The regulation of products of modern biotechnology methods in the U.S. and often elsewhere is still evolving, although the key federal agencies have remained the same for quite some time: the Food and Drug Administration (FDA), the Environmental Protection Agency (EPA), and the Animal Plant Health Inspection Service (APHIS) within the U.S. Department of Agriculture (USDA). Since the birth of commercial applications in the early 1980s, nearly three decades will have elapsed to approach finalization of the key U.S. federal oversight mechanisms unrelated to intellectual property matters.

The journey has been long and continues to be tortuous. The reasons are many; some simple, most, complex. Not the least of the problems has been defining the triggers for regulation. Those that have been based on the use of process language such as "genetic engineering," "recombinant DNA (R-DNA)," or "new" or "modern" biotechnology methods have often been fraught with ambiguity. The regulatory triggers therefore have sometimes encompassed products of older techniques that have never been regulated or regulated less stringently. This result has led to debates about the appropriateness of regulation of such older products, which typically have a safe history of use even though their genetic methods of production are less precise or more random than those of newer biotechnology methods such as R-DNA technology. Such regulation has resulted in the so-called "product versus process" debate, which even today has yet to be resolved satisfactorily. This controversy involves the principle that the risks (and benefits) of modern biotechnology methods can be more appropriately related to the products of such technologies than the methods or processes used to make them. A somewhat related notion is that regulations should be performance-based, oriented around achieving desired results, in part because such standards can accommodate technological advances easier; design standards focus on the methods for achieving such results and often are technology-oriented.

Another major contributor to the slowness of adoption of U.S. approaches is the reliance on current laws, which have been deemed adequate for oversight. Although not without significant merit, this principle of operation has led to a complex maze of statutes, federal departments, agencies, regulations, policies, guidances, and other governmental statements governing experimental and commercial uses in the health and environmental areas. The sheer diversity in the types of products and their uses has demanded that such laws and regulations occasionally be stretched in unprecedented and unusual ways. Indeed, many new regulations had to be adopted, particularly in the environmental area, to cover certain products of modern biotechnology methods. Sometimes regulatory overlap also has created additional complexity. Then, too, as the technologies themselves evolve as well as the resultant products, or as new research applications lead to commercialization, additional debates and renewed tensions have been created regarding the adequacy of the applicable laws and regulations to protect against health and environmental risks, real or imagined.

Product types, regulation, and policies have evolved significantly over the last thirty years. Technologies and products now include pharmacogenomics and other "omics;" biosimilars or follow-on biologics; microassay diagnostics for genetic defects; plant and animal pharma products; stacked plant incorporated protectant traits; genes, stem cells and other cellular and tissue therapies; drug-biologic or drug-medical device combination products; xenotransplantation of engineered tissues; cloning involving somatic cell nuclear transfer (SCNT) methods; RNA interference technology for health and environmental uses; and other therapeutic, prophylactic, diagnostic, pesticidal or industrial products.

Past and continuing domestic efforts by the individual states and international tensions among nations importing products involving "genetically modified organisms" (GMOs) from the U.S. also have been frequent sources of controversy. The role of treaties such as the Convention on Biological Diversity and others to which the U.S. is not a party, such as the Cartegena Protocol, also have helped to continue to put the U.S. at odds with other countries' approaches to the regulation of GMOs, creating strained relationships.

DEFINING "BIOTECHNOLOGY": WHY IT MATTERS

Many consumers, federal agencies, the news media, and others sometimes use the term differently. From a somewhat technical standpoint, "biotechnology" is really a collective term, encompassing a number of technologies, some old, others new. Plant and animal breeding are examples of traditional biotechnological methods. Hybrid corn; foods such as bread, cheese, and yogurt; and medicines such as vaccines and hormones, are well-known products of older biological methodologies. Modern biotechnology techniques involve the more precise ability to effect genetic and other changes and newer techniques such as R-DNA, cell fusion resulting in hybridomas, or SCNT. These methods are sometimes referred to collectively as genetic engineering or bioengineering, among other names. Commercial applications of modern biotechnology methods largely involve different manufacturing processes to prepare both new and old products. Many of the technologies are not necessarily interchangeable as a technical matter, though sometimes they are treated as if they were all the same.

