[Federal Register: January 18, 2001 (Volume 66, Number 12)]
[Proposed Rules]
[Page 4706-4738]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18ja01-29]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 192 and 592
[Docket No. 00N-1396]
RIN 0910-AC15
Premarket Notice Concerning Bioengineered Foods
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to require
the submission to the agency of data and information regarding plant-
derived bioengineered foods that would be consumed by humans or
animals. FDA is proposing that this submission be made at least 120
days prior to the commercial distribution of such foods. FDA is taking
this action to ensure that it has the appropriate amount of information
about bioengineered foods to help to ensure that all market entry
decisions by the industry are made consistently and in full compliance
with the law. The proposed action will permit the agency to assess on
an ongoing basis whether plant-derived bioengineered foