OFFICE OF SCIENCE AND TECHNOLOGY POLICY

AGENCY: Executive Office of the President, Office of Science and Technology Policy.

51 FR 23302

June 26, 1986

Coordinated Framework for Regulation of Biotechnology

ACTION: Announcement of policy; notice for public comment.

SUMMARY: This Federal Register notice announces the policy of the federal agencies involved with the review of biotechnology research and products. As certain concepts are new to this policy, and will be the subject of rulemaking, the public is invited to comment on these aspects which are specifically identified herein.

DATE: Comments must be received on or before August 25, 1986.

Public Participation: The Domestic Policy Council Working Group on Biotechnology through the Office of Science and Technology Policy, is seeking advice on certain refinements published herein to the previously published proposed coordinated framework for regulation of biotechnology. These new aspects include the Biotechnology Science Coordinating Committee's (BSCC's) definitions for an "integeneric organism (new organism)" and for "pathogen." These definitions are critical to the coordinated framework for the regulation of biotechnology because they establish the types of the organisms subject to certain kinds of review.

It is the intention of the Domestic Policy Council Working Group on Biotechnology, the Biotechnology Science Coordinating Committee (BSCC), the Department of Agriculture (USDA), the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), the National Institutes of Health (NIH), the National Science Foundation (NSF), and the Occupational Safety and Health Administration (OSHA) that the policies contained herein be effective immediately. In consideration of comments, modifications, if any, may be published either in a separate notice or as part of proposed rulemaking by the involved agencies.

Information submitted to an agency that is trade secret information or confidential business information should be clearly marked so that it can be accorded the protection provided to such by each respective agency.

ADDRESS: Comments specific to the BSCC definitions or overall comments to the Coordinated Framework for the Regulation of Biotechnology statements should be addressed to: BSCC: Docket #BSCC 0001, Office of Science and Technology Policy, Executive Office of the President, NEOB-Room 5005, Washington, DC 20506.

Comments relating to the policy statements of a particular agency should be sent directly to the agency contact identified at the beginning of the respective agency policy statement.

FOR FURTHER INFORMATION CONTACT:

Dr. David T. Kingsbury, Assistant Director for Biological, Behavioral, and Social Sciences, National Science Foundation, 1800 G Street, N.W., Washington, D.C. 20550, (202-357-9854).

Jerry D. Jennings,

Executive Director, Office of Science and Technology Policy

June 18, 1986

Table of Contents

I. Preamble

A. Introduction

B. The Coordinated Framework for the Regulation of Biotechnology

C. Interagency Coordination Mechanisms

D. BSCC Definitions

E. International Aspects

II. Statements of Policy

A. Food and Drug Administration

B. Environmental Protection Agency

C. U.S. Department of Agriculture

D. Occupational Safety and Health Administration

E. National Institutes of Health

TEXT: A. Introduction

This notice describes the comprehensive federal regulatory policy for ensuring the safety of biotechnology research and products. Specifically addressed are agency policies that formed part of the previously proposed Coordinated Framework for the Regulation of Biotechnology, published in the Federal Register December 31, 1984 (49 FR 50856, hereinafter "the December 84 Notice"). These agency policies build upon experience with agricultural, pharmaceutical, and other commercial products developed by traditional genetic modification techniques.

Existing statutes provide a basic network of agency jurisdiction over both research and products; this network forms the basis of this coordinated framework and helps assure reasonable safeguards for the public. This framework is expected to evolve in accord with the experiences of the industry and the agencies, and, thus, modifications may need to be made through administrative or legislative actions.

The application of traditional genetic modification techniques is relied upon bradly for enhanced characteristics of food (e.g., hybrid corn, selective breeding), manufactured food (e.g., bread, cheese, yogurt), waste disposal (e.g., bacterial sewage treatment), medicine (e.g., vaccines, hormones), pesticides (e.g. Bacillus thuringiensis) and other uses. Federal agencies implement an array of laws which seek to ensure the safety of these products. A concise index of these U.S. laws was published in the Federal Register November 14, 1985 (50 FR 47174, hereinafter "the November 85 Notice"). These laws are product-specific because they regulate certain product uses, such as foods or pesticides. This approach provides the opportunity for similar products to be treated similarly by particular regulatory agencies.

Biotchnology also includes recently developed and newly emerging genetic manipulation technologies, such as recombinant DNA (rDNA), recombinant RNA (rRNA) and cell fusion, that are sometimes referred to as genetic engineering. While the recently developed methods are an extension of traditional manipulations that can produce similar or identical products, they enable more precise genetic modifications, and therefore hold the promise for exciting innovation and new areas of commercial opportunity.

Concerns were raised as to whether products resulting from the recently developed techniques would pose greater risks than those achieved through traditional manipulation techniques. For example, what might be the possible environmental consequences of the many anticipated agricultural and environmental applications that will take place outside the physical contraints of a contained facility? In particular, the environmental application of genetically engineered microorganisms may elicit concern because they are of microscopic size, and some may be able to reproduce, proliferate, and become established.

The underlying policy question was whether the regulatory framework that pertained to products developed by traditional genetic manipulation techniques was adequate for products obtained with the new techniques. A similar question arose regarding the sufficiency of the review process for research conducted for agricultural and environmental applications.

The Administration, recognizing its responsibility to confront these concerns, formed an interagency working group under the former White House Cabinet Council on Natural Resources and the Environment in the spring of 1984. The working group sought to achieve a balance between regulation adequate to ensure health and environmental safety while maintaining sufficient regulatory flexibility to avoid impeding the growth of an infant industry.