The precise definitions of "biotechnology" and of other terms such as "R-DNA" are of extreme importance when used as part of statements by federal regulatory agencies. They outline the bounds of product regulation or jurisdiction. "Biotechnology" has been defined as processes using living organisms or parts of organisms to make or modify products, to improve plants or animals, or to develop microorganisms for specific uses,¹ or as "the application of biological systems in organisms to technical and industrial processes."² "R-DNA molecules," typically representative of "modern biotechnology" or "bioengineering," have been defined either as molecules developed outside living cells by joining natural or synthetic DNA segments to DNA that can replicate in a living cell or as DNA molecules that result from the replication of such DNA.³

PRODUCT REGULATORY OVERVIEW

Some of the more important federal laws and regulations, as well as the key federal agencies currently involved in biotechnology oversight, are discussed further in Part III and listed in Table I. Particular emphasis is on products involving modern biotechnology methods and premarket clearance or approval mechanisms. State laws and local ordinances also can apply, as they often can and do influence research and marketing activities, especially in the area of deliberate or planned releases of genetically altered organisms into the environment.

Discussion is confined primarily to U.S. federal regulatory authorities, as any detailed review of state statutes and the related notion of federal preemption of state-related activities would necessarily entail the preparation of a lengthy treatise. This website therefore does not attempt to cover state regulatory considerations, or other areas or issues concerning "genetic engineering," such as legal liability and ethical matters or intellectual property considerations. Worker safety issues also are not reviewed.

Because commercial applications of biotechnology methods encompass a variety of industries and a wide range of technologies and products, the applicable laws are equally as diverse. Also, while federal regulation often is thought to be confined to industrial, commercial-type applications, regulatory authority can exist over what are considered purely research activities involving non-profit motives, especially when funding is obtained at least in part by federal grants.

FDA, USDA, and EPA have considerable regulatory authority to oversee biotechnology applications via their premarket clearance powers, although they each also have extensive post-marketing authorities. If a marketed product is found to pose health or environmental hazards, various ways usually exist for the federal government to address such hazards and remove the product from the marketplace. This latter point sometimes gets lost in debates about the adequacy of U.S. or other regulation. EPA administers a comprehensive system of environmental laws and regulations. The focus here with respect to biotechnology is primarily on EPA's jurisdiction under the Toxic Substances Control Act (TSCA) and the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA). The former law enables the agency to regulate process and product hazards, thus providing regulation of all existing and new chemicals; the latter statute governs pesticides.

FDA and USDA also have extensive prior clearance or approval powers over numerous products, usually in the form of product authorizations through the issuance of licenses, permits, and other types of prior clearances over experimental or commercial activities. The Federal Food, Drug, and Cosmetic Act (FFDCA) is the statute or law primarily responsible for FDA's regulatory powers, whereas USDA administers a variety of other laws that give it broad authority over a diverse range of articles, including meat, poultry and egg products, noxious weeds and other plant pests, and non-human animal pathogens.

A key law that applies to most federal agencies as part of their permitting or approval processes is the National Environmental Policy Act (NEPA). It requires most federal agencies to take into account the environmental effects of their actions. They typically have developed their own regulations implementing NEPA in the form of categorical exclusions from NEPA requirements for certain agency actions, requirements for environment assessments (EAs) if a categorical exclusion does not apply and, finally, requirements for an environmental impact statement or EIS. Categorical exclusions generally encompass those agency actions that individually and cumulatively have no significant environmental impacts that require an EA or an EIS. An EA is otherwise prepared to enable the agency to decide whether to prepare an EIS or a finding of no significant impact (FONSI). Not surprisingly, NEPA has been a constant source of challenge to a plethora of technological developments; modern biotechnology applications have fared no differently. Many suits have been brought involving the products of modern biotechnology, as discussed in Part III.

