H U M A N G E N E T H E R A P Y 1:151-161 (1990) Mary A n n Liebert, Inc., Publishers

L e g a l Regulation o f H u m a n G e n e T h e r a p y

JUDITH AREEN1 and PATRICIA KING2

ABSTRACT The adequacy of existing legal mechanisms to regulate clinical trials of human gene therapy is examined. Existing legal controls include the federal Guidelines for Research Involving Recombinant D N A Molecules and federal regulations for the protection of h u m a n subjects. Another significant mechanism is provided by judicial oversight, i.e., judicial decisions involving recombinant D N A research. H u m a n gene therapy does raise new issues that still must be resolved. At least two weaknesses exist in the present regulatory system: first, Recombinant D N A Advisory Committee ( R A C ) only has authority over federally funded research, not work done with private support, and second, R A C is not mandated to focus on difficult ethical issues, e.g., germ-line therapy, that arise from h u m a n genetic engineering technology.

OVERVIEW S U M M A R Y Human gene therapy not only must satisfy scientific, medical, and ethical requirements, but also must take place within a legal framework. Areen and King examine this framework, discuss h o w it arose historically, and point out weaknesses in it that need to be addressed. IT has been 14 years since the issuance of the first federal guidelines governing research involving recombinant D N A (U.S. Department of Health and H u m a n Services (DoHHS), 1976). At the time, the driving force behind the guidelines was concern about the possibility of an inadvertent release into the environment of dangerous organisms created by using recombinant D N A techniques. A s a result, the initial guidelines emphasized containment (U.S. D o H H S , 1976).(1) B y 1983, researchers were seeking to test genetically engineered bacteria in open fields (Schmeck, 1983). The legal response, consequently, focused on theriskof dispersal.(2) N o w a third regulatory challenge is on the horizon: It is likely that a protocol will be submitted in the near future seeking approval from the National Institutes of Health (NIH) to use recombinant

Georgetown University Law Center, Washington D C 20001; member of Human Gene Therapy Subcommittee ofthe Recombinant D N A Advisory Committee, NIH. Georgetown University Law Center, Washington, D C 20001; former member, President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research; former member, National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research; former member, Recombinant D N A Advisory Committee. Numbered notes indicated in the text appear at the end of this article, before the references. 151

A R E E N A N D KING DNA techniques to treat patients suffering from a genetic defect.(3) [Ed. Note: see News and Comments, p. 193] This article analyzes the adequacy of existing legal mechanisms to regulate clinical trials of human gene therapy.

OVERVIEW OF EXISTING LEGAL CONTROLS Federal guidelines for research involving recombinant DNA molecules Issued initially in 1976, the Federal Guidelines for Research Involving Recombinant D N A Molecules establish both biological and physical containment standards for the research (U.S. D o H H S , 1976). Generally, the more risk posed by an experiment, the stricter the containment measures required by the Guidelines. The Guidelines apply to all recombinant D N A research conducted at or sponsored by an institution that receives support for recombinant D N A research from NIH. They require each covered institution to establish an Institutional Biosafety Committee (IBC) with authority to ensure that experiments are in compliance with the Guidelines.(4) Certain high-risk experiments must also be approved by the Recombinant D N A Advisory Committee (with the symbolic acronym R A C ) of NIH. In 1984, in response to the fact that it had not been constituted with human clinical trials in mind and aware that such trials were on the horizon, the R A C created a "Working Group on H u m a n Gene Therapy" to advise it on protocols that involve human gene therapy (U.S. D o H H S , 1984).(5) The Working Group was later renamed the H u m a n Gene Therapy Subcommittee ofthe Recombinant D N A Advisory Committee. In 1985, the H u m a n Gene Therapy Subcommittee issued guidance to researchers in the form of a document entitled, "Points to Consider in the Design and Submission of H u m a n Somatic-Cell Gene Therapy Protocols" (U.S. D o H H S , 1985). The Points to Consider document formally requests information on a variety of topics that the H u m a n Gene Therapy Subcommittee considers relevant to the task of deciding whether to recommend approval of a specific protocol for human gene therapy; implicitly, however, it imposes requirements on researchers seeking approval that go beyond the R A C Guidelines. For example, the Points to Consider asks researchers to confirm that as a condition of participation in the research, all subjects will be required to agree to long-term follow-up (for a period of at least 3-5 years) after receiving altered genetic material (U.S. D o H H S , 1985, sec. I.D.5.C.). The researchers are asked to confirm that each subject will be told that it would be medically inadvisable to withdraw from the protocol once the genetically altered cells have been placed in the subject's body, a process that is probably irreversible (U.S. D o H H S , 1985, sec. I.D.5.b.). Researchers must confirm that they will report immediately to N I H any serious, adverse effects experienced by the subjects (U.S. D o H H S , 1985, sec. IV. A.). Finally, because ofthe enormous public attention paid to both patients and families in recent cases involving other new therapies (e.g., Baby Fae, the first recipient of an animal heart, and the artificial heart transplant recipients), researchers are asked to report what steps will be taken to protect the privacy of patients and families involved in human gene therapy.(6) Federal regulations for the protection of human subjects H u m a n gene therapy, unlike earlier recombinant D N A research, is governed by a second set of federal regulations: the regulations that apply to any federally funded research involving human subjects.(7) These regulations were established in 1974 in the wake of public concern about the failure of researchers to obtain informed consent from subjects in a number of controversial experiments, including the highly publicized Tuskeegee Syphilis Study conducted on poor, black men by the United States Public Health Service (Jones, 1981).(8) The human subject regulations establish both a framework of substantive conditions that research must meet and a procedural mechanism for ensuring compliance. The heart of the procedural mechanism is the 152