Upon examination of the existing laws available for the regulation of products developed by traditional genetic manipulation techniques, the working group concluded that, for the most part, these laws as currently implemented would address regulatory needs adequately. For certain microbial products, however, additional regulatory requirements, available under existing statutory authority, needed to be established.

The existing health and safety laws had the advantage that they could provide more immediate regulatory protection and certainty for the industry than possible with the implementation of new legislation. Moreover, there did not appear to be an alternative, unitary, statutory approach since the very broad spectrum of products obtained with genetic engineering cut across many product uses regulated by different agencies.

Because of the rapid growth in the scientific knowledge base, the working group felt strongly that the federal agencies needed to have an interagency mechanism for sharing scientific information related to biotechnology, particularly information on research and product applications submitted to the agencies.

The December 1984 Notice described the regulatory framework envisioned by the working group, and recognizing the evoluntionary nature of its development, asked for comments. In summary, the Notice stated that the Food and Drug Administration (FDA) would regulate genetic engineering products no differently that those achieved through traditional techniques. The Environmental Protection Agency (EPA) described existing and proposed new policies for regulating pesticidal and nonpesticidal microorganisms. The Department of Agriculture (USDA) stated that under its different legislative authorities it could broadly regulate genetically engineered plants and animals, and plant and animal pathogens. The Notice also proposed an interagency science coordinating mechanism.

Many comments were received in response to the Notice. These contributed to the refinement of both the regulatory requirements and the interagency science coordintion mechanism.

The interagency coordination merchanism, the Biotechnology Science Coordinating Committee (BSCC), discussed in more detail in section C, of this Preamble, came into being while the agencies were still in process of refining their regulatory proposals. Consequently, the BSCC was able to play a helpful role in the formulation of two basic principles: (1) Agencies should seek to adopt consistent definitions of those genetically engineered organisms subject to review to the extent permitted by their respective statutory authorities; and, (2) agencies should utilize scientific reviews of comparable rigor.

The regulatory framework anticipates that future scientific developments will lead to further refinements. Experience with earlier basic scientific research has shown that as the science progressed and became better understood by the public, regulatory regimens could be modified to reflect more complete understanding of the potential risks involved. Similar evolution is anticipated in the regulation of commercial products as scientists and regulators learn to predict more precisely particular product use that require greater or lesser controls or even exemption from any federal review.

This framework has sought to distinguish between those organisms that require a certain level of federal review and those that do not. This follows a traditional approach to regulation. Within agriculture, for example, introductions of new plants, animals and microorganisms have long occurred routinely with only some of those that are not native or are pathogenic requiring regulatory approval. It should be noted that microorganisms play many essential and varied roles in agriculture and the environment and that for decades agricultrual scientists have endeavored to exploit their advantages through routine exerimentation and introduction into the environment; and as a rule these agricultural and environmental introductions have taken place without harm to the environment.

B. The Coordinated Framework for the Regulation of Biotchnology

General Comments

This notice includes separate descriptions of the regulatory policies of FDA, EPA, OSHA and USDA and the research policies of the National institutes of Health (NIH), NSF, EPA and USDA. The agencies will seek to operate their programs in an integrated and coordinated fashion and together should cover the full range of plants, animals and microorganisms derived by the new genetic engineering techniques. To the extent possible, responsibility for a product use will lie with a single agency. Where regulatory oversight or review for a particular product is to be performed by more than one agency, the policy establishes a lead agency, and consolidated or coordinated reviews. While this preamble seeks to convey an overview of the coordinated framework, it must be noted that the regulatory requirements are highly technical; reliance only on the simplified summary statements herein could be misleading and, thus, the agency policy statements must be consulted for specific details. In the event that questions arise regarding which federal agency has jurisdiction, an information contact is provided at the beginning of this notice.

While in part certain USDA and EPA requirements are new, the underlying regulatory regimens are not new. Members of the agricultural and industrial communities are familiar with the general requirements under these laws which include the Federal Plant Pest Act, The Plant Quarantine Act, the Toxic Substances Control Act (TSCA), and the Federal insecticide, Fungicide, and Rodenticide Act (FIFRA).

Because this comprehensive regulatory framework uses a mosaic of existing federal law, some of the statutory nomenclature for certain actions may seem inconsistent. Certain laws, such as USDA's Federal Plant Pest Act, require a "permit" before a microorganism pathogenic to plants may be transported or imported. Under other laws such as FIFRA, the agencies "license" or "approve" the use of particular products. TSCA requires a "premanufacturing notification (PMN)". There are also some variations among the agencies in the use of the phrase "genetic enginering." Regardless of the nomenclature, the public should be aware that the reviews conducted by each of the regulatory agencies are intended to be of comparable rigor. Agencies have agreed to have scientists from each other's staff participate in reviews. Each regulatory review will require that the safety, or safety and efficacy, of a particular agricultural or industrial product be satisfactorily demonstrated to the regulatory agency prior to commercialization.

The National Environmental Policy Act (NEPA) imposes procedural requirements on all federal agencies to prepare an analysis prior to making a decision to take any action that may significantly affect the environment. Depending on the characteristics of a proposal, an environmental assessment, or a broader environmental impact statement may need to be prepared in connection with the release of genetically manipulated organisms. EPA's actions under most of its environmental statutes have been considered to be the functional equivalent of NEPA compliance.