TYPES OF PREMARKET PRODUCT CLEARANCES

The burdensome nature of any federal agency's regulatory powers and the related notion of ease of entry into the marketplace are directly tied to an agency's premarket clearance powers. Such "prior regulation" can take many forms and be differently named depending on the federal agency involved. It can occur in the form of required permits, authorizations, licenses, regulations, premanufacture notification submissions, registrations, and product clearances or approvals. The focus here therefore is on the ability and authority of a federal agency to require prior clearances or other types of research or marketing prior agency reviews, as such mechanisms often require a large amount of effort and funds, and can result in significant time delays.

With the growing recognition that the effort expended to obtain necessary regulatory clearances can be time-consuming and costly, various laws have also been enacted that grant market exclusivity, data production, and patent extension rights. These laws can allow for protection against certain types of market competition for a specific period of time and for extension of certain patents for a period of the time it takes to obtain regulatory clearances. Although obtaining any necessary premarket clearances does create a certain degree of market protection, almost a "limited monopoly," such prior regulation is not a substitute for patent protection.

Federal agency premarket oversight authority can be divided into two basic mechanisms: clearances by "regulation" or by "license." Agency "approval" usually implies licensing of a particular manufacturer's method of production of a regulated product. For example, despite the actual terminology used, class III medical devices, prescription drugs (including veterinary and human biologics), and pesticide products are all "licensed"; each manufacturer must obtain separate premarket clearances for its product, even if the "same" version already is marketed, although there may be less data requirements for such duplicates or follow-on "copies."

On the other hand, oversight by regulation applies to new chemicals under TSCA, color and direct food additives, many over-the-counter (OTC) drugs, and in certain respects to class I and class II medical devices. Once a company obtains the necessary premarket clearances, any manufacturer may market the "same" article in accordance with applicable existing clearances. Manufacturers may not be required to obtain separate, new clearances for their versions of previously marketed products.

PRODUCT REGULATORY CLASSIFICATION

Determining the appropriate regulatory class of a product is the first important step toward ascertaining the steps and costs involved in U.S. marketing. For example, whether a product is intended for uses in human beings or other animals, and is a food, drug, pesticide, biologic, diagnostic, or a plant or non-human animal pest, often determines the relevant regulatory criteria applicable to research and commercial activities. Table I and Part III provide some guidance as to which agencies are involved in the oversight of some products.

Often the regulatory class is clear (e.g., lettuce is obviously a food), but the intended use of a product can alter its status. If lettuce is advertised and labeled for use as a cure for cancer, it may become a "new drug" and therefore possibly need FDA clearances or approval prior to marketing for use in cancer treatment. While use of modern biotechnological techniques, such as R-DNA methods, generally does not and should not alter a product's regulatory class, it may affect its regulatory status. In other words, somewhat simplistically, if a product manufactured by one method is cleared for marketing by a regulatory agency, an "identical" product may not automatically be cleared when a new method of manufacture such as "modern biotechnology" is utilized. This is particularly true in the area of pharmaceuticals.

Whether new clearances must be obtained when a less conventional or different method of manufacture is employed depends on the type or class of the product, because products such as drugs, biologics, medical devices, pesticides, and other chemicals can be regulated very differently. Many of the important regulatory issues surrounding modern applications of biotechnology relate not only to how to regulate new products that have never been marketed, but also to whether the use of such new manufacturing methods as R-DNA can alter the regulatory status of previously cleared products, as well as the agency requirements for obtaining permission to market.

The legal or regulatory class to which a product is assigned often depends on four considerations: its claims, mechanism of action, and ingredients or nature.