LEGAL REGULATION OF H U M A N GENE THERAPY Institutional Review Board (IRB) that must be established at each research center that receives federal funding for research. Each I R B must review proposed research involving h u m a n subjects(9) and approve protocols only if "risks to subject are minimized ... by using procedures which do not unnecessarily expose the subject torisk"and if "risks to subjects are reasonable in relation to anticipated benefits, if any, to the subjects."(10) In addition, informed consent must be obtained from each subject or his or her legally authorized representative.00 Even more stringent requirements apply if children are to be the subjects, reflecting the traditional parens patriae responsibility of the state toward minors. Thus, the regulations direct that research involving child-subjects, in addition to meeting the requirements imposed on research involving adult subjects, m a y pose no more than minimalriskto the children unless the research "holds out the prospect of direct benefit to the individual subjects."(12) Unfortunately, no guidance is given to clarify h o w likely the prospect of direct benefit must be to comply with the regulations.

Judicial oversight Recombinant D N A research m a y also be subject to judicial oversight even if it is in compliance with all relevant federal regulations. T h e first judicial decision involving recombinant D N A research, M a c k v. Califano,(l3) suggested that the courts would refrain from interfering in research that was in compliance with the relevant N I H guidelines. InMack, a resident of Frederick, Maryland, sought a temporary restraining order to stop any recombinant D N A experiments from being conducted at nearby Fort Detrick. The request was denied by the court on the grounds that N I H , the agency conducting the research, was in full compliance with the N I H guidelines on recombinant D N A research that had been issued 2 years earlier. The court specifically noted with approval that both physical and biological containment measures were being followed by the researchers. Seven years later, by contrast, in Foundation on Economic Trends v. Heckler,(14) the United States Court of Appeals for the District of Columbia Circuit upheld a lower court order that had enjoined a recombinant D N A experiment involving the deliberate release of genetically engineered organisms into the air. T h e researchers involved were proposing to test whether it was possible to increase the frost resistance of certain crops by using genetically altered bacteria. T h e researchers had already obtained R A C approval as the experiment w a s to be conducted in compliance with N I H guidelines. The appellate court nonetheless upheld the injunction until an adequate environmental impact statement was completed. T h e judges expressed concern that the R A C might not have given sufficient attention to the risk of dispersion, noting that the minutes of the R A C meeting contained only one sentence on the issue, and it was taken almost verbatim from the proposal.(15) The court added: Remarkably . . . R A C completely failed to consider the possible environmental impact from dispersion of genetically-altered bacteria, however small the number and however subject to procedures limiting survival.(16) Factual differences in the two cases m a y explain the difference in outcome. Deliberate release experiments clearly pose different safety issues than experiments intended to be confined to a laboratory setting. In M a c k moreover, unlike Foundation on Economic Trends, an environmental impact statement was completed prior to the court's decision. Nonetheless, Foundation on Economic Trends demonstrates that compliance with relevant federal regulations will not necessarily insulate future experiments from judicially imposed prior restraints, at least if the experiments poserisksthat appear not to have been adequately considered during the review process. O n the other hand, the court in Foundation on Economic Trends declined to enjoin N I H from approving other deliberate release experiments until it had completed a "programmatic" environmental impact statement. T h e court simply directed N I H to consider whether a programmatic environmental impact 153

