ican Association for the Advancement of Science Working Group. Available at http://www.aaas.org/spp/dspp/sfrl/germ line/main.htm (accessed April 24, 2003).

Frankel, M.S., and A.R. Chapman. 2001. Facing Inheritable Genetic Modification. Science 292:1303.

Friedmann, T. 2003. Approaches to Gene Transfer to the Mammalian Germ Line. In Designing Our Descendants: The Promise and Perils of Genetic Modification, edited by A.R. Chapman and M.S. Frankel, 39-54. Baltimore: Johns Hopkins University Press.

King, N. 2002. RAC Oversight of Gene Transfer Research: A Model

Worth Extending?Journal of Lau. Medicine & Ethics 30:381-9. Kopelman, L. 2000. Moral Problems in Assessing Research Risk. IRB: Ethics and Human Research 22(5):3-6.

National Commission for the Protection of Human Subjects of Biomed- ical and Behavioral Research. 1974. Research on the Fetus: Delibera- tions and Conclusions. Reprinted in Villanova Law Review 22(1976- 77):300-14.

National Human Genome Research Institute. 2002. Workshop Sum- mary (July 22). Available at http://www.genome.gov/10004761 (accessed July 17, 2003).

National Institutes of Health (NIH). 1994. Final Report of the Human Embryo Research Panel. Bethesda, Md.

National Institutes of Health (NIH). 2002. Points to Consider in the Design and Submission of Protocols for the Transfer of Re- combinant DNA Molecules into the Genome of One or More

Human Participants (April). In Guidelines for Research Involving DNA Molecules. Available at http://www4.od.nih.gov/oba/rac/guidelines/ guidelines.html (accessed April 25, 2003).

This content downloaded from ������������104.222.18.130 on Wed, 02 Dec 2020 03:54:09 UTC�������������

All use subject to https://about.jstor.org/terms

Genetic Modification of Preiniplantation Embryos 213

Palmer, J.G., and R. Cook-Deegan. 2003. National Policies to Oversee Inheritable Genetic Modification Research. In Designing Our Descen- dants: The Promise and Perils of Genetic Modification, edited by A.R. Chapman and M.S. Frankel, 275-95. Baltimore: Johns Hopkins University Press.

Parens, E., and E. Juengst. 2001. Inadvertently Crossing the Germline. Science 292:397.

Recombinant DNA Advisory Committee. 2000. Prenatal Gene Transfer: Scientific, Medical and Ethical Issues. Available at http://www.4od.nih. gov/oba/rac/gtpcreport.pdf (accessed April 25, 2003).

Recombinant DNA Advisory Committee. 2002. Frequently Asked Questions: Recombinant DNA and Gene Transfer. Available at http://www4.od.nih.gov/oba/RACFAQs.htm (accessed June 6, 2003).

Resnik, D.B. 2002. Bioethics of Gene Therapy. In Encyclopedia of Life Sciences, 166-73. London: Nature, Macmillan.

Resnik, D.B., H.B. Steinkraus, and P.J. Langer. 1999. Human Germline Gene Therapy: Scientific. Moral and Political Issues. Austin, Tex.: R.G. Landes.

Schultz, R.M., and C.J. Williams. 2002. The Science of ART. Science 296:2188-90.

Stock, G., and J. Campbell. 1998. Summary Report: Engineering the Human Germline Symposium. Available at http://research.mednet.ucla.edu/ pmts/germcont.htm (accessed April 24, 2003).

Stock, G., and J. Campbell. 2000a. Other Voices. In Engineering the Human Germline, edited by G. Stock and J. Campbell, 97-8. New York: Oxford University Press.

Stock, G., and J. Campbell. 2000b. The Road Ahead: A Panel Discus- sion. In Engineering the Human Germline, edited by G. Stock and J. Campbell, 73-95. New York: Oxford University Press.

Sutcliffe, A. 2002. Health Risks in Babies Born after Assisted Repro- duction. BMJ 325:117-8.

U.S. Congress. 1996. Public Law 104-99: 128 (January 26). U.S. Congress. 2003. Fetal Research. United States Code Annotated

42:?289g(b). U.S. Department of Health, Education and Welfare (U.S. DHEW). 1979.

Report of the Ethics Advisory Board. Federal Register 44:35,033-58.

U.S. Department of Health and Human Services (U.S. DHHS). 2001. Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research. Federal Register 66:56,778-80.

U.S. Department of Health and Human Services (U.S. DHHS). 2002a. Additional DHHS Protections for Children Involved as Subjects in Research. Code of Federal Regulations 45: ??46.401-9.

This content downloaded from ������������104.222.18.130 on Wed, 02 Dec 2020 03:54:09 UTC�������������

All use subject to https://about.jstor.org/terms

214 Rebecca Dresser

U.S. Department of Health and Human Services (U.S. DHHS). 2002b. Secretary's Advisory Committee on Human Research Protections Charter. Available at http://ohrp.osophs.dhhs.gov/ sachrp/charter.pdf (accessed July 16, 2003).

Walters, L., and J.G. Palmer. 1997. The Ethics of Human Gene Therapy. New York: Oxford University Press.

Willard, H.E 2000. Artificial Chromosomes Coming to Life. Science 290:1308-9.

Acknowledgments: My research was supported by the National Human Genome Research Institute. I am grateful to Joel Frader, Mark Frankel, Nancy King, and Sue Levi-Pearl for their helpful comments on an earlier version of this article.

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