The first criterion, which is by far usually the most important, involves the intended use of the product gleaned from advertisements and information printed on product labels or other labeling. For example, statements of prevention, cure, and mitigation of diseases of animals (including human beings) usually give rise to FDA drug regulation. Claims regarding usefulness in repelling or killing insects or other pests such as weeds likely will result in a pesticide classification and EPA regulation. Product claims involving both disease prevention and pest resistance could result in the product's dual classification as both a drug and a pesticide, and in its being regulated by two different federal agencies, FDA and EPA. Thus, products can fall within more than one regulatory class and within the purview of more than one regulatory agency.

The mechanism of action of a product also can determine its legal class. For example, the FFDCA specifies that a medical device cannot achieve any of its primary intended purposes through metabolism or chemical action within or on the body of man or other animals. Interestingly, the FFDCA does not specify how drugs or foods function, although there is some language defining drugs as articles (other than food) intended to affect the structure or function of the body of man or animals. The mechanism of action also is relevant to certain types of pesticides called "plant regulators," a term defined to include any substance intended, through physiological action, to alter the behavior of plants. Products acting through a specific immune mechanism intended for treatment of diseases probably are biologics and can be regulated as biological drugs or devices either by FDA or USDA, depending typically on whether their use is for human beings or other animals.

The nature of the ingredients used in a product or the product itself usually does not determine the product's class, except when the ingredient or product has certain types of properties or characteristics. For example, oral health products containing fluoride typically are considered drugs, because of the anticaries properties of this ingredient. Products intended for therapeutic or diagnostic applications and that contain antibodies are likely to be considered biological drugs or biological devices, because this class often includes components of the immune system, although they may not always be regulated as biologics.

BIOTECHNOLOGY PRODUCT REGULATION: EARLY EVOLUTION

The systematic regulation of biotechnology by the federal government probably can be said to have officially began on June 23, 1976, when the first Guidelines for Research Involving R-DNA Molecules were promulgated by NIH to oversee research activities.⁴ Because the Guidelines were and still are mandatory only for government-funded research, the federal regulatory and other agencies originally sought to utilize their powers to require compliance not only by academic researchers, but also by the private industrial sector. A number of local municipalities and states also responded by enacting laws controlling the kind and scope of experiments that industry could conduct.

As various modern biotechnological methods and their applications evolved, so did the Guidelines. They expanded from research to large-scale orientation; from containment to environmental releases and back to containment; and from in vitro work to human applications of gene therapy. The first human gene experiment involving a genetic marker to measure the progress of an experimental cancer treatment was intensely scrutinized by NIH and FDA. A lawsuit to block the experiment was dismissed after settlement.⁵ The current focus of the Guidelines has largely been on select human gene therapy experiments, with FDA now playing a key major role because such therapies are considered to be biological drugs (see Part III).

Some of the later, more heated debates about products of modern biotechnology can perhaps be exemplified by two early planned releases into the environment of genetically modified microorganisms. A Montana State University professor had inoculated young elm trees with genetically modified Pseudomonas syringae, a bacteria producing a chemical that prevents Dutch Elm disease. This pesticidal experiment, which was conducted without prior approval from the federal government or the local biosafety committee, raised a number of questions about the definition of R-DNA and what constitutes a "deliberate release."

Initially, it was unclear whether the bacteria contained R-DNA and, hence, whether the Guidelines applied. Although recombinant technology was involved in the construction of the plasmid that was used, the portions that were joined by R-DNA techniques were lost. The test, therefore, was found not to be subject to the Guidelines; EPA oversight was still involved, however, as its pesticide jurisdiction covers all genetically altered organisms whether formed by conventional or recombinant methods. The fact that this incident occurred at all and that EPA only restricted further work of the university professor raised questions about the complexity and adequacy of existing federal biotechnology regulations.

The Montana State incident was preceded by a similar occurrence involving a pseudorabies vaccine, a veterinary biologic prepared by using new genetic techniques and tested in swine. The vaccine stirred debate again about whether the Guidelines applied; there were also questions about whether the R-DNA existed and whether the organism was "introduced into the environment." It was concluded that the intent of the Guidelines was violated, although, interestingly, USDA took the position that animal biologics such as the pseudorabies vaccine are not "deliberate releases."