AREEN A N D KING statement is required/17) Subsequent decisions by this and other federal courts suggest that the judiciary may be returning to the more deferential stance toward decisions m a d e by regulatory agencies about recombinant D N A research embodied in M a c k v. Califano.(m

N E W ISSUES RAISED BY H U M A N G E N E THERAPY Human gene therapy poses ethical issues different from those presented by earlier recombinant DNA research. It m a y be very difficult to determine, in some instances, whether the proposed benefits justify the risks posed to the subjects. It is likely, for example, that a m o n g the first subjects proposed for gene therapy will be children suffering from a potentially lethal genetic defect. A prime candidate for the first tests is the adenosine deaminase ( A D A ) gene, the absence of which results in severe combined immunodeficiency disease (SCID) (Anderson, 1984).(19) Children with S C I D have greatly weakened resistance to infection, and usually do not survive the usual childhood diseases.(20) The most effective treatment currently available for these children is a bone marrow transplant, but the treatment itself posesrisks,and a suitable donor is not always available (Ballow and Hirschhorn, 1985).(23) The first protocols submitted for approval are likely to propose treating each subject by removing some of his or her o w n blood cells, delivering the missing genetic material to the blood cells by using a retrovirus(22) to which the missing gene has been added using recombinant D N A techniques, and then reimplanting the treated blood cells in the subject (Anderson, 1984; Gilboa etal., 1986; Parkman, 1986;Dzierzakefa/., 1988). The regulatory bodies reviewing the early protocols for h u m a n gene therapy must first grapple with the issue of whether the potential benefits of the protocol outweigh the potential risks. For children w h o are suffering from a fatal genetic disease for which a bone cells transplantation is not available, this assessment will be difficult, although the assessment of benefits will be similar to that m a d e by institutional review boards for other n e w therapies or drugs. This benefit assessment will look both at the theoretical justification proffered, and at the available data from animal studies.(23) The risk assessment, by contrast, will involve weighing risks that are not c o m m o n to most biomedical research involving h u m a n subjects. For example, h u m a n gene therapy poses theriskof transmission of the genetic changes to any future offspring ofthe subjects. The gene therapy protocol described above is designed to involve only somatic cells, rather than germ-line cells, and thus it should not pose suchrisksto offspring. Indeed, a strong scientific consensus has developed that somatic cell h u m a n gene therapy is not different in any relevant ways from a number of other medical interventions such as organ transplantation, and bone marrow injection (U.S. Congress, Office of Technology Assessment, 1985; U.S. D o H H s , 1985, 33464). Somatic cell h u m a n gene therapy, therefore, does not pose the difficult ethical issues raised by germ-line therapy (Walters, 1986). Nonetheless, theriskof inadvertently affecting germ-line cells, however small, will need to be weighed by the Subcommittee in deciding whether to approve a particular protocol. Next, there are therisksgenerated if the transplanted gene is deposited randomly in a cell's chromosomes. R a n d o m insertion raises the possibility of inadvertently triggering one of a number of oncogenes(24) in the cell (Anderson, 1984). This risk can be reduced, but not eliminated, by engineering the vector virus to remove activating sequences (Temin, 1990). The use of a retrovirus to transfer the missing gene also creates theriskthat the vector will recombine with the genomes of the infected cells or another virus to form an infectious virus that could be transmitted to third parties. Again, however, the retrovirus can be engineered to minimize thisrisk.Even if an infectious virus is formed, moreover, it is unlikely to be pathogenic, as most endogenous retroviruses are not (Temin, 1990). The risk is further reduced by the fact that most retroviruses are not easily transmitted. H u m a n immunodeficiency virus (HIV), for example, the retrovirus that causes A I D S , can be transmitted only by infected body fluids