For the handling of microorganisms, agencies of the Department of Health and Human Services have established recommendations for the safe use of infectious agents. The CDC/NIH publication, Biosafety in Microbiological and Biomedical Laboratories, describes combinations of standard and special microbiological practices, safety equipment and facilities which are recommended for working with a variety of infectious agents in research laboratories, academic and industrial. The USDA also has issued guidance on other infectious agents.

The NIH has published guidelines for the contained use of DNA organisms in the NIH Guidelines for Research Involving Recombinant DNA Molecules, Federal Register, May 7, 1986 (51 FR 16958, NIH guidelines). The guidelines recommend physical containment at specific levels for different experiments, and exempt other experiments from containment requirements. However, they recommend Biosafety Level 1, the least stringent level of physical containment, for some "exempt" experiments. For large-scale exempt experiments, the NIH guidelines recommended "Biosafety Level 1-Large-Scale" although following review by the Institutional Biosafety Committee, "some latitude" in the application of these requirements is permitted.

The appropriate large-scale containment requirements for many low risk DNA derived industrial microorganisms will be no greater than those appropriate for the unmodified parental organisms. This concept is discussed further in the Organization for Economic Cooperation and Development (OECD) document, described in the International Aspects section below.

OSHA in its Federal Register Notice of April 12, 1984 (50 FR 14468) stated that its authority under the Occupational Safety and Health Act of 1970 (29 U.S.C. et seq.) provides an adequate and enforceable basis for protecting the safety and health of employees in the field of biotechnology and that no additional regulation is necessary. After consideration of comments in the April 1984 notice, OSHA is publishing this policy statement in final form without change.

Product Regulation

Agencies involved with regulating agriculture, foods, medical devices, drugs, biologics and pesticides have had extensive experience with products that involve living organisms in their manufacture and/or ultimate use including releases into the environment for these purposes. By the time a genetically engineered product is ready for commercialization, it will have undergone substantial review and testing during the research phase, and thus, information regarding its safety should be available. The manufacture by the newer technologies of food, the development of new drugs, medical devices, biologics for humans and animals, and pesticides, will be reviewed by FDA, USDA and EPA in essentially the same manner for safety and efficacy as products obtained by other techniques. The new products that will be brought to market will generally fit within these agencies' review and approval regimens.

The regulatory scheme for products is described in Chart I Coordinated Framework -- Marketing Approval of Biotechnology Products.

CHART I. -- COORDINATED FRAMEWORK -- AP-
PROVAL OF COMMERCIAL BIOTECHNOLOGY
PRODUCTS
	Responsible
Subject	agency(ies)
Foods/Food Additives	FDA, *
	FSIS. n1
Human Drugs, Medical Devices and Biologics	FDA.
Animal Drugs	FDA.
Animal Biologics	APHIS.
Other Contained Uses	EPA.
Plants and Animals	APHIS, *
	FSIS n1
	FDA. n2
Pesticide Microorganisms Released in the En-	EPA, *
vironment All.	APHIS. n3
Other Uses (Microorganisms):
Intergeneric Combination	EPA, *
	APHIS. n3
Intrageneric Combination:
Pathogenic Source Organism:
1. Agricultural Use	APHIS.
2. Non-Agricultural use	EPA, * n4
	APHIS. n3
No Pathogenic Source Organisms	EPA Report.
Nonengineered Pathogens:
1. Agricultural Use	APHIS.
2. Non-agricultural Use	EPA, n4
	APHIS. n3
Nonengineered Nonpathogens	EPA Report.

* Lead agency.

n1 FSIS, Food Safety and Inspection Service, under the Assistant Secretary of Agriculture for Marketing and Inspection Services is responsible for food use.

n2 FDA is involved when in relation to a food use.

n3 APHIS, Animal and Plant Health Inspection Service, is involved when the microorganism is plant pest, animal pathogen or regulated article requiring a permit.

n4 EPA requirements will only apply to environmental release under a "significant new use rule" that EPA intends to propose.

Jurisdiction over the varied biotechnology products is determined by their use, as has been the case for traditional products. The detailed description of the products and their review are found in the individual agency policy statements contained in this Federal Register Notice. The following is a brief summary of jurisdiction as described in Chart I.

Foods, food additives, human drugs, biologics and devices, and animal drugs are reviewed or licensed by the FDA. Food products prepared from domestic livestock and poultry are under the jurisdiction of the USDA's Food Safety Inspection Service (FSIS).

Animal biologics are reviewed by the Animal and Plant Health Inspection Service, (APHIS). APHIS, also reviews plants, seeds, animal biologics, plant pests, animal pathogens and "regulated articles", i.e., centain genetically engineered organisms containing genetic material from a plant pest. An APHIS permit is required prior to the shipment (movement) or release into the environmental of regulated articles, or the shipment of a plant pest or animal pathogen.

"Other contained uses" refers to the closed system uses of those microorganisms, subject the TSCA, that are intergeneric combinations, i.e., deliberately formed microorganisms which contain genetic material from dissimilar source organisms. These are subject to EPA's PMN requirement. EPA is considering promulgating a rule to exempt certain classes of microorganisms from this requirement.

Microbial pesticides will be reviewed by EPA, with APHIS involvement in cases where the pesticide is also a plant pest, animal pathogen, or regulated article requiring a permit. (FDA may become involved in impementing pesticide tolerances for foods.)

"Other uses (microorganisms)" include uses involving release into the environment. For these, jurisdiction depends on the characteristics of the organism as well as its use. "Intergeneric combination" * microorganisms will be reported to EPA under PMN requirements, with APHIS Involvement in cases where the microorganism is also a regulated article requiring a permit.

