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6 Governmental Regulation of Biotechnology THE USE OF RECOMBINANT DNA has been subject to public overview almost since the technology's inception. In 1973, as word of the exciting new ability to join DNA from different organisms began spreading through the scientific community, a group of scientists involved with the research sent a letter to Philip Handler, then president of the National Academy of Sciences, pointing out that the new capability presented possible hazards as well as great scientific promise. Out of that letter arose a chain of events that led to two of the most important events in the early history of genetic engineering: a voluntary moratorium on certain types of recombinant DNA experi- ments deemed particularly hazardous, and the International Confer- ence on Recombinant DNA Molecules, which was held at the Asilomar Conference Center in Pacific Grove, California, February 24-27, 1975. Although primarily a scientific meeting, Asilomar was marked by a debate that had a prominent public policy component. On one side were those who held that research with recombinant DNA should proceed This chapter includes material from the presentations by Alexander Rich, Albert Gore, Jr., Richard J. Mahoney, William B. Ruckelshaus, Joseph G. Perpich, Bernadine Healy, William J. Gartland, Jr., Harry M. Meyer, Jr., Brian Cun- ningham, John A. Moore, Geoffrey M. Karny, Orville G. Bentley, Irving S. Johnson, Robert P. Nicholas, Thomas O. McGarity, and Zsolt Harsanyi at the symposium. 64
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 65 Participants at the 1975 Asilomar conference. The legacy of Asilomar remains a powerful influence on biotechnology even 10 years after the conference occurred. untrammeled by guidelines or regulations. On the other were those who believed that the potential dangers demanded restrictions, or at least that self-imposed guidelines were far preferable to regulations imposed from outside the scientific community. In the end the latter group prevailed, and a statement of principles outlining a proposed set of standards for recombinant DNA research was drafted. The day after the conference a committee of scientists appointed by the National Institutes of Health, now known as the Recombinant DNA Advisory Committee (RAO, began converting the statement of principles into formal guidelines. Issued in June 1976, the Guidelines for Research Involving Recombinant DNA Molecules assigned different types of experiments to different categories of risk. Certain experi- ments were prohibited outright. Others had to be conducted using
66 BIOTECHNOLOGY various levels of physical and biological containment, involving special laboratory equipment and procedures or attenuated hosts (most com- monly the K-12 strain of the bacterium Escherichia coli). Ten years after Asilomar, impressions of the meeting and its after- math still differ. "For many people in the nonscientific community, it is viewed as an act of scientific statesmanship at a high level," says Alexander Rich of the Massachusetts Institute of Technology. "The other side of the coin, for many members of the scientific commu- nity, is that it was a mistake, that the scientists overreacted, that had they thought more carefully and looked at the available evi- dence they would have understood that the hypothetical risks were in fact imaginary." As experience with recombinant DNA accumulated, it became clear that many of the risks associated with the research either did not exist or were initially overestimated. "We have had between 100,000 and a million experiments worldwide in recombinant DNA activities with- out, as one scientist has said, a sniffle," Rich points out. "The scare scenarios were in fact erroneous." This reevaluation of risk has led to successive revisions of the NIH guidelines. In 1978, just one year after the National Academy of Sciences Forum on Research with Recombi- nant DNA, where the hypothetical risks were a great concern, the ban on the forbidden experiments was lifted, although several still require the approval of the RAG and the director of NIH. Today nearly 90 percent of the experiments involving recombinant DNA are exempt from the guidelines. Nevertheless, new regulatory concerns have emerged. As biotechnol- ogy begins to generate products for the marketplace, federal regulatory agencies have channeled those products into existing regulatory pro- cesses. The Food and Drug Administration traditionally approves new drugs and biologics before they can be marketed. The Environmental Protection Agency regulates certain microorganisms to be used in the environment. The U.S. Department of Agriculture oversees the impor- tation and interstate commerce of agriculturally important plants, animals, and microbes. At the same time, research has progressed so quickly that previously prohibited experiments for which concern about safety or ethics still exists, such as the release of genetically engineered organisms into the environment or human gene therapy, are ready to begin. This rapid evolution of biotechnology has left the government with several distinct goals. It has the responsibility to protect human health and the environment from any risks posed by biotechnology, even though the extent of possible risks is conjectural. Simultaneously, it