(Cumn etal., 1988). 154

LEGAL REGULATION OF H U M A N GENE THERAPY ASSESSMENT OF EXISTING LEGAL CONTROLS Any protocol for human gene therapy conducted at an institution receiving NIH research funds will need the approval of at least four different regulatory bodies before going forward: the local IBC, the local I R B , the R A C , and the F D A . O n e might conclude that this is far more regulatory oversight than is needed, and indeed, is more than m a n y areas of scientific breakthrough could have survived in their infancy. Nevertheless, w e believe such oversight is appropriate, at least at the initial stages of research on h u m a n gene therapy. If the interests of subjects could be protected adequately merely by obtaining their informed consent, then this extensive review process might not be warranted; submission to an IRB would probably be sufficient. But as the regulations governing the operation of IRB's recognize, review by an I R B involves more than oversight of informed consent. The regulations provide, for example, that the I R B should independently weigh the risks and benefits of proposed research to the subjects even //the subjects give their "informed consent."(25) It is even less plausible to justify reliance on consent provided by a lay person when the protocol involves a very n e w area of science, such as h u m a n gene therapy. Concern about not giving undue weight to informed consent only increases, moreover, w h e n the subject is unable to give consent because he or she is a minor. The inadequacies of informed consent do not m e a n that it should be dispensed with; on the contrary, it should always be obtained from a subject or his or her legal guardian. But as the regulations m a k e clear, informed consent is not sufficient to relieve an institution of the responsibility for independently assessing whether the potential benefits of a proposed experiment to be conducted at that institution justify the possible risks to the subjects or to others. A local IRB, like lay subjects, will generally not include (or have access to) sufficient scientific expertise to assess therisksto h u m a n subjects of research involving breakthrough technologies. For such n e w technologies, there is good reason to involve a national review body that can draw on scientific expertise throughout the nation in assessing therisksand benefits. Such a body should not be composed only of scientists, however, because the decisions to be m a d e will at times transcend the boundaries of scientific expertise by raising such matters as whether the selection of subjects is fair. In short, there would be good reason to create something like the H u m a n Gene Therapy Subcommittee if the R A C had not already done so. The initial bureaucratic infighting over the composition and jurisdiction of the Subcommittee, on the other hand, reveal the fragility of any review process grounded only in administrative rather than legislative authority.(26) The jurisdiction of the Subcommittee was called into question again in 1988 w h e n three N I H scientists, Dr. W . French Anderson of the National Heart, Lung and Blood Institute and Drs. R. Michael Blaese and Steven A . Rosenberg ofthe National Cancer Institute, submitted a proposal involving transfer of a bacterial gene coding for neomycin phosphotranferase into the cells of human.patients. The gene was to be used as a marker to trace the path of "tumor infiltrating lymphocytes" (TIL), administered as part of an ongoing experimental cancer treatment.(27) The proposal w a s submitted to the Subcommittee on July 29, 1988. O n September 29, 1988, the Subcommittee decided to defer approval pending the receipt of specific additional data. Nonetheless, on October 3, 1988, the R A C voted 16 to 5 to approve the protocol, after receiving data not provided to the Subcommittee. The Director of N I H sent the protocol back to the Subcommittee, however, and on December 9, 1988, the Subcommittee approved the protocol 12 to 0. The R A C then voted its approval 21 to 0 by mail. O n January 30,1989, the Foundation on Economic Trends filed a law suit challenging the approval process. O n M a y 15, 1989, the litigation was settled after the Secretary ofthe Health and H u m a n Services agreed that in the future all R A C deliberations and votes would take place in open public session (Associated Press, 1989).(28) Judge David Bazelon has warned that the idea of nonscientists having anything to do with science is relatively recent in origin (Bazelon, 1977). H e further cautioned that m a n y scientists believe that science has arightto proceed as if it were an autonomous, self-governing republic. But it is n o w increasingly recognized that m a n y modern technologies involve issues that go far beyond scientific expertise. 155

A R E E N A N D KING Establishment ofthe Subcommittee was a commendable effort made by the RAC to rectify weaknesses in its o w n composition in light of the anticipated requests to initiate human gene therapy. Because the Subcommittee was staffed without public consultation, however, it and the R A C should approve any protocol only after consulting as widely as possible both with experts around the nation in scientific and medical fields relevant to human gene therapy, and with other interested persons.