"Intrageneric combinations" are those microorganisms formed by genetic engineering other than intergeneric combinations. For these, when there is a pathogenic n1 source organism, and the microorganism is used for agricultural purposes, APHIS has jurisdiction. If the microorganism is used for nonagricultural purposes, then EPA has jurisidiction, with APHIS involvement in cases where the microorganism is also a regulated article requiring a permit. Intrageneric combinations with no pathogenic source organisms are under EPA jurisdiction although EPA will only require an informational report.

n1 "Integeneric organisms (new organisms)" and "pathogen" are defined in section D. of the preamble.

"Nonengineered pathogens" that are used for an agricultural use will fall under APHIS jurisdiction. Those that are for a nonagricultural use come under EPA jurisdiction, with APHIS involvement in cases where the microorganism is also a plant pest or animal pathogen requiring a permit. Nonengineered nonpathogenic microorganisms are under EPA jurisdiction which will require only an informational report.

Research

The coordinated framework for the regulation of biotechnology establishes requirements for the conduct of research.

Approximately ten years ago the NIH issued the NIH guidelines describing the manner in which research with organisms derived by rDNA techniques should be conducted. Since then the guidelines have been modified many times with gradual relaxation of these requirements. The guidelines prescribe the conditions under which institutions which receive NIH funds must conduct experiments. For a very small category of NIH funded experiments including environmental release, the guidelines require that the Director, NIH, approve each experiment on an individual basis. For each of these experiments, the RAC conducts a scientific review with an opportunity for public comment, and makes a recommendation to the NIH Director. As research experiments have expended out of the biomedical area to environmental applications both agricultural and nonagricultural, other agencies have become involved, with shifting of responsibility for research approval to NSF (described in the November 85 Notice), USDA's S&E, and EPA. These other agencies' policies build, in part, on the NIH guidelines and NIH experience.

The S&E guidelines for agricultural research published separately for comment in this issue of the Federal Register have adopted the NIH guidelines with certain modifications including expansion of the scope to manipulation techniques other than rDNA; the table included with the S&E guidelines shows where particular elements of the NIH guidelines are used.

It should be noted that not all experiments involving the environmental release of genetically engineered organisms require prior federal approval. In plant applications there is a substantial body of research indicating that such experiments are of low risk. For certain categories of microorganisms modified by traditional genetic modification techniques, there is also a substantial body of research indicating low risk for environmental experiments.

Chart II -- Coordinated Framework -- Biotechnology Research Jurisdiction shows which agency has responsibility for a particular experiment. If more than one agency has potential jurisdiction, one agency has been designated as the lead agency and it is marked with an asterisk on Chart II. The lead agency designation depends on which research agency is funding the research (e.g., NIH, S&E, or NSF) or which regulatory agency reviews specific purpose research (e.g. pesticides). In the chart and in this discussion, the authority refers to approval of the actual execution of experiments and not to their funding.

CHART II. -- COORDINATED FRAMEWORK --
BIOTECHNOLOGY RESEARCH JURISDICTION
	Responsible
Subject	agency(ies)
Contained Research, No Release in Environ-
ment:
1. Federally Funded	Funding
	agency. n1
2. Non-Federally Funded	NIH or S&E
	voluntary
	review
	APHIS. n2
Foods/Food Additives, Human Drugs, Medical
Devices, Biologics, Animal Drugs:
1. Federally Funded	FDA *, NIH
	guidelines
	& review.
2. Non-Federally Funded	FDA *, NIH
	voluntary
	review.
Plants, Animals and Animal Biologics:
1. Federally Funded	Funding
	agency, n1 *
	APHIS. n2
2. Non-Federally Funded	APHIS *,
	S&E
	voluntary
	review.
Pesticide Microorganisms:
Genetically Engineered:
Integeneric	EPA, *
	APHIS, n2
	S&E
	voluntary
	review.
Pathogenic Integeneric	EPA, *
	APHIS, n2
	S&E
	voluntary
	review.
Intrageneric Nonpathogen	EPA, * S&E
	voluntary
	review.
Nonengineered:
Nonindigenous Pathongens	EPA, *
	APHIS.
Indigenous Pathogens	EPA, * n3
	APHIS.
Nonindingenous Nonpathogen	EPA. *
Other Uses (Microorganisms) Released in the
Environment:
Genetically Engineered:
Intergeneric Organisms:
1. Federally Funded	Funding
	agency, * n1
	APHIS, n2
	EPA. n4
2. Commercially Funded	EPA, APHIS,
	S&E
	voluntary
	review.
Intrageneric Organisms:
Pathogenic Source Organism:
1. Federally Funded	Funding
	agency, * n1
	APHIS, n2
	EPA. n4
2. Commercially Funding	APHIS, n2
	EPA (* if
	non-
	agricul.
	USE).
Intrageneric Combination:
No Pathogenic Source Organisms	EPA Report.
Nonengineered	EPA
	Report, *
	APHIS. n2

* Lead Agency.

n1 Review and approval of research protocols conducted by NIH, S&E, or NSF.

n2 APHIS issues permits for the importation and domestic shipment of certain plants and animals, plant pests and animal pathogens, and for the shipment or release in the environment of regulated articles.

n3 EPA jurisdiction for research on a plot greater than 10 acres.

n4 EPA reviews federally funded environmental research only when it is for commercial purposes.

