Reproduction and Responsibility:

The Regulation of New Biotechnologies

Table of Contents

Modification of Traits and Characteristics

Advances in molecular biology and increases in genomic knowledge have begun to raise the possibility that scientists may one day be able not merely to screen and select embryos (or gametes) for particular traits and characteristics, but also to modify and engineer them. Should this capacity arrive, it would greatly increase our control over the genetic make-up of future generations and alter the relationships between parents and their engineered children. Such a capacity could, in principle be used both to treat genetic abnormalities and to try to engineer desired enhancements.

For now, and for the foreseeable future, such a prospect is purely speculative. The following chapter attempts to assess the state of the science in this area, as well as the ethical, social, and regulatory questions such a capacity would present to us, if it ever came to be.

I. Techniques and Practices

Gene-transfer is the process by which a DNA sequence containing a functional gene (or part of a gene or another regulatory genetic element) is inserted into cells, resulting in the expression (or silencing) of a gene product. This transfer is achieved by means of a "vector"-usually a modified virus that penetrates the targeted cells and introduces the new genetic information in a stable way. There are two broad categories of gene-transfer, defined according to which cells are modified. "Somatic gene-transfer" is the delivery of genes (or other genetic elements) to the differentiated cells of the body (or even totipotent stem cells). Here the effects of genetic modification are limited to the individual who receives the new DNA sequence. By contrast "germ-line gene-transfer" refers to a delivery of genes that affect the reproductive cells, thus causing a genetic modification that is heritable.ⁱ

Somatic gene-transfer for humans is now being developed for therapeutic purposes ("gene-therapy"), in an effort to correct genetic abnormalities or cure genetic diseases.ⁱⁱ The first such effort was undertaken by researchers at the National Institutes of Health (NIH) in 1990 to treat patients with severe combined immunodeficiency syndrome (SCIDS).¹ Currently, there are more than 500 gene-transfer research protocols under development,² all of them limited to genetic modification of somatic cells. While some people have suggested that germ-line gene-transfer might be a useful means of preventing the transmission of genetic abnormalities to offspring, there are currently no protocols for such treatment in humans.

Several experimental methods of germ-line modification are, however, being studied in animals, and not only for the treatment of genetic disease. One method, using mouse embryos, employs gene-transfer into the fertilized ovum. This has the effect of modifying all of the cells of the developing embryo, including the reproductive cells. In research to date, the resulting offspring expressed the new genetic information in variable ways-many of which have resulted in harmful abnormalities.³ Those offspring that express the new genetic materials in the desired manner are bred to produce a line of mice containing the new genetic characteristic. This approach has succeeded also in primates.⁴ An alternative method, currently in the very early stages of development, effects inheritable genetic modification by inserting an artificial chromosome that carries new genetic information into the reproductive cells of the recipient animal.⁵

Two principal obstacles to the safe and effective use of gene-transfer (in children or adults) are the difficulty of controlling, first, the exact locations in the host DNA into which new genetic information is inserted and, second, the extent to which the new genes are expressed in the right cells at the correct developmental time (without inducing other unwanted gene expression or altered regulation of resident genes). Unintended and unforeseen genetic expression has been responsible for the development of leukemia in children participating in clinical trials investigating gene-transfer for SCIDS.^{iii 6} These difficulties would likely worsen in attempts to modify the germ-line. The practitioner must contend not only with difficulties of placement and function of the new gene in the recipient, he must also try to anticipate and control these effects for the future generations who will inherit the genetic change. It would be difficult to study this approach in a scientifically rigorous way, given that the full results might not be known for decades. For these reasons, deliberate germ-line gene-transfer in human beings is risky, and unintentional germ-line modification is a danger to be avoided.

The problem of controlling placement and gene expression might perhaps be greater in the hypothetical case of genetic modification of embryos. There are now no effective means of ensuring the appropriate distribution, levels, or timing of expression of an inserted gene in an embryo. The risks of germ-line gene modification in this context would be profound.