T H E NEXT STEPS Two weaknesses in the present regulatory system need to be addressed. First, neither the Subcommittee nor the R A C have authority to review human gene research conducted by an institution that does not receive funds from the U.S. Department of Health and H u m a n Services, unless the research is voluntarily submitted for review. Such research m a y be subject to the controls of other federal agencies, however [e.g., the Food and Drug Administration if the research is relied on in seeking approval for a new drug (U.S. D o H H S , 1986)]. Otherwise federal or state legislation will be required to establish an appropriate review process.(29) Second, the Subcommittee and the R A C are not mandated to focus on the difficult ethical questions raised by (1) germ-line gene therapy or by (2) the use of recombinant D N A techniques to enhance human traits such as intelligence or strength rather than to treat genetic disease. Although objections have been raised to germ-line therapy,(30) w e believe enhancement engineering poses even more difficult ethical issues (Anderson, 1989). First there is the challenge of distinguishing gene therapy from enhancement engineering. If parents want scientists to increase the height of their child, for example, h o w short must the child be for society to consider the request to be for treatment rather than enhancement? Second, if enhancement engineering ever does move from the realm of science fiction into science fact/31) extremely serious issues of access to and fair distribution of such possibilities will arise.(32) B y contrast, n o w that there is growing agreement that it is ethical to treat a single child suffering from SCID, it seems likely that in the future there will also be agreement that it is appropriate to approve germ-line as well as somatic cell therapy for the disease, thus treating the child and his children and their children.(33) For a time, it appeared that Congress would establish a permanent, national body to assess the long-term benefits andrisksof human gene therapy including gene-line therapy. Thus, in 1985, Congress overrode a presidential veto to approve the establishment of a Bioethics Board (BEB), modeled on the Office of Technology Assessment (U.S. Congress, Senate, 1985). The Board, which was to be made up of 12 members (6 from each House of the Congress) was directed to: study and report to the Congress on a continuing basis on the ethical issues arising from the delivery of health care and biomedical and behavioral research, including the protection of human subjects of such research and developments in genetic engineering (including activities in recombinant D N A technology) which have implications for human genetic engineering. To conduct the studies and prepare the reports, the Board was to appoint a Biomedical Ethics Advisory Committee ( B E A C ) of 14 members: 4 distinguished in biomedical or behavioral research, 3 distinguished in medicine or the provision of health care, 5 distinguished in ethics, theology, law, the natural sciences, the social sciences, health administration, government and/or public affairs, and 2 citizens with an interest in biomedical ethics. The structure of a board plus a committee held promise. The members of the B E B were to be chosen from both political parties in equal numbers, thus in theory providing more consistent political direction than a Presidential commission considering the dramatic shifts in membership that can occur when a N e w President is elected. The B E B had the benefit, moreover, of being able to draw on the work of the R A C and the two previous national commissions on bioethics.(34) In 1986, thefirstmembers ofthe B E B were named(35) and an attempt was made to appoint the B E A C . O n e 156

LEGAL REGULATION OF H U M A N GENE THERAPY of its original 14 members died, however, before the BEAC first met. Paralyzed by its inability to agree on a replacement m e m b e r , the B E A C m a d e no substantive headway. O n N o v e m b e r 9, 1989, Congress voted to terminate all funding for the B E B and the B E A C (U.S. Congress, Senate, 1989). T h e authorizing legislation remains in place, but without funding, no committee w o r k can proceed. T h e science of h u m a n gene therapy continues to develop. T h e only oversight in place, however, is the F D A , the R A C , and its Subcommittee. With each passing year, time runs out on the opportunity to wrestle with the long-term ethical and policy issues raised by gene therapy before it has b e c o m e an accomplished fact.