For contained federally funded research for biomedical and agricultural purposes, research approval will be granted by the funding agency. The NIH guidelines relate primarily to biomedical experiments and only to those using rDNA techniques. Research on foods/food additives, human drugs, medical devices and biologics will continue to rely on the NIH guidelines, with NIH approval required for certain experiments such as human gene therapy, and FDA permission for clinical trials.

Fashioned after the NIH guidelines, the S&E guidelines apply to agricultural research on plants, animals, and microorganisms and provide guidance for laboratory and field testing of organisms derived using rDNA manipulation and other technologies. Adherence to the appropriate set of guidelines is required for institutions receiving financial support from NIH, S&E, or NSF. These guidelines specify what type of review procedures are required for specific categories of experiments. Some experiments require individual approval by the respective agency providing institutional support. For those experiments that require agency approval, advisory committees at NIH, S&E, and NSF, composed primarily of nongovernment scientists, may be asked to provide expert review. In addition, research on plants, animals, and animal biologics will come under APHIS permit requirements if a regulated article, plant pest, animal pathogen is involved. An APHIS permit is required prior to the shipment (movement) or release of a regulated article, or the importation or shipment of a plant pest or regulated article used in any research experiment.

EPA has authority for all environmental research on microbial pesticides regardless of whether research is federally funded or not. EPA will regulate research under a two level review system based upon its evaluation of the potential risks posed by various types of microorgranisms with lesser notification required for level reporting and full review for level II.

For the "the uses" category from Chart II (research involving nonpesticide microorganisms released into the environment), jurisdiction for release may be under S&E, NSF, APHIS, or EPA depending primarily upon the source of the funding, but also upon the purpose of the research and the characteristics of the genetically engineered microorganism. Thus, federally funded research conducted for an agricultural use will require adherence to S&E guidelines and approval of certain experiments by S&E or NIH depending on which is the funding agency. EPA will review commercial research. APHIS's jurisdiction applies to issuing permits for regulated articles, plant pests, or animal pathogens. EPA will require an informational report for nonengineered microorganisms released into the environment, with APHIS involvement for the review of plant pests or animal pathogens.

There may be situations where one agency may choose to defer to, or ask advice from, another agency. If experiments requiring NIH, NSF or S&E review/approval are submitted for review to another agency, then NIH, NSF, or S&E may determine that such review serves the same purpose, and based upon that determination, notify the submitter that no NIH, NSF, or S&E review will take place, and the experiment may proceed upon approval from the other agency.

C. Interagency Coordination Mechanisms

The Domestic Policy Council Working Group on Biotechnology

The Domestic Policy Council Working Group on Biotechnology has been responsible for this coordinated framework for the regulation of biotechnology; it also considers policy matters related to agency jurisdiction, commercialization, and international biotechnology matters. The Working Group monitors developments in biotechnology and is ready to identify problems and make appropriate recommendations for their solution. The Domestic Policy Council Working Group on Biotechnology is a continuation of a similar group established under the former Cabinet Council on Natural Resources and the Environment.

Although at the present time existing statutes seem adequate to deal with the emerging processes and products of modern biotechnology, there always can be potential problems and deficiencies in the regulatory apparatus in a fast moving field. The Working Group will be alert to the implications these changes will have on regulation, and in a timely fashion will make appropriate recommendations for administrative or legislative action.

The Bitechnology Science Coordinating Committee (BSCC)

The BSCC is responsible for coordination and consistency of scientific policy and scientific reviews. The BSCC, established October 31, 1985 as part of the Federal Coordinating Council for Science, Engineering and Technology (FCCSET), consists of senior policy officials of agencies involved in the oversight of biotechnology research and products. FCCSET is a statutory interagency coordinating mechanism managed by the Office of Science and Technology Policy, Executive Office of the President, with a mission to coordinate federal science activities among federal agencies. The November 85 Notice described the structure and activities of the BSCC.

One of the primary activities of the BSCC has been the development of definitions because a common scientific approach is essential to a coordinated federal regulatory framework. The underlying scientific issue, therefore, was defining those organisms subject to certain types of agency review.

The definitions are included in the following section of this preamble and have been incorporated, with modification, into the individual policy notices of the involved agencies. Explanatory material is also included in the agency policy statements. As mentioned elsewhere, the BSCC is seeking comments on these definitions

Research to develop genetically modified organisms for environmental and agricultural applications (as for research on traditionally modified organisms) generaly proceeds in a stepwise manner from highly contained facilities to progressively lesser degrees of containment as the investigator determines the safety and efficacy of experimental applications; there are conducted sequentially under controlled laboratory conditions, greenhouse testing, small field trials, and full field trials. The BSCC recognizes the need for further work to define the nature and extent of physical and biological barriers that limit or manage environmental release of modified organisms during greenhouse testing and field research.

The BSCC is authorized to hold public meetings in order to discuss public concerns about scientific and other issues. Accordingly, the BSCC will hold its first public meeting shortly after publication of this notice for discussion of the scientific aspects of this notice and the receipt of comments from the public. The public meeting will be held in July 1986. Details regarding time and location will be separately announced in the Federal Register.

D. BSCC Definitions

Any proposal to regulate the research and products of genetic manipulation techniques quickly confronts the issue of what organisms should be considered appropriate for certain types of review. The BSCC formulated definitions are effective immediately but are open to comment; the text following the definition of "pathogen" contains details of the request for comments.