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 67 Demonstrators at the 1977 National Academy of Sciences Forum on Research with Recombinant DNA. The early fears about the safety of recombinant DNA research have largely quieted as experience with the new techniques has accumulated. has an interest in seeing the biotechnology industry prosper, not only because of the specific products that will emerge from the industry but because of the broad economic benefits to be expected of a vibrant and expanding industrial sector. "A central purpose of any governmental effort in this area must be to encourage and facilitate the growth of biotechnology research, development, and implementation," says Sen- ator Albert Gore, Jr. "We are already beginning to face serious competition from other nations for leadership in biotechnology. I, for one, am determined that we remain in the forefront. The government should help guide biotechnology, but it must not control it." Industry leaders share these convictions, pointing out that the United States' current lead in converting the results of basic biomed- ical research into commercial products is fragile. (Chapter 10 discusses international competition in biotechnology in more detail.) They assert that if the government imposes burdensome regulations on biotechnol- ogy, new products will take longer to reach the marketplace. Biotechnology firms in countries with less encumbering regulations could then catch up with and surpass their American counterparts, securing patents and market presences that would thereafter be denied
68 BIOTECHNOLOGY to American firms. "It would be a tragedy of enormous proportions if the promise of biotechnology were unfulfilled," contends Richard J. Mahoney of Monsanto. "I, for one, don't relish the prospect of American farmers buying their genetically engineered wheat and corn seeds from Japan or Europe or elsewhere, or turning elsewhere for their latest miracle drugs. . . . But mark my words, there is a possibility that if regulatory delays prevent the timely development of these products in the United States, we will lose our lead. America has pioneered a truly great technology, and we deserve some of the economic benefits that will flow from it." At the same time, industry acknowledges the many benefits to be gained from a stable and sound regulatory regime. For one thing, strong governmental oversight can help build the public trust that is essential for industries perceived as potentially hazardous to progress. According to William B. Ruckelshaus, former head of the Environmen- tal Protection Agency, "If there is one thing that we learned from the recent upheavals at the EPA, it is that when the agency charged by society with protecting the public health and the environment comes apart, to the point that society no longer really trusts that institution, then those dependent on those decisions for the marketing of their products are in more trouble than anyone else." The biotechnology industry is in a position somewhat similar to that of the scientists who gathered at Asilomar. It realizes that regulations emerging from a cooperative effort between industry and government will be preferable to regulations in which the industry has no say. "Industry has a vested interest in sensible, science-based regulation," says Mahoney. "It seems to me that business has two choices: become a partner in developing the guidelines that will ensure adequate protection, or be an adversary. In the latter case, regulations will emerge just as surely, but they will make our jobs a lot more difficult." The government therefore faces the difficult task of coordinating its charge to protect human health and the environment with its desire to see the biotechnology industry thrive. It is a delicate balance, and errors in either direction could upset the competitive advantage that American biotechnology firms now enjoy. "If the government doesn't do its job, it is unlikely that the United States will stay ahead either in the research or the commercialization of this new technology," says Ruckelshaus. "There are two ways in which that could happen. One is that the government would do too much; there would be very heavy- handed regulation, needless time-delaying, red tape, nitpicking, an unwillingness on the part of the government ever to make a decision. If there is too much regulation, we could stifle this emerging technol-
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 69 ogy. On the other side, that could also happen if there is too little regulation, or if it is unwise or sloppy or not open. [That] could just as certainly doom our efforts to take advantage of our current lead." "This may be the last chance to do it right the first time," Ruckelshaus continues. "There is the potential for a cooperative effort on the part of the government, industry, academia, and public interest groups to move all of this forward in a way that is consistent with the protection of the environment and the commercialization of these products." The Strengths and Weaknesses of the NIH Guidelines One of the most remarkable features of the NIH guidelines is the pervasive influence they have had even though they are merely guidelines. Technically, they apply only to institutions that receive federal funds, and the penalty for violating the guidelines cannot extend beyond withdrawal of those funds. However, other governmen- tal agencies in addition to NIH have also required that the guidelines be followed, and several states and localities have established the guidelines by law. In addition, private companies that work with recombinant DNA have adopted the guidelines and have submitted research proposals to the RAC. Even many foreign countries conduct- ing recombinant DNA research have adopted slightly modified ver- sions of the guidelines. The RAC's distinguished members, its sophisticated deliberations, and the widespread influence of its guidelines have made it a respected central clearinghouse for discussion of the scientific and social issues surrounding biotechnology. The quasi-regulatory nature of the guide- lines has also given them flexibility, allowing them to be revised in light of constantly accumulating scientific information. When gaps in expertise have been identified in the RAC, it has accepted additional members or enlisted outside consultants. Representatives of industry and government alike have praised its past performance and have urged that it continue in its role. "It is a testament to the NIH and to the scientific community for maintaining and nurturing this system over the past 10 years, and to a lot of very gifted people working on the RAC to develop and revise the guidelines," says Joseph G. Perpich of Meloy Laboratories, Inc. "We are here today talking about promise and products because of them." At the same time, several limitations of the NIH guidelines and the RAC as they are presently organized have become apparent. First, the NIH guidelines do not have the force of law, and compliance with them