NOTES 1. For accounts ofthe events that preceded issuance ofthe regulations see Areen et al. (1984, 2-50); Califano (1981); Rogers (1977); Watson and Tooze (1981); Areen (1985-1986); Swazey et al., (1978). 2. See Foundation on Economic Trends v. Heckler, 756 F.2d 143 ( D . C Cir. 1985) discussed in text at note 11. 3. Although claims that human gene therapy trials were about to begin were first made in 1984, researchers have had more difficulty achieving successful results in animal studies than originally expected. Nonetheless, there continue to be signs of progress. See, e.g., Marx (1986); Robertson (1986). The first clinical trial involving an engineered gene marker was approved in 1988. See text at notes 26 to 27. 4. For a thoughtful overview of the operation of institutional biosafety committees, see Bereano (1984). 5. The Working Group initially consisted of four physicians, two molecular biologists, three lawyers, three ethicists, two public policy experts, and one representative ofthe general public (U.S. D o H H S , 1985, 2940). In 1986, 1-, 2-. or 3-year terms were assigned by lot to the initial members of the committee. In 1987, the first rotation of new members onto the Subcommittee changed the composition to include seven physicians, two molecular biologists, three lawyers, two ethicists, and one representative ofthe general public. 6. The original version of the Points to Consider also asked researchers to answer a series of policy-related questions such as, "Is it likely that somatic-cell therapy for human genetic disease will lead to (a) germ line gene therapy, (b) the enhancement of human capabilities or (c) eugenic programs encouraged or even mandated by the government." These questions were deleted in the 1985 revision of the document as a result of a new consensus on the Subcommittee that it is the responsibility ofthe Subcommittee and other regulatory bodies to weigh these issues in deciding whether or not to approve a specific protocol. Moreover, most researchers are not in a position to provide expert answers to such questions, as they involve predictions about political and social events as much as about scientific development. 7. 39 Fed. Reg. 18, 914 (1974) [codified at 45 C.F.R. 46 (1985)]. As early as 1966, the Surgeon General required an investigator's institutional associates to review proposals submitted for financial support from the Public Health Service "To assure an independent determination of the protection of therightsand welfare of the individual or individuals involved, of the appropriateness of the methods used to secure informed consent and of therisksand potential medical benefits ofthe investigation." See Areen et al. (1984, 959). 8. For more background on the regulations see Faden et al. (1986). 9. 45 C.F.R. 46 (1988). The regulations exempt certain types of experiments from this process because they involve little or no risk to the subjects 45 C.F.R. 46.101 (1988). 10. 45 C.F.R. 46.111 (a)(1), (2). 11. 45 C.F.R. 46.111, 46.116. 12. 45 C.F.R. 46.405. T w o other sections ofthe regulations m a y be relevant to human gene therapy protocols, depending on the amount ofriskposed to the subject. Section 46.406 ofthe regulations governs research involving "greater than minimalrisk"that constitutes a "minor" increase over minimal risk. The section permits such research if it is "likely to yield generalizable knowledge about that subjects' disorder or condition which is of vital importance for the understanding or amelioration ofthe subjects' disorder or condition." Section 46.407 applies to research not covered by other sections. Thus, it would apply to research involving greater than minimalriskwhere theriskis not justified by the anticipated benefit to the subjects. Research covered by section 46.407 should be approved only if: (a) The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and (b) The Secretary [of the U.S. Department of Health and H u m a n Services], after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment [determines]: (i) The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children. . . 157