Organisms meeting two different sets of criteria are proposed. First are organisms formed by deliberate combination of genetic material from sources in different genera. It was recognized, however, that in certain precisely constructed "intergeneric organisms" the genetic material is not considered to pose an increased risk to human health or the environment; thus, such combinations are excluded from the definition. A detailed explanation of the scientific basis for these exclusions is found in the footnote after the definition of pathogen. The BSCC specifically requests comments on whether also to consider for exclusion those organisms that exchange DNA by known physiological processes, as explained in the text immediately following the definition of "intergeneric organism (new organism)."

The second definition is "pathogen." This includes microorganisms that belong to a pathogenic species or that contain genetic material from source organisms that are pathogenic. In certain precisely constructed modified organisms, the genetic material from a pathogenic donor is not considered to pose an increased risk to human health or the environment; and, therefore, such combinations are excluded from the definition.

The BSCC definitions of "intergeneric organism (new organism)" and "pathogen" describe the combinations genetic material that would cause a modified organism to come under review. This does not mean to suggest that the dehavior of a genetically manipulated organism exempted from these definitions is wholly predictable (since any biological organism is never 100% predictable), but that the probability of any incremental hazard compared to the unmodified organism host is low. Also, this does not mean that any product manufacture or research experiment using an organism exempted from the definition should be conducted without adherence to proper manufacturing standards or research guidelines.

Given the statutory differences in the laws that they administer, the agencies adopted the principles underlying the definitions in ways consistent with their legislation. EPA, APHIS, and S&E are using the definitions to identify levels of review for microbial products within their jurisdiction. EPA, APHIS, FDA, S&E, and NSF are using the definitions as factors to consider in the review of products or experiments.

The BSCC is attempting to define what constitutes "release into the environment." The BSCC is establishing a working group on greenhouse containment and small field trials in order to develop scientific recommendations. The concept of "containment" has traditionally been used to describe physical conditions which severely limit release (for example, a contained laboratory fermentation facility). Containment can also be "biologic" because the ability of an organism to reproduce, exchange genetic information, or become established can be effectively limited biologically. Thus, the BSCC's exploration of the conditions that constitute release into the environment will consider circumstances of both physical and biological containment for particular organisms and the circumstances of their release. While the concept of physical containment may imply the high containment conditions found in certain laboratories and greenhouses, in agricultural practice many simpler effective barriers are rountinely used; these include microplots for soil bacteria and fungi, paddocks for noninfective animals, and removing or covering the reproductive parts of plants and animals.

Release into the environment, for the time being, will have somewhat varying definitions for the regulatory and research review of the different agencies. There may be minor differences between agricultural and nonagricultural approaches and between macro-and microorganisms.

Intergeneric Organism (New Organism)

Those organisms deliberately formed to contain an intergeneric combination of genetic material; excluded are organisms that have resulted from the addition of intergeneric materials that is well-characterized and contains only non-coding regulatory regions such as operators, promoters, origins of replication, terminators and ribosome binding regions.

"Well-characterized and contains only non-coding regulatory regions" means that the producer of the microorganism can document the following:

a. The exact nucleotide base sequence of the regulatory region and any inserted flanking nucleotides;

b. The regulatory region and any inserted flanking nucleotides do not code independently for a protein, peptide of functional RNA molecules;

c. The regulatory region solely controls the activity of other sequences that code for protein or petide molecules or act as recognition sites for the initiation of nucleic acid or protein synthesis.

Pathogen

A pathogen is a virus or microorganism (including its viruses and plasmids, if any) that has the ability to cause disease in other living organisms (i.e., humans, animals, plants, microorganisms).

A microorganism (including viruses) will be subject to regulatory policies regarding pathogens if;

a. the microorganism belongs to a pathogenic species, according to sources identified by the agency, or from information known to the producer that the organism is a pathogen; excepted are organisms belonging to a strain used for laboratory research or commercial purposes and generally recognized as non-pathogenic according to sources identified by a federal agency, or information known to the producer and the appropriate federal agency (an example of a nonpathogenic strain of a species which contains pathogenic strains is Escherichia coli K-12; examples of nonpathogenic species are Bacillus subtilis, Lactobacillus acidohilus, and Saccharomyces species); or

b. The microorganism has been derived form a pathogen or has been deliberately engineered such that it contains genetic material from a pathogenic organism as defined in item a. above. Excepted are genetically engineered organisms developed by transferring a well-characterized, non-coding regulatory region from a pathogenic donor to a non-pathogenic recipient.

"Well-characterized, non-coding regulatory region" means the the producer of the microorganism can document the following:

a. The exact nucleotide base sequence of the regulatory region and any inserted flanking nucleotides;

b. The regulatory region and any inserted flanking nucleotides do not code independently for a protein, peptide, or functional RNA molecules; and,

c. The regulatory region solely controls the activity of other sequences that code for protein or peptide moldecules or act as recognition sites for the initiation of nucleic acid or protein systhesis.

This definition excludes organisms such as competitors or colonizers of the same substrates, commensal or mutualistic micoorganisms, or opportunistic pathogens.

The footnote contains the scientific basis for exempting non-coding regulatory regions from the definitions of intergeneric organisms and pathogen. n2

n2 The BSCC has based the exemption of intergeneric transfers of regulatory regions on their lack of coding capacity for the production of proteins, peptides or functional RNA molecules. It has been recommended by other members of the scientific community that there should be additional exemptions such as ribosomal proteins, ribosomal RNAs and transfer RNAs. The BSCC has chosen to examine these suggestions in more detail during the next few months. At the present the BSCC has excluded:

1. Origins of replications;

2. Ribosome binding sites;

3. Promoters;

4. Operators; and,

5. Terminators.

The basis for these exemptions is as follows. Each of these regulatory elements has no coding capacity for the production of any gene product and therefore does not promote the production of any new material. What these elements are responsible for is the initiation and modulation of nucleic acid synthesis at the specific region where they appear in the chromosome.