70 BIOTECHNOLOGY by private companies is voluntary. Recently several companies have bypassed the RAC entirely and have submitted research proposals involving recombinant DNA to federal agencies with specific jurisdic- tion over anticipated products. Second, the NIH guidelines, because of their history and evolution, inevitably focus more on research than on commercial development. This has led to questions from both inside and outside the RAC about the propriety of its continuing to oversee commercial developments in biotechnology. "If there is an inadequacy in the current federal struc- ture, it is in the availability of a scientific review mechanism that can deal with the broad range of commercial products now emerging and on the horizon," says Bernadine Healy, formerly of the White House Office of Science and Technology Policy. "The NIH RAC is neither equipped nor desirous of taking on that role on a government-wide basis. The NIH is oriented toward basic biomedical research and not toward commercial scale-up or engineering. It has limited environmental and ecological expertise, and it does not want to take on that expanded chore." The RAC's apparent jurisdiction over some commercial biotechnol- ogy products has also brought it into potential conflict with other federal agencies. Both the RAC and the Food and Drug Administration claim authority over clinical trials of human gene therapy. The Environmental Protection Agency and the U.S. Department of Agri- culture both assert that they should oversee the use in the environment of certain genetically engineered microorganisms. "For commercial productsâfoods, drugs, and chemicalsâthere is a clearly established statutory responsibility in several other agencies outside of the NIH," says Healy. Furthermore, the RAC only oversees research involving recombi- nant DNA. Genetic techniques such as cell fusion or mutagenesis are not part of its charter. Finally, the RAC meets only four times a year, raising concerns that it might be unable to handle the full range of proposals that may need attention in the future. The problems with the RAC's quasi-regulatory status became appar- ent during the initial wrangling over one of today's most pressing regulatory issuesâthe release of certain genetically engineered micro- organisms into the environment. (For a discussion of the scientific issues surrounding environmental release, see Chapter 5.) The NIH guidelines require that any experiment involving the environmental release of genetically engineered organisms first be approved by both the RAC and the director of NIH. Between 1981 and 1983 the RAC and
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 71 the NIH director approved three such experiments. The first was a field test of corn modified by recombinant DNA techniques to contain other corn gene sequences, but the experiment was never conducted because the corn turned out not to be ready to test. The second was a field test of modified tobacco and tomato plants, but this experiment was also scuttled because of technical problems. The third was a field test of bacteria that had been genetically modified to reduce frost dam- age in plants. (The principle behind this experiment is described in Chapter 3.) In September 1983 a lawsuit was filed against NIH by the Founda- tion on Economic Trends, a public interest group, alleging that in approving these tests it had not complied with the National Environ- mental Protection Act, which requires that federal agencies prepare environmental impact statements for "major Federal actions signifi- cantly affecting the quality of the human environment." In response, U.S. District Court Judge John Sirica issued a preliminary injunction prohibiting the field test of the bacteria and prohibiting NIH from approving any further environmental releases of genetically engi- neered organisms. NIH appealed the order, and on February 24, 1985, the U.S. Court of Appeals for the District of Columbia ruled that NIH did not have to file an environmental impact statement but that it did have to prepare a less extensive environmental assessment. In the meantime, the Environmental Protection Agency stated that it, too, had authority over the environmental release of the genetically engi- neered microorganism in question. The lawsuit appeared to contribute to a renewed concern in Congress over genetic engineering: several legislators questioned whether new laws were needed to regulate forthcoming applications of biotechnology. To those people who have followed genetic engineering since its origins, the recent furor over environmental release has a familiar ring. "The discussions about the possible hazards of releasing engi- neered organisms are reminiscent of the situation that existed before the Asilomar conference, when many different hazard scenarios were being raised," says William J. Gartland, Jr., of NIH's Office of Recom- binant DNA Activities. "I think the issues here, though, are going to be much more complex than the issues that the Asilomar conference had to deal with. Asilomar was largely concerned with biomedical research, and it was largely concerned with practically one organism, namely E. coli K-12. I think, at the outset of this new phase of research with deliberate release, that there will probably be dozens of organisms that will be proposed to be released in dozens of different settings. It will be a much more complex issue to deal with."