II. Ethical Considerations

A. Safety of Embryonic Genetic Modification

B. Sources of Disquiet Regarding Genetic Modification

The possible creation of children with specific and deliberately chosen genetic characteristics-at present wholly speculative-raises many of the same ethical concerns as genetic screening and selection, but is distinct in some noteworthy respects. A child who is designed to certain specifications might be viewed as more of an artifact-or more answerable to the will of his or her parents-than a child who is merely selected for his or her existing characteristics. In this way, genetic modification of developing human beings, should it become feasible, might have even broader and more significant consequences: turning procreation into a form of manufacture; promoting a new eugenics, where parents and society seek only the "best" children; allowing individuals or society to alter the native human capacities of offspring in a direct way, and perhaps to engineer novel capacities not hitherto present in human beings; and binding the next generation to a genetic fate that suits the will of the present one.

It bears repeating that "designer babies" and "super babies" are not at all likely in the foreseeable future, and that even the introduction into embryos of any specific genes, with the aim of particular modest improvements, is not now feasible or safe. At present, therefore, these broader ethical and social concerns are wholly speculative.^v

III. Current Regulation

There is currently no regulation specifically governing attempts at genetic modification of gametes or early embryos. Yet the extensive federal regulations on gene-transfer research-undertaken for the purpose of gene-therapy of existing individuals-are broad enough to cover any such activities. There is no state regulation of genetic modification. There have been instances of individuals using tort litigation as a means of bringing regulatory pressure to bear on the practice of genetic modification, but this is relatively new.

A. Federal Regulation of Gene-Transfer Research

1. FDA Oversight.

No gene-therapy products are currently approved for general use in human beings. Accordingly, any transfer to a human subject of products that introduce genetic material into the body to replace faulty or missing genetic material (or to alter the regulation of resident genes) for the treatment or cure of disease constitutes a gene-transfer clinical trial, requiring prior submission of an investigational new drug (IND) application to the FDA.^vi "Gene-therapy products" include biologically based articles, such as a subject's own cells that have been extracted and modified outside the body prior to re-transfer into the human subject, or articles (natural or synthetic) that are directly transferred to the human subject with the intention of genetically altering his or her cells.

The FDA has asserted authority over gene-transfer technologies, regarding them as a type of drug or biologic, under the federal Food, Drug, and Cosmetic Act (FDCA) and Public Health Service Act (PHSA). The FDA claimed this authority as early as 1984, when it issued a policy statement noting that "nucleic acids used for human gene-transfer research trials will be subject to the same requirements as other biological drugs."⁷ Since that time, the FDA has provided guidance to the research community through a series of informational publications. One such guidance document, issued in 1998, gave comprehensive direction regarding technical and safety requirements.⁸ It included advice on matters such as preclinical safety data, molecular sequence of gene vectors, characterization of cell lines used in vectors, and the long-term monitoring of the health of human subjects.⁹

The most comprehensive articulation of FDA's legal authority to regulate in this area came in the form of a Federal Register notice in 1993.¹⁰ It defined gene-therapy products as those articles that "contain genetic materials administered to modify or manipulate the expression of genetic material or to alter the biological properties of living cells."¹¹ Such products are subject to the licensing, false labeling, and misbranding provisions for biologics (under PHSA¹²) and drugs (under the FDCA).^vii In the case of gene-transfer, the product in question will fall into one or both categories, depending on whether it is of synthetic or biological origin. The biological products that are the source materials for gene-transfer are also subject to the aforementioned licensing requirements. The FDA additionally claims jurisdiction to regulate gene-therapy products pursuant to its authority to prevent the interstate spread of communicable disease under Section 361 of the PHSA.