Bacterial genes are precisely regulated and this regulation is based on a series of regulatory elements. The principal regulatory unit is the operon. Operons are controlled primarily, but not exclusively, through the regulation of the rate of initiation of messenger RNA synthesis. This regulation is based on the interaction of two short nucleotide sequences in the DNA, the promoter, which is the site of RNA polymerase binding and the operator, which follows closely and acts as an off-on switch for the movement of the polymerase into the structural gene which follows. The function of the operator is to bind a cellular repressor protein which is synthesized in response to changing nutritional stimuli. Terminator regions are short nucleotide sequences which signal the termination of mRNA synthesis by the polymerase. They act as a signal for the dissociation of the polymerase from the DNA.

Replication of DNA in every biological system that has been examined is initiated at a specific site or group of sites in the chromosome. Those sites have broad specificity and a DNA molecule without the appropriate site will not be replicated. The sites which are critical to the initiation of replication are known as origins of replication. These regions are short nucleotide sequences which serve as initiation sites for specific enzyme action during the DNA replication process. For example, in order for mammalian DNA to replicate in bacteria, it must be associated with a bacterial origin of replication and vice versa.

Ribosome binding sites are short nucleotide segments at the beginning of messenger RNA molecules which signal the attachment of ribosomes for the initiation of protein synthesis. Functioning in this role they are not translated into the protein or peptide being processed.

The BSCC is requesting comments on these definitions during the period of sixty days following the date of this notice and specifically seeks comments addressing the following:

1. The suitability and applicability of these definitions to applications involving release into the environment, contained industrial large-scale applications, foods/food additives, drugs, medical devices, and other possible products.

2. Whether combinations of genetic material from organisms that exchange DNA by known physiological processes should be excluded from the definition of intergeneric organisms: i.e., should organisms be excluded which contain intergeneric combinations of certain specified rDNA molecules that consist entirely of DNA segments from different genera that exchange DNA by known physiological processes? As certain rDNA organisms are exempted under section III-D-4 of the NIH guidelines, the question was raised whether these organisms when used in the environment should be similarly exempted from federal product review. This exemption would not, however, exclude from review such "natural exchangers" that are also pathogens or plant pests. In the event that the exclusion of such different species that exchange DNA by known physiological processes is accepted as appropriate, a list of such species combinations that has been maintained and updated by the Office of Recombinant DNA Activities of the National Institutes of Health will be updated, in light of environmental use.

3. What are the most appropriate definitions of "release into the environment" for macro- and microorganisms.

E. International Aspects

The United States seeks to promote international scientific cooperation and understanding of scientific considerations in biotechnology on a range of technical matters. These activities add to scientific knowledge and ultimately contribute to protection of health and the environment.

The United States also seeks to reduce barriers to international trade. U.S. agencies apply the same regulation and approval procedures on domestic and foreign biotechnological products. We are seeking recognition among nations of the need to harmonize, to the maximum extent possible, national regulatory oversight activities concerning biotechnology. Barriers to trade in biotechnological products should be avoided as nations join together in working toward this mutual goal.

The U.S. agencies that have published separate policy statements as part of this notice are committed to the policy described in this section on international harmonization and have incorporated by reference the language in this International Aspects section as part of their respective agency policy statements.

Organization for Economic Cooperation and Development (OECD)

The approach of the comprehensive framework contained in this notice takes into account, inter alia, the broad goals described by an Ad Hoc Group of Government Experts convened by OECD in their recent report entitled, "Recombinant DNA Safety Considerations, Safety Considerations for Industrial, Agricultural and Environmental Applications of Organisms Derived by Recombinant DNA Techniques," The United States is pleased to have had the opportunity for its experts to work with those of other governments in the preparation of this report. The report includes the following concepts:

Summary of Major Points

Recombinant DNA techniques have opened up new and promising possibilities in a wide range of applications and can be expected to bring considerable benefits to mankind. They contribute in several ways to the improvement of human health and the extent of this contribution is expected to increase significantly in the near future.

The vast majority of industrial rDNA large-scale applications will use organisms of intrinsically low risk which warrant only minimal containment, Good Industrial Large-Scale Practice (GILSP).

When it is necessary to use rDNA organisms of higher risk, additional criteria for risk assessment can be identified and furthermore, the technology of physical containment is well known to industry and has successfully been used to contain pathogenic organisms for years. Therefore, rDNA microorganisms of higher risks can also be handled safely under appropriate physical and/or biological containment.

Assessment of potential risks of organisms for environmental or agricultural applications is less developed than the assessment of potential risks for industrial applications. However, the means for assessing rDNA organisms can be approached by analogy with the existing data base gained from the extensive use of traditionally modified organisms in agriculture and the environment generally. With step-by-step assessment during the research and development process, the potential risk to the environment of the applications of rDNA organisms should be minimized.

I. General Recommendations

1. Harmonization of approaches to rDNA technology can be facilitated by exchanging: Principles or guidelines for national regulations; developments in risk analysis; and practical experience in risk management. Therefore, information should be shared as freely as possible.

2. There is no scientific basis for specific legislation for the implementation of rDNA technology and applications. Member countries should examine their existing oversight and review mechanisms to ensure that adequate review and control may be applied while avoiding any undue burdens that may hamper technological developments in this field.