72 BIOTECHNOLOGY The Roles of Other Federal Agencies in Regulation The positions taken by federal agencies other than NIH will be crucial in determining the future course of the RAG and the overall regulation of biotechnology. These positions are still in the process of being established, and they are bound to change as the technology and the regulatory climate evolve. But a broad statutory and regulatory framework for biotechnology already exists, and it is this framework that will largely determine the future regulation of the industry. The Food and Drug Administration The Food and Drug Administration (FDA) will regulate applications of genetic engineering primarily under the Food, Drug and Cosmetic Act and the Public Health Service Act. These statutes give FDA authority over human and animal drugs, human biologics, food and color additives, and medical devices (including in vitro diagnostic tests that employ monoclonal antibodies), among other substances. Before a manufacturer begins to market a new drug or biologic, it must prove to the FDA through a variety of means, including clinical tests on humans, that the substance is "safe and effective." In turn, a "new" drug is defined as one that is not yet recognized by qualified scientific experts as safe and effective for its proposed use. The FDA has traditionally allowed manufacturers to use certain abbreviated approval processes for products identical to already ap- proved or existing substances that were manufactured by identical techniques. But it has decided that at least for the time being it will treat all drugs and biologics derived from methods involving recombi- nant DNA as new, requiring them to undergo the entire approval process. The reason for this caution is concern over the possibility of undetected or novel contaminants in the productâfor instance, the endotoxins produced by E. coli as part of its metabolic processesâor the possibility of genetic instability in a recombinant organism. The approval process for new drugs begins with the submission by a manufacturer of an investigational new drug notice (IND). The IND contains information about the structural composition of the drug, the manufacturing process, the results of animal testing, the plans for clinical trials in humans, the consent forms to be used with human subjects, the background of the investigators, and other data required to demonstrate that the drug will be safe for human testing. Unless the FDA disapproves the IND, the clinical investigations can begin. These are also closely monitored by the FDA.
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 73 The second major step in the approval process is the submission of a new drug application (NDA). The NDA contains a full report of the results of the clinical trials in humans, a statement of the drug's quantitative composition, and a description of the methods and controls used to manufacture, process, and package the drug. If changes are made to an IND or NDA before or after its approval, amendments must be submitted and approved by the FDA, some of which may require additional clinical testing. The approval process is somewhat different for human biologics, which the law defines as any "virus, therapeutic serum, toxin, anti- toxin, vaccine, blood, blood component or derivative, allergenic product or analogous product . . . applicable to the prevention, treatment, or cure of diseases or injuries." The IND phase of the application is similar, but the successful completion of clinical testing results in a license rather than in the approval of an NDA. The biologic must meet certain standards of safety, purity, potency, and efficacy; its manufac- turing facilities must undergo prelicense inspections (and are them- selves licensed); and the licensed products are subject to lot-by-lot testing by the FDA. The procedures for the approval of a new drug or food additive for animals are similar to those for drugs or food additives for humans. In addition, drugs for use in animals must not leave unsafe residues in the edible tissues of food products. New medical devices must also be approved by the FDA before they can be marketed. However, the law does contain provisions for the rapid approval of medical devices that are "substantially equivalent" to preexisting devices. This clause has been used to gain rapid approval of many in vitro diagnostic tests using monoclonal antibodies that replace other antibody tests. As might be expected, securing the approval of a new drug or biologic is usually a long and expensive process. The approval of an NDA by the FDA typically takes anywhere from six to eight years and costs tens of millions of dollars. However, in certain cases things can proceed much more quickly. It took only four years for the FDA to approve Eli Lilly's human insulin from the time it was first produced by genetically engineered E. coli. According to Harry M. Meyer, Jr., of the FDA's Center for Drugs and Biologics, current legislation should be sufficient for FDA to regulate the products expected to emerge from biotechnology. "We feel that we can regulate the products of biotechnology on an individual basis under our existing authorities," he says. "For example, as part of the review of any new drug or biologic, the manufacturing process is carefully
74 BIOTECHNOLOGY studied. We do a case-by-case review, and with that, nuances that influence safety and problems that could reduce the effectiveness can be identified and dealt with." Nevertheless, according to Meyer, the FDA has been making changes in its staff and internal structure to interact more effectively with the biotechnology industry and academic researchers. In antici- pation of future developments, the agency has established new re- search programs in areas related to biotechnology and has been bringing in additional scientific talent. It has also developed a series of "points to consider" documents for scientists working on specific prod- ucts that will be submitted to the agency. Says Meyer, "Our regulation over the past several years of recombinant-produced human insulin, growth hormone, interferon, lymphokines, vaccines, and numerous products produced by hybridomas has been characterized, at least in my opinion, by what I see as our posture for the futureâproblem solving through joint efforts with industry and the use of scientific consensus to guide the