A R E E N A N D KING 13. 447 F. Supp. 668 (D.D.C 1978). 14. 756 F.2d 143 (D.C. Cir. 1985). 15. "Although some movement of bacteria toward sites near treatment locations by insect or aerial transport is possible, the numbers of viable cells transported had been shown to be very small; and these cells are subject to biological and physical processes limiting survival." 756 F. 2d at 153 (emphasis by court). 16. Id. 17. 756 F.2d at 160. 18. See Foundation on Economic Trends v. Bowen, Cir. N o . 87-3393 (D.D.C Oct. 4, 1989) (summarily dismissing claim that N I H must complete an Environmental Impact Statement before supporting research involving cloning of oncogenes, cloning of HIV, and engineering genetic codes of A I D S into originals that is in compliance with Recombinant D N A Guidelines); Foundation on Economic Trends v. Lyng, 817 F.2d 882 (D.C. Cir. 1987) (holding Department of Agriculture does not need to prepare a programmatic environmental impact statement for animal productivity research as the research consists of projects too diverse and discrete to constitute a "major Federal action" or to require a programmatic environmental impact statement); Foundation on Economic Trends v. Johnson, 661 F. Supp. 107 (D.D.C. 1986) (dismissing challenge to coordinated framework for regulating biotechnology for lack of justiciable case or controversy); Foundation on Economic Trends v. Thomas, 661 F.Supp. 713 ( D . D . C 1986) (rejecting challenge to E P A procedures governing oversight of deliberate release research); Foundation on Economic Trends v. Thomas, 637 F. Supp. 25 (D.D.C. 1986) (denying request for preliminary injunction to stop deliberate release experiment). Courts have been less deferential to decisions by military agencies about the use of recombinant D N A techniques in connection with biological warfare. In Foundation on Economic Trends v. Weinberger, 610 F. Supp. 829 ( D . D . C ) , for example, a federal district court enjoined the construction of a proposed aerosol test facility as well as toxic agent support facilities at the U.S. A r m y s D u g w a y Proving Ground in Dugway, Utah. D u g w a y was established as a test facility in 1942 to test and assess the military value of chemical warfare and biological defense systems. During the 1970s, parts ofthe facility "fell into disuse and disrepair [because of decisions] made at the highest level of government, to 'de-emphasize' the use of chemical and biological warfare in possible future armed conflicts. . Convinced that the Soviet Union has maintained its offensive biological warfare program and that it is exploring genetic engineering to expand [the] program's scope," the Department of Defense in 1984 obtained Congressional approval to reprogram $8.4 million in military construction funds to renovate and expand the facilities at D u g w a y (610 F. Supp. at 832-833). A s required by law, the A r m y prepared a Record of Environmental Consideration that contained an Environmental Assessment. The Assessment concluded that the proposed activity "should cause no significant impact on the quality of the human environment," largely based on the Army's assertion that the new laboratory would not be used to conduct experiments that differed in any significant manner from those currently being conducted. Id. at 834. The court found that no affirmative proposal to use recombinant D N A had yet been made, so the A r m y did not need to file a new Environmental Assessment on that basis. The court nonetheless enjoined construction until an acceptable Environmental Assessment could be prepared because of potentialrisksto the environment from the pathogenic agents and toxins that would be used in the new facility. Id. at 844. In 1987, the Department of Defense agreed as part of a court settlement to conduct a study of the possible environmental effects of its biological warfare program (Hilts, 1987). 19. Other candidate genes are hypoxanthine-guanine phosphoribosyl transferase (HPRT), the absence of which results in Lesch-Nyhan disease and purine nucleoside phosphorylase (PNP), the absence of which results in severe immunodeficiency disease. Id. 20. One of the best known victims of S C I D was David, the boy w h o lived for 12 years in a germ-free bubble at Baylor College of Medicine (Thompson, 1984). For more detailed information about SCID, see Gelfand and Dosch (1983): The single most common presenting feature of SCID is failure to thrive. These infants are often below the 3rd % for weight. . . Significant failure of weight gain generally presents between 3-6 months of age; rarely, an infant may thrive for up to 10-12 months of age. Despite normal caloric intake, weight gain is poor, even when the calories are provided by other than the gastrointestinal route. Recurrent infections generally begin between 3 and 6 months of age, at a time when maternally endowed humoral immunity has virtually disappeared. . . Bacterial otitis media, pneumonitis, and sepsis have all been described but, perhaps due to the liberal use of antibiotics, m a y not be the major problem. Recurrent and persistent oral and perianal candidiasis are frequent. Diarrhea and malabsorption, commonly secondary to one ofthe enteric viruses. . are c o m m o n . . Pulmonary infections are also c o m m o n . Pneumocystis carinii pneumonitis is often seen in SCID. ... A variety of skin rashes have been associated with S C I D — m a n y are bizarre in appearance and location and not easily diagnosed. 158