3. Any approach to implementing guidelines should not impede future developments in rDNA technology. International harmonization should recognize this need.

4. To facilitate data exchange and minimize trade barriers between countries, further developments such as testing methods, equipment design, and knowledge of microbial taxonomy should be considered by both national and international levels. Due account should be taken of ongoing work on standards within international organizations such as: World Health Organization; Commission of the European Communities; International Standards Organization; Food and Agricultural Organization; and, Microbial Strains Data Network.

5. Special efforts should be made to improve public understanding of various aspects of rDNA technology.

6. For rDNA applications in industry, agriculture and the environment, it will be important for OECD Member countries to watch the development of these techniques. For certain industrial applications and for environmental and agricultural applications of rDNA organisms, some countries may wish to have a notification scheme.

7. Recognizing the need for innovation, it is important to consider appropriate means to protect intellectual property and confidentiality interests while assuring safety.

II. Recommendations Specific for Industry

1. The large-scale industrial application of rDNA technology should wherever possible utilize microorganisms that are intrinsically of low risk. Such microorganisms can be handled under conditions of Good Industrial Large-Scale Practice (GILSP).

2. If, following assessment using the criteria outlined in the document, a rDNA microorganism cannot be handled merely by GILSP, measures of containment corresponding to the risk assessment should be used in addition to GILSP.

3. Further research to improve techniques for monitoring and controlling non-intentional release of rDNA organisms should be encouraged in large-scale industrial applications requiring physical containment.

III. Recommendations Specific for Environmental and Agricultural Applications

1. Considerable data on the environmental and human health effects of living organisms exist and should be used to guide risk assessments.

2. It is important to evaluate rDNA modified organisms for potential risk, prior to applications in agricultural and the environment. However, the development of general international guidelines governing such applications is premature at this time. An independent review of potential risks should be conducted on a case-by-case basis prior to application. Case-by-case means an individual review of a proposal against assessment criteria which are relevant to the particular proposal; this is not intended to imply that every case will require review by a national or other authority since various classes of proposals may be excluded.

3. Development of organisms for agricultural or environmental applications should be conducted in a stepwise fashion, moving, where appropriate, from the laboratory to the growth chamber and greenhouse, to limited field testing and finally, to large-scale field testing.

4. Further research to improve the prediction, evaluation, and monitoring of the outcome of applications of rDNA organisms should be encouraged.

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

AGENCY: Food and Drug Administration.

[Docket No. 84N-0431]

Statement of Policy for Regulating Biotechnology Products

ACTION: Final policy statement for regulating biotechnology products.

SUMMARY: In the Federal Register of December 31, 1984 (43 FR 50878), the Food and Drug Administration (FDA) published a policy statement for regulating biotechnology products. The policy statement was part of a larger document that included an index of U.S. laws related to biotechnology, a description of the policies of the major regulatory agencies that are involved in reviewing the products of biotechnology, a description of a proposed scientific advisory mechnism for assessment of biotechnology issues, and an explanation of how the activities of the Federal agencies involving biotechnology will be coordinated. Of the comments FDA received on the policy statement, most favored the policy statement; some requested further clarification and guidance. The current action constitutes FDA's final policy statement which has been revised in response to the comments.

ADDRESS: Written comments should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, Room 4-62, 5600 Fishers Lane, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Dr. Mary Ann Danello (HF-5), Food and Drug Administration, Room 14-90, 5600 Fishers Lane, Rockville, MD 20857, 301-443-4650.

SUPPLEMENTARY INFORMATION: FDA's policy statement of December 31, 1984 stated the FDA regulation must be based on the rational and scientific evaluation of products, and not on a priori assumptions about certain processes. Accordingly, FDA's administrative review of products, including those that employ specialized biotechnological techniques, is conducted in the light of the intended use of a product on a case-by-case basis. FDA believes the agency need not establish new administrative procedures to deal with generic concerns about biotechnology.

These views were supported by the majority of comments received in response to FDA's notice. Thirty-four comments were received, with 12 from manufacturers of regulated products, 16 from associations and universities, and 6 from individuals. A summary of the comments and the agency's response to them follow:

1. Many commenters urged the agency to publish additional "Points to Consider" documents to provide further guidance for biotechnology product applicants. These commenters specifically requested guidance in the area of animal drugs (especially protein drugs) and human foods and food additives.

FDA agrees that "Points to Consider" documents provide useful guidance, especially in areas involving new biotechnology, and will consider developing these documents where appropriate.

2. Related comments raised questions on FDA's general requirements for approving bioltechnology products that are animal drugs, human foods, or food additives.

In response to these comments, FDA has amended the animal drug section ("General Requirements for Animal Food Additives and Drugs") to be more informative and has added a new section concerning its policies on human foods and food additives (see "General Requirements for Human Foods and Foods Additives").

3. Many comments questioned the need for new or supplemental marketing applications for biotechnology products that are identical to products derived from conventional technology.

The agency has re-examined this issue and continues to believe that, as a general principle, new marketing applications will be required for most products manufactured using new biotechnology. For example, use of recombinant DNA (rDNA) technology has the potential to lead to new structural features in the product, result in product micro-heterogeneity, or introduce new contaminants (e.g., associated with new cell substrates), each of which may affect the safety, efficacy and stability of the product. Because of potential differences in the products resulting from use of recombinant DNA technology, the resulting products may be "new" products requiring separate approval under the applicable statutory provisions. However, each case will be examined separately to determine the appropriate information to be submitted. In some instances complete new applications may not be required. For example, the sponsor of a