direction of investigational efforts." In addition to regulating human drugs and biologics for domestic use, the FDA oversees the export of these substances to foreign countries. In particular, the FDA interprets the Food, Drug and Cosmetic Act as forbidding the export for commercial purposes of new drugs or biologics that have not been approved in the United States. The FDA does allow the export under certain conditions of small amounts of new drugs or biologics for clinical testing. But once approved in a foreign country, a new drug cannot be exported for sale until approved in the United States. This provision of the Food, Drug and Cosmetic Act, which has been retained in part to prevent companies from "dumping" ineffective drugs in foreign countries, has had an unfortunate effect on the U.S. biotechnology industry. A company wishing to sell an unapproved drug that has been approved in another country faces two unappealing alternatives. First, it can build production facilities in countries where the drug is already approved or where the law does not prohibit its export. This option is generally not available, however, for smaller biotechnology companies with limited resources. Second, a company can enter into joint agreements with foreign firms, supplying the production technology to the foreign partner in return for a share of the proceeds. The greatest damage caused by this second option may occur in the long run. "The prohibition compels the transfer of biotechnology to foreign countries," says Brian Cunningham of the biotechnology firm Genentech, "because the foreign partners must be given the ability to develop the bulk products themselves from the microorga-
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 75 nisms that were genetically engineered in this country. This transfer of technology is not mitigated once the United States finally approves the new drug or biological product, because by the time U.S. approval is obtained, foreign production is already well under way. The foreign country continues to be the location from which world markets are supplied." The FDA has joined with American manufacturers in backing legislation that would allow the export of unapproved new drugs or biologics, under strict conditions designed to prevent drug dumping, to countries where the substances have been approved, but past initia- tives have been unsuccessful. "We believe that the governments of other nations are the proper authorities to assess their health needs, the diseases and health-related characteristics of their populations, the nature of their health care systems, and the availability of treatment alternatives," says Meyer. "In other words, we think they are the ones in the best position to make a benefit-to-cost decision about a drug or a biologic to be used in their country. However, for us to implement this philosophy would require a change in the law." The Environmental Protection Agency The Environmental Protection Agency (EPA) will regulate applica- tions of genetic engineering primarily under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA); the Toxic Substances Control Act (TSCA); and a handful of antipollution statutes directed at specific parts of the environment. Under current interpretations, these laws give the EPA authority over a wide range of chemical and biological products of biotechnology. Like the Food, Drug and Cosmetic Act, FIFRA requires a manufac- turer to demonstrate that the use of an insecticide, fungicide, or rodenticideâmore generally, a pesticideâwill not cause "unreason- able adverse effects" on human health or the environment. When satisfied that this criterion has been met, the EPA registers the product for use. In the past the EPA has taken the position that any microor- ganism used as a pesticide falls under FIFRA and has required premarketing registration for any such product. It will continue to apply this standard for microbial pesticides produced through genetic engineering, which it has denned very broadly to include not only recombinant DNA but cell fusion and a variety of other genetic techniques. Under FIFRA, the EPA can also require that a manufacturer obtain an experimental use permit (EUP) before field testing a pesticide. In
76 BIOTECHWLOGY the past the EPA has generally not required an EUP for field testing on a small scale, which it has traditionally denned as less than 10 acres of land or 1 acre of water. However, because of the possibility of geneti- cally engineered or nonindigenous microbial pesticides escaping from the bounds of a field test and multiplying, the EPA has decided that as an interim policy it will require companies to provide it with certain information at least 90 days before any field testing is begun. Such notification is not required for experiments in contained laboratories, growth chambers, greenhouses, or other facilities where there is no release of the microorganism into the environment. The EPA has already begun to receive requests from companies for comments on limited field tests of genetically engineered microbial pesticides. Says John A. Moore of the EPA's Pesticides and Toxic Substances Division, "The theoretical is now. It is not off in the future." Like the FDA, the EPA plans to take a case-by-case approach to submissions by manufacturers, using the scientific capability within and outside the agency and referring significant issues and problems to a science advisory panel mandated by FIFRA. Moore, like others, is "less than sanguine" about the uncertainties still surrounding the risk of releasing genetically engineered microor- ganisms into the environment. The only way to reduce these uncer- tainties, he says, is through research into the organisms and situations that are being considered. "What we have to do is to bring those people who are most knowledgeable on the subject to focus on the particular issues, and indeed give us the best guidance and judgment that they can, based on what we do know, then make what hopefully is the most appropriate judgment." Although FIFRA is a strong law, its applicability is somewhat limited because it applies to genetically engineered microorganisms only if they are to be used as pesticides. Genetically engineered microorganisms used in the environment for other purposes, such as treating oil spills or toxic waste dumps, would not fall under FIFRA. To ensure adequate overview of these applications, the EPA plans to apply the Toxic Substances Control Act. The Toxic Substances Control Act (TSCA) is essentially a gap-filling statute under which the EPA can regulate the production, distribution, use, and disposal of chemicals that it believes pose an "unreasonable risk" to human health or the environment. Unlike FIFRA or the Food, Drug and Cosmetic Act, TSCA does not require that a chemical be approved before it is marketed. Rather, it requires that a manufacturer submit a premanufacturing notice (PMN) before it begins to make a "new chemical substance," which is defined as a substance not on an