On an international level, the Guidelines also were an early harbinger of other potential definitional problems. They were eventually amended to clarify their applicability to projects abroad, as a result of a 1986 field test in Argentina of a genetically engineered rabies vaccine produced in the United States by NIH funding. The question again was a definitional one, regarding what constitutes "funding" and the applicability of the Guidelines. The definition of "R-DNA molecules" was also later changed to include certain types of transposable elements, which are mobile genetic segments that can be inserted into a variety of places in DNA.

BIRTH OF COORDINATED FEDERAL AGENCY OVERSIGHT

In April 1984, the Reagan Administration, prompted largely by industry complaints of lack of coordination and uncertainty as to the course of regulatory oversight of biotechnology, formed an interagency working group under the White House Cabinet Council on Natural Resources and the Environment. The Working Group's purpose was to study and coordinate the government's regulatory policy for biotechnology. Composed of approximately thirteen member agencies, the Working Group was an interagency effort to review regulatory requirements that have been applied to conventional technologies, to clarify the regulatory requirements for new product marketing, and to determine whether current regulatory requirements were adequate. The initial results of the Working Group's deliberations are reflected in a December 31, 1984 Federal Register notice.⁶ This document includes a regulatory matrix providing an index of current laws that are applicable to biotechnology; policy statements about the regulatory roles of USDA, FDA, and EPA; a scientific advisory mechanism in the form of a Biotechnology Science Board, composed of five agencies that would provide expert advice on scientific issues related to approval of biotechnology-derived products and research applications; and a glossary of technical terms.

A year and a half passed before follow-up statements were issued. During this period, the Occupational Safety Health Administration (OSHA) issued an announcement requesting comment on its position with respect to biotechnology, and responsibilities for biotechnology coordination within the Administration shifted to the Domestic Policy Council Working Group on Biotechnology, a part of the Office of Science and Technology Policy (OSTP). Also, in the interim, the notion of a Biotechnology Science Board was abandoned and replaced on October 31, 1985, with the establishment of a Biotechnology Science Coordinating Committee (BSCC), as part of the Federal Coordinating Council for Science, Engineering and Technology (FCCSET). FCCSET consisted of a number of agency representatives involved in the oversight of biotechnology research and products; it is a statutory interagency coordinating mechanism managed by OSTP with the charge of coordinating the federal science activities among the federal agencies.

The BSCC was to be primarily a scientific coordination body, seeking to establish a common scientific approach within the coordinated federal regulatory framework for biotechnology. As time evolved it became clear that the BSCC was actually less of a scientific body and more of a policy-oriented group trying to coordinate regulatory initiatives, particularly in the environmental release area.

After much reported disagreement among the federal agencies with respect to their respective regulatory turfs, the final OSTP notice of how each agency would regulate biotechnology applications appeared in the Federal Register on June 26, 1986.⁷ This broadly expanded document, which has become widely known as the "Coordinated Framework" because of its title, was immediately challenged in court.⁸ The court dismissed the challenge on a number of grounds, including lack of ripeness for judicial review and lack of standing.

The OSTP Notice not only included follow-up statements from FDA, EPA and USDA, but also from OSHA and NIH. NIH's statement was a recapitulation of the major provisions of the Guidelines. After consideration of comments in the April 1984 notice, OSHA published its policy statement without change. One significant and new aspect of the 1986 OSTP Notice was that definitions were proposed for such important terms as "intergeneric organisms," "pathogen," and "released into the environment," which were critical to defining the precise regulatory boundaries of the federal agencies, particularly EPA under TSCA.