Because gene-therapy products are regarded as biologics or drugs or both, manufacturers and developers of gene therapies who wish to introduce technologies for general use must apply for premarket approval in the form of biologics license applications (BLAs), in the cases of biologics, or new drug applications (NDAs), in the cases of drugs.¹³   To qualify for such licenses, manufacturers of gene-therapy products must provide the FDA with voluminous information. In addition, the FDA requires such manufacturers to test the gene-therapy products in human subjects in clinical trials, which may be initiated only after the issuance of an IND. An IND requires the sponsor to explain to the FDA the nature of the study, the risks to the human subjects, the relevant human-subject protections in place (including institutional review board [IRB] approval), and the data supporting the study.¹⁴

As discussed in Chapter 2, the FDA has, on one occasion, prominently exercised its authority over gene-therapy products in the context of assisted reproduction. Upon learning of the efforts of clinicians at St. Barnabas Hospital in Livingston, New Jersey, to perform ooplasm transfer, the FDA asserted its authority on the grounds that such activities constituted unauthorized clinical trials in gene-transfer. Thus, the FDA informed St. Barnabas that it must halt all such activity and submit an IND before proceeding further.

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

As of 2000, FDA was overseeing more than 200 gene-transfer research clinical trials.¹⁵ None involve germ-line gene modification, which in the FDA's view cannot now be undertaken in a manner safe and effective enough to satisfy the IND requirement. Indeed, any gene-transfer research protocol that carries a serious risk even of inadvertent germ-line modification is unlikely to meet IND requirements. From a legal perspective, however, the proscription of germ-line modification does not exist for the benefit of the unconceived embryo, since the FDA has no clear legal authority to consider the safety of future generations. Rather, the FDA's justification for treating germ-line therapy with such caution is framed in terms of safety, efficacy, and the protection of human subjects in clinical trials (not including the embryos, who are not considered legal subjects).^viii

2. NIH/RAC Oversight.

NIH is a "major funder of human gene-transfer research and the basic science that underpins it."¹⁶ As such, it shares with FDA some responsibility for oversight of gene-transfer research. Any project funded by NIH, or conducted at an institution that receives NIH funding, is subject to NIH review. NIH also accepts and reviews protocols from researchers who voluntarily submit them, regardless of the funding source. The approval process itself considers the ethical, scientific, and safety dimensions of each protocol. The document that governs this process is the "NIH Guidelines for Research Involving Recombinant DNA Molecules," which provides the standards researchers must meet to ensure safety and safe handling of the articles used and derived in such research. The NIH Guidelines additionally provide the requirements for institutional oversight by the Institutional Biosafety Committees (IBC) and the RAC. The NIH Guidelines also provide extensive guidance to researchers on the standards and procedures for the conduct of their clinical trials.¹⁷

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

Once it has received the aforementioned information, OBA forwards the application for preliminary consideration by the RAC. The RAC is a panel of experts-including scientists, physicians, lawyers, ethicists, and laypersons-that advises the NIH director and the OBA on recombinant DNA research. In addition to reviewing specific research proposals involving gene-transfer, the RAC recommends changes to the NIH Guidelines. While the RAC has no formal authority to accept or reject research proposals, submission to the RAC is a compulsory aspect of the NIH review process. Thus, the RAC's current refusal to "entertain proposals for germ-line alterations"¹⁸ effectively ensures that no such protocols will receive NIH funding.

Following its review of a given proposal, the RAC determines whether the protocol "raises important scientific, safety, medical, ethical, or social issues that warrant in-depth discussion at the RAC's quarterly public meeting."¹⁹ Any protocols that present "unique applications of gene transfer research, the use of new or otherwise salient vector or gene delivery systems, special clinical concerns, or important social or ethical issues"²⁰ are singled out for further review and public discussion.