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 77 inventory of existing substances. The EPA has 90 days to review the PMN and inform the manufacturer whether it will require additional data or testing on the effects of the substance on human health or the environment. If the EPA does nothing, the manufacturer is free to begin production. The EPA has proposed to apply TSCA to genetically engineered microorganisms by denning "chemical substances" to include both DNA and the microorganisms that contain that DNA. (It plans to leave jurisdiction over plants and animals to the USDA and the Department of the Interior.) If this definition stands, it would give the EPA authority over a large segment of the biotechnology industry's products (although chemicals regulated by the FDA are exempted from TSCA). The agency could require a PMN not only for new genetically engi- neered microorganisms to be used in the environment but also for those to be used in fermentation processes. However, the EPA has not yet taken a final position on its definition of "new." One possibility it has proposed is to define chemical substances produced by recombinant organisms as new to prevent those substances from slipping through cracks in the regulatory framework. The Toxic Substances Control Act exempts "small quantities" of new chemicals from overview if used solely for research and development. But because of the possibility that genetically engineered microorga- nisms might transgress the bounds of a field test and multiply, the EPA is considering defining any quantity of such organisms used in field tests as not small. Certain kinds of research involving genetically engineered microorganisms would therefore always require a PMN. As with other aspects of its proposed regulation of biotechnology, the EPA has sought public comment on this issue. The categorization of DNA and genetically engineered microorga- nisms as "new chemical substances," although generally supported in Congress and in the biotechnology industry, is controversial and may be challenged in court. TSCA is also not as strong a statute as FIFRA or the Food, Drug and Cosmetic Act because the burden of proof is on the EPA rather than the manufacturer to prove "unreasonable risk." Largely for these reasons, Congress has held hearings to determine whether additional legislation in this area is necessary to ensure adequate regulation of biotechnology. But TSCA also has "a large number of strengths that should not be overlooked," says Geoffrey M. Karny, a Washington, D.C., attorney and former senior analyst at the Office of Technology Assessment. "First of all, it is designed as an information-gathering statute. It is a middle- of-the-road approach between no regulation or voluntary regulation
78 BIOTECHNOLOGY and some kind of stringent premarket approval mechanism. It is designed to be flexible, to deal with substances on a case-by-case basis, and to accommodate change in safety data. Finally, it involves a balancing, because the operative language is 'unreasonable risk.' " Like the FDA, the EPA has been building up its staff in anticipation of the flood of products expected from biotechnology. Some still ques- tion, however, whether the agency will have the manpower to effec- tively regulate the wide variety of substances over which it has claimed jurisdiction. The question has also been raised of whether government agencies will have access to the information and technologies needed to evaluate the claims of manufacturers working in biotechnology. The U.S. Department of Agriculture The U.S. Department of Agriculture (USDA), under a variety of statutes, regulates the importation and interstate shipment of broad categories of plants, animals, and agricultural microorganisms. It has stated that it plans to treat products produced through biotechnology in the same way that it treats products produced through conventional means. It does not expect to encounter any problems unique to applications of biotechnology, although it does plan to continually reevaluate its position as the state of the art evolves. The department also has authority over animal biologics, which in the past has created some overlap and conflict with the FDA. The two agencies have developed a "memorandum of understanding" in an attempt to resolve jurisdictional disputes. The USDA also claims authority over microorganisms that are plant pests or pathogens, bringing it into potential conflict with the EPA. The USDA has the most experience of any federal agency regarding the introduction and monitoring of novel plants, animals, and micro- organisms in the environment. According to Orville G. Bentley, the USDA's Assistant Secretary for Science and Education, it also has an extensive research network that it can call on in evaluating agricul- tural products developed through biotechnology. "This institutional expertise and capability," says Bentley, "will serve as a powerful source in the regulatory process and in averting any particular prob- lems that might come as a result of the application of biotechnology." Other Agencies and Legislation A number of other federal agencies also have either a direct or indirect influence over the development or use of biotechnology. The