Several aspects of the 1986 OSTP Notice deserve special mention. Existing laws were deemed adequate to oversee modern biotechnology applications, a position still held by the federal agencies today. Since the possibility of overlap of regulatory initiatives exists, particularly among EPA, FDA, and USDA, the notice set forth which regulatory bodies were designated as the lead agency where the possibility of duplication of oversight exists. Basically, FDA was the lead agency responsible for articles within its jurisdiction, except biotechnology applications involving plants and animals were under the primary jurisdiction of USDA. Pesticide microorganisms released in the environment as well as microorganisms involving intergeneric combinations and other contained uses were handled primarily by EPA. Other releases involving pathogens and agricultural uses were primarily the responsibility of USDA. Nonagricultural uses of products and nonpathogens, were subject to EPA jurisdiction. A similar scheme was provided for biotechnology research applications; products of such technologies as R-DNA may be regulated differently, however, depending on whether, for example, a pesticide, food, drug, or pathogen was involved.

The previous regulatory situation became even more complicated because USDA, as part of the 1986 OSTP Notice, issued its own proposed Guidelines for Biotechnology Research, which were patterned after and similar to the NIH Guidelines. The proposed development of the additional set of Guidelines caused some confusion, particularly with regard to whether NIH Guidelines or USDA Guidelines applied since the USDA proposal stated that it was applicable to all "biotechnology research." The draft USDA Guidelines included all activities not involving classical genetic manipulation of organisms, such as those not occurring in nature or involving conventional breeding (e.g., hand pollination and artificial insemination). Final USDA Guidelines were eventually published in 1991, entitled Guidelines for Research Involving Planned Introduction into the Environment of Genetically Modified Organisms, although their current applicability to agricultural work remains unclear.

The BSCC asked the National Research Council (NRC) to evaluate scientific information pertinent to making regulatory decisions about the introduction of genetically modified microorganisms and plants into the environment. This request followed a more general report published by the National Academy of Sciences entitled Introduction of R-DNA-Engineered Organisms into the Environment: Key Issues.⁹ This publication, which was later followed by others, concluded that the risks associated with the introduction of R-DNA-engineered organisms are the same as those associated with introductions of unmodified organisms and those modified by other methods:

• No evidence of unique hazards exists with the use of R-DNA techniques or in the movement of genes between unrelated organisms.
  
  
• Assessment of risks of introducing R-DNA-engineered organisms in the environment should be based on the nature of the organism and the environment into which it is introduced, not the method by which it is produced.¹⁰

The BSCC eventually became involved in a debate about the scope of organisms that should be subject to oversight prior to their environmental release. Initially, the question arose in the context of the guidelines USDA was developing for environmental releases. In an attempt to coordinate various federal agencies' approaches to the subject of environmental releases, however, the question of scope became much broader with respect to the types of organisms regulated by EPA under TSCA and FIFRA and USDA under the former Federal Plant Pest Act, which now has been superseded by the Federal Plant Protection Act. Various federal agencies often took differing positions.

After much debate and deliberation, a draft scope document was reviewed by the White House Council on Competitiveness to ascertain its impact on the ability of U.S. biotechnology industry to compete in the international marketplace. The scope document completed Competitiveness Council review in late June 1990 and was published for public comment in the Federal Register on July 31, 1990.¹¹

The latest document was newer technology based, as it often excluded from oversight plants, animals and microorganisms developed by traditional techniques such as breeding, transduction, transformation, and conjugation. Organisms excluded from oversight included:

(1) Plants and animals that result from natural reproduction or the use of traditional breeding techniques. These include, for example, for vascular plants, mutagenesis and hand pollination, and for vertebrate animals, artificial insemination, superovulation, and transfer of embryos.

(2) Microorganisms modified solely: (a) through chemical or physical mutagenesis; (b) by the movement of nucleic acids using physiological processes including, but not limited to transduction, transformation, or conjugation; or (c) by plasmid loss or spontaneous deletion.

(3) Vascular plants regenerated from tissue culture, including those produced through selection of somaclonal variants, embryo rescue, protoplast fusion, or treatments that cause changes in chromosome number.