LEGAL REGULATION OF H U M A N GENE THERAPY See also Ballow and Hirschhom (1985): "Severe combined immunodeficiency (SCID) is a heterogeneous group of congenital disorders which are characterized by a profound impairment of both humoral and cell-mediated immunity. These immune abnormalities result in severe, recurrent infections which often lead to death within the first 2 years of life if untreated." 21. Unfortunately, only about one-third of the infants with S C I D have compatible marrow donors (U.S. Congress, Office of Technology Assessment, 1987). 22. Gilboa etal. (1986): Retroviruses are RNA viruses, that is the viral genes are encoded in an RNA molecule rather than in a D N A molecule. W h e n the virus penetrates a cell, the viral R N A is first converted to D N A , the D N A enters the nucleus and integrates randomly into a chromosome, becoming indistinguishable from any other. . . gene. . With a few exceptions, the presence of the viral genome in the infected cell [has] no apparent effect on the viability ofthe infected cell. Thus, retroviruses have features that make them particularly suitable for gene transfer. By replacing the viral genes with the gene of interest and using the efficient viral integration process, it is now possible to transfer a gene into the infected cell. For a more complete description of reverse transcriptase, the process by which DNA is converted to RNA by retroviruses ("retro" is shorthand for reverse transcriptase) see Varmus (1987). 23. Researchers have been encouraged by several reports including the successful insertion of a gene into the red blood cells of mice (Dzierzak ef a/., 1988; Miller ^r al., 1990). 24. Oncogenes are genes that can participate in the multistep process that can turn a normal cell into a cancer cell. 25. 45 C.F.R. 46.111 26. In the summer of 1985, for example, just as the revised version of the Points to Consider was about to be published, the Commissioner ofthe Food and Drug Administration (FDA) asked that publication be delayed until an interagency regulatory body could be established. For a more detailed discussion ofthe troubled history ofthe review process see Areen (1985-1986). 27. See U.S. D o H H S (1989) for a more detailed history of these events. 28. The test began on M a y 22, 1989. O n September 18, 1989. Steven A. Rosenberg reported that the protocol was proceeding smoothly on five patients after TIL therapy. Science 245, 1325 (Sept. 22, 1989). 29. A handful of states currently regulate research involving human subjects. The most comprehensive state regulations are in California (1984, sec. 24170-24179-5), N e w York (1985, sec. 2440-2446), and Virginia (1984, sec. 37.1-234-371.1-241). 30. In 1983, for example, a number of religious leaders signed a "Theological Letter Concerning the Arguments Against Genetic Engineering ofthe H u m a n Germline Cells" (1983). See also Thomas (1985): I have no trouble in thinking about somatic alterations for the purpose of treating otherwise fatal human diseases; I a m all in favor, and hope that the technology moves fast enough to make Tay-Sachs disease, say, a curable disorder. But I have no such quick answer to the question about altering the human germ plasm and producing changes that will last through all the generations to come. Or rather, I do have a quick answer and it is that biomedical science should not do such a thing, n o w or ever. But that, I must quickly qualify, is m y personal judgment and not in any sense a scientific opinion, to which I do not in this case feel entitled. 31. Cf. Singer (1985) (responding to the statement by Jeremy Rifkin that it would soon be possible to engineer and produce human beings by the same principles employed in industrial processes is "science fiction" and displays an ignorance of both what is known and what is not known about human organisms). 32. For a provocative discussion of the ethical and legal issues that would be posed if researchers were to develop the capacity to produce stronger, more intelligent human beings, see Attanasio (1986). 33. For an elaboration of this position see Fletcher (1983). 34. The National Commission for the Protection of H u m a n Subjects of Biomedical and Behavioral Research was established in 1974 by Pub. L. N o . 93-348, 86 Stat. 342. The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research was established in 1978 by Pub. L. 95-622, later amended by Pub. L. 97-377 (1982). Both commissions issued a number of volumes relevant to the matters to be reported on by the Board. 35. The six members from the House of Representatives named were Mr. W a x m a n of California, Mr. Luken of Ohio, Mr. Rowland of Georgia, Mr. Gradison of Ohio, Mr. Tauke of Iowa, and Mr. Bliley of Virginia (U.S. Congress, House, 1986); from the Senate, M r . Weicker of Connecticut, Mr. Durenberger of Minnesota, Mr. Humphrey of N e w 159

AREEN A N D KING Hampshire; Mr. Kennedy of Massachusetts, Mr. Bumpers of Arkansas, and Mr. Gore of Tennessee (U.S. Congress, Senate, 1986). After his reelection defeat, Mr. Weicker was replaced by Mr. Nickles of Oklahoma.

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