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 79 National Institute of Occupational Safety and Health, the Centers for Disease Control, and the Occupational Safety and Health Administra- tion oversee the health and safety of people who work with recombi- nant molecules or organisms in commercial settings. The Department of Defense has been sponsoring genetic engineering research, all of it unclassified, on various medical and materials problems of interest to the military. The Agency for International Development sponsors research on how genetic engineering might be applied to solve prob- lems that occur in less developed nations. The Department of Com- merce maintains export controls over biological research materials in an attempt to keep certain items from reaching the Eastern bloc. Other federal agencies with various degrees of sway over genetic engineering and biotechnology include the National Science Foundation, the Patent Office, the Department of Energy, the Department of the Interior, the National Bureau of Standards, and the Department of State. An important piece of federal legislation that has already left its mark on the development of biotechnology is the National Environ- mental Protection Act (NEPA), which requires federal agencies to prepare environmental impact statements for major actions that sig- nificantly affect the environment. In the past this act has led to a substantial amount of litigation, some of it designed only to harass or delay a proposed project. According to Karny, it is the responsibility of the courts to see that NEPA is used for its intended purposes rather than for purely obstructionist reasons. "I think judges have an obliga- tion to throw out frivolous lawsuits in no uncertain terms," comments Karny. "Hopefully, they will be encouraged to do so if they have confidence in the existing regulatory system, especially if they see that it operates to accomplish the goals of the National Environmental Protection Act without all of the formalities." Finally, there is a large body of state tort law, which allows for private lawsuits for damages caused by a civil wrong. Because of the potentially large damage amounts involved, private lawsuits can provide a strong incentive for safety-conscious conduct by companies. The Cabinet Council Working Group on Biotechnology In response to perceived gaps, conflicts, and inefficiencies in the regulation of biotechnology, the Cabinet Council on Natural Resources and the Environment formed the Cabinet Council Working Group on Biotechnology in April 1984 under the leadership of the White House Office of Science and Technology Policy. The working group's mandate was to review current regulations and policies afiecting biotechnology,
80 BIOTECHNOLOGY determine if additional regulation was necessary, and develop recom- mendations for administrative and legislative actions to resolve iden- tified problems. In its own words, the working group sought to point the way toward "a coordinated and sensible regulatory review process that will minimize the uncertainties and inefficiencies that can stifle inno- vation and impair the effectiveness of U.S. industry." In December 1984 the working group published a detailed descrip- tion of the federal laws and proposals affecting biotechnology and its proposed framework for the future regulation of biotechnology. The proposal called for a two-tiered science review system based on the expertise and flexibility demonstrated by the RAC. Scientific advisory committees modeled on the RAC would be established in each of the five agencies that have significant jurisdiction over biotechnology: the Food and Drug Administration, the Environmental Protection Agency, the U.S. Department of Agriculture, the National Science Foundation, and the National Institutes of Health. In several cases, committees already in existence at these agencies would continue to serve slightly modified roles. These committees, composed of recognized experts in disciplines related to biotechnology, would do the detailed case-by-case review of individual submissions, observing the needs of their agencies with regard to time constraints and confidentiality. The NIH and NSF would concentrate on scientific research, while the FDA, EPA, and USDA would focus on the commercial products emerging from biotechnology. In addition, each of these committees would provide information to an interagency coordinating committee on biotechnologyâsometimes dubbed the super-RAC. This committee would consist of members from the agencies' committees along with other scientists and nonscientists as appropriate. The coordinating committee would review the sum- mary reports of the individual committees and would have the option of recommending that a specific application be reviewed by another agency. It could also conduct analyses of broad scientific or social issues with an eye toward developing generic guidelines applicable across the entire field. The committee would be subject to periodic review to determine if it should continue to exist. The working group envisioned that the coordinating committee would provide direction to the scientific research underlying the regulation of biotechnology. "A central core of scientific expertise for all the agencies, we believe, would promote consistent assessments of risk," says Healy, the working group's chairman. "That is a key to final analysis and streamlined regulatory decision making." At the same time, the committee, like the RAC, would remain purely advisory in
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 81 nature. "It provides the necessary input to the regulatory process, but it does not make the regulatory decisions. [That] is the responsibility, under law, of the agencies." While many people have lauded the recommendations of the working group, others have found fault. Specifically, the establishment of an interagency coordinating committee to oversee committees within the agencies has been viewed as posing the risk of "redundant review and the interpolation of additional layers of bureaucracy," according to Irving S. Johnson of Eli Lilly and Company. "We feel that instituting this two-tiered approach may have a serious impact on and inhibit the development of biotechnology and its products, and perhaps compro- mise our competitive position in the international arena." Johnson and others also question the need for a proliferation of scientific advisory committees in the regulatory system. In their view, the RAG is well equipped to continue to provide the exemplary guidance it has provided in the past. If anything, argues Johnson, the functions of the RAC should be expanded, making it in essence the super-RAC proposed by the working group. "I would strongly urge that the RAC or its equivalent be allowed to continue as a single oversight group, and that the remainder of the system be adjusted to accommo- date it," he says. According to Johnson, the RAC has a number of resources that it could call on if it were to assume such a role. Several institutes within NIH could provide technical assistance in areas related to the commer- cialization of biotechnology. As in the past, the RAC could also enlist outside consultants and form working groups to deal with topics of special interest. Finally, the workload of the RAC will not necessarily increase, because many of the major concerns associated with bio- technology have already been resolved. "Most of the serious generic issues have been or are in the process of being addressed by the RAC," says Johnson. "After deliberate release of microorganisms and the concept of gene therapy, I am not sure what the next major issue is going to be." The Role of Congress and the Public in Biotechnology The Cabinet Council Working Group on Biotechnology concluded that no new legislation was needed to give federal agencies adequate regulatory authority over the anticipated products of biotechnology. Many legislators and industry leaders have reached similar conclu- sions. "I continue to believe that no new legislation is needed at this time," says Senator Albert Gore, Jr. "The various agencies all seem to
82 BIOTECHNOLOGY feel that they have adequate statutory authority to do the job. As long as the current evaluation continues on a serious course, I think the necessary oversight can occur with minimal legislative adjustments." Despite the prevalence of this opinion, interest in biotechnology has recently swelled in Congress, and it can be expected to remain strong, according to Robert P. Nicholas, former staff director of the Subcom- mittee on Investigations and Oversight under the House Committee on Science and Technology. Legislation may be forthcoming in such areas as the export of unapproved drugs and biologics, human gene therapy, patent laws, and environmental risk assessment. In addition, the hearings held over the past few years on a wide range of subjects related to biotechnology, from environmental release to university- industry relations, testify to the widespread feeling in Congress that developments in biotechnology should be closely monitored. In part, this continuing governmental oversight of biotechnology reflects an aspect of the field that has been apparent since Asilomar. Because of biotechnology's close association with life's most fundamen- tal processes, public concern over developments in biotechnology must always be taken into account, whether by the scientific community, by industry, or by the government. "Many, if not most, of the questions that regulatory agencies are going to have to deal with when they assess the risks and benefits of these new technologies have strong public policy components," says Thomas O. McGarity of the University of Texas School of Law at Austin. "In the end, whether or not these new biotechnologies really get off the ground in this country is going to depend upon whether we can erect a regulatory regime that can secure public trust." "Biotechnology is at a turning point," explains Nicholas. "The same questions that were being asked previously are again being asked, and they have become more important, since the end result of most of the [ongoing] industrial activity will be some release of a product. Unless these questions are sensitively addressed from here on out, there is a real risk that the consensus that has underpinned the development and financial support of biotechnology will recede." According to William Ruckelshaus, a critical element in building the public trust necessary for biotechnology to prosper is public education. He maintains that the public must be informed "fairly, honestly, and straightforwardly" about both the potential benefits and the potential risks of biotechnology. The risks of a new technology inevitably become known at some point, and if the public has not been adequately informed about these risks, they may turn to any of a number of tactics available to slow down or halt the progress of a new field.
GOVERNMENTAL REGULATION OF BIOTECHNOLOGY 83 As a first step, public education could focus on the wide range of applications of biotechnology, differentiating the issues that are in- volved in each. "We must really talk about not biotechnology in the singular but biotechnologies," says Zsolt Harsanyi of E. F. Hutton and Company. "We have a variety of technologies that are quite disparate. In one case, you are talking about the insertion of a gene into a human being; in another case, you are talking about using immobilized enzymes to produce high-fructose corn syrup; in other cases, you are talking about microbes that might be released into the environment. . . . You have to get down to some very specific points and say what it is about any particular use that is going to be unique." The best way to go about educating the public, according to Ruckelshaus, would be through an "elaborate, comprehensive, and sophisticated communication plan." Such a plan should recognize that different audiences require different messages. It could focus first on those who will most directly affect biotechnologyâCongress, the reg- ulatory agencies, industry, the press, environmentalists, academics. It could also take advantage of specific eventsâan important technical development, a particular experiment, regulatory approval of a prod- uctâto further public understanding of the field. Taken together, such efforts could begin to close the gap that has traditionally existed in the United States between scientific developments and public understand- ing. Concludes Ruckelshaus, "We need to do a much better job, not just in this area but across the board, as we try to grapple with the complexity involved in public participation in decisions of enormous scientific uncertainty." Additional Readings Thomas O. McGarity. 1985. "Regulating Biotechnology." Issues in Science and Technology 1(Spring):40-56. Office of Science and Technology Policy. 1984. "Proposal for a Coordinated Framework for Regulation of Biotechnology." Federal Register 49 (December 31):50856-50907. Sandra Panem and Hans Weill, eds. In press. Biotechnology: Implications for Public Policy. Washington, D.C.: Brookings Institution. Joseph Perpich, ed. In press. Biotechnology in Society: Private Initiatives and Public Oversight. New York: Pergamon Press.