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

Within twenty days of enrolling and obtaining consent from the first research subject, the researcher must submit to the OBA a number of items, including a copy of the informed consent form approved by the IRB, a copy of the protocol approved by the IBC and IRB, a copy of final IBC approval from the clinical trial site, a copy of final IRB approval, the applicable NIH grant numbers, the FDA IND number, and the date of the initiation of the trial. Additionally, the researcher must provide a "brief written report that includes . . . (1) how the investigator(s) responded to each of the RAC's recommendations on the protocol (if applicable); and (2) any modifications to the protocol as required by FDA."²¹ During the course of the clinical trial, researchers have an ongoing obligation to inform OBA, the IRBs, IBCs, FDA, and the sponsoring NIH institutions within fifteen days of serious unexpected adverse events that might be associated with the gene-transfer project. If such adverse events involve death or risk of death, this must be reported within seven days. Additionally, researchers must provide OBA with an annual report.

B. Tort Litigation as a Regulatory Mechanism

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

Claimants in clinical-trial cases have sued researchers for negligence in the conduct of the clinical trial. Such a claim requires the plaintiff to demonstrate that the researcher owed a duty of care to the subject, which he breached, resulting in cognizable injury. The question of whether a duty is owed by a researcher in this context has been the subject of some debate. Most courts that have considered the issue have found that a duty exists, by virtue of the special relationship between researcher and subject, the quasi-contract formed by the informed-consent agreement, or implied by the federal guidelines for human-subject protections. The standard of care owed under these circumstances-a question analytically separate from whether a duty exists-has also been the subject of some discussion. Most courts addressing the question have held that the standards for informed consent set forth by the Common Rule and FDA's human-subject protections constitute the relevant standard of care, the breach of which may be considered actionable. Two courts have gone farther: one holding that the researcher must disclose any conflicts of interest,²² and another holding that parents are legally incapable of subjecting their children to any risks in nontherapeutic research.^{ix 23} In addition to the standards for informed consent in the federal guidelines, some commentators have suggested that courts should import medical malpractice jurisprudence to determine the standard of care. They argue that the researcher owes the subject "implementation of knowledge, skill and care ordinarily possessed and employed by members of the profession in good standing."²⁴ Deviation from this standard, under this analysis, would constitute actionable breach. Claimants could prove the contours of this standard of care through the introduction of extrinsic evidence at trial, as through expert witness testimony. This might be problematic in the gene-transfer context; it is such a new technique that "custom" might be hard to establish.

To recover, the claimant must also demonstrate that the researcher's breach caused the relevant injury. Again, this might be difficult for gene-transfer research, given the complexity and novelty of the procedure. Moreover, even if the claimant could show that, but for the researcher's conduct, the harm would not have occurred, the court may not be willing, on grounds of public policy, to impose liability. Courts have sometimes been hesitant to impose such liability on researchers for fear that to do so would have a chilling effect on scientific experimentation that is socially beneficial.²⁵

Proving harm might also be very difficult in the context of gene-transfer research, particularly when the individual harmed is unborn when the harm occurs or, as in the case of germ-line gene-transfer, unconceived. Courts have been hesitant to impose liability on harm to future generations.²⁶

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

C. Nongovernmental Regulation

Various professional societies have issued statements offering guidance and reflection on the ethics of genetic engineering and gene-transfer. For example, the American Medical Association (AMA) has issued ethics opinions on each of these subjects. The AMA's statement on genetic engineering makes it clear that if and when this practice becomes ready for clinical application, the AMA standards on clinical investigation, medical practice, and informed consent apply. Moreover, the AMA holds the following: genetic engineering should be conducted safely, no dangerous viruses should be employed, and the safety and effectiveness of any such procedures should be evaluated very closely.²⁷

The AMA's statement on gene-transfer asserts that there should be no germ-line modification at this time because of the "welfare of future generations and its association with risks and potential for unpredictable and irreversible results." Nontherapeutic applications of gene-transfer are "contrary to the ethical traditions of medicine and against the egalitarian values of society." Such uses of gene-transfer can be undertaken only if the following three conditions are satisfied: (1) there is a clear and meaningful benefit to the affected person, (2) there is no "trade off" with other characteristics or traits, and (3) "all citizens would have equal access to the technology, irrespective of income or other socioeconomic characteristics."²⁸

IV. Conclusion

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FOOTNOTES

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Endnotes