(4) Organisms that have been modified by the introduction of noncoding, non-expressed nucleotide sequences that cause no phenotypic or physiological changes in the parental organism.

(5) Organisms resulting from deletions, rearrangements, and amplifications within a single genome, including its extrachromosomal elements.

(6) Organisms with a new phenotypic trait(s) conferring no greater risk to the target environment than the parental strain, which is considered to be safe.

The Council on Competitiveness on August 14, 1990, then issued four principles of regulatory review of biotechnology. The principles were developed in response to the President's request that the Council institute a review of regulatory issues. The four principles were:

• Federal government regulatory oversight should focus on the characteristics and risks of the product - not the process by which it is created.
  
  
• For biotechnology products that require review, regulatory review should be designed to minimize regulatory burden while assuring protection of public health and welfare.
  
  
• Regulatory programs should be designed to accommodate the rapid advances in biotechnology. Performance-based standards are, therefore, generally preferred over design standards.
  
  
• In order to create opportunities for the application of innovative new biotechnology products, all regulation in the environmental health areas (whether or not they address biotechnology) should use performance standards rather than specifying rigid controls or specific designs for compliance.

In February 1991, the Council on Competitiveness published a report on national biotechnology policy.¹² This report addressed Administration policies and initiatives to encourage science and technology development as well as risk-based regulation.

Finally, nearly two years after the initial scope document was published in 1990, a final document was published as a statement of policy on February 27, 1992.¹³ This document, which became the last official Administration statement on planned introductions of biotechnology products into the environment. It enunciated a risk-based approach to regulation, not regulation based on the process by which products are created.

Despite this lengthy effort to develop federal principles of regulation of the new technologies, especially relating to environmental releases, later extensive debates still occurred about how different products would be regulated, by whom, how, and the need for special labeling requirements identifying products that have or have not been derived through the use of modern biotechnology methods. The controversy continues about the adequacy of oversight mechanisms.

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¹  Office of Tech. Assessment, U.S. Congress, Commercial Biotechnology: An International Analysis 3 (1984).

² Office of Sci. & Tech. Policy, Proposal for a Coordinated Framework for Regulation of Biotechnology, 49 Fed. Reg. 50856, 50906 (1984).

³ NIH Guidelines for Research Involving Recombinant DNA Molecules, 59 Fed. Reg. 34496, 34497 (1994), as amended.

⁴ See Dept. of Health, Education and Welfare, National Institutes of Health, Recombinant DNA Research; Guidelines, 41 Fed. Reg. 27902 (1976).

⁵ Foundation on Economic Trends v. Bowen, 722 F. Supp. 787 (D.D.C. 1989).

⁶49 Fed. Reg. at 50856.

⁷  Office of Sci. & Tech. Policy, Coordinated Framework for Regulation of Biotechnology; Announcement of Policy; Notice for Public Comment, 51 Fed. Reg. 23303 (1986).

⁸ See Foundation on Economic Trends v. Thomas, 661 F. Supp. 713 (D.D.C. 1986).

⁹  NAT'L ACAD. SCI., INTRODUCTION OF R-DNA-ENGINEERED ORGANISMS INTO THE ENVIRONMENT: KEY ISSUES (Nat'l Acad. Press 1987).

¹⁰  Id. at pp. 6-7.

¹¹ Office of Sci. & Tech. Policy, Principles for Federal Oversight of Biotechnology; Planned Introduction Into the Environment of Organisms With Modified Hereditary Traits; Announcement of Policy; Notice for Public Comment, 55 Fed. Reg. 31118 (1990).

¹² See PRESIDENT'S COUNCIL ON COMPETITIVENESS, REPORT ON NATIONAL BIOTECHNOLOGY POLICY (1991).

¹³ See Office of Sci. & Tech. Policy, Exercise of Federal Oversight Within Scope of Statutory Authority: Planned Introductions of Biotechnology Products Into the Environment, 57 Fed. Reg. 6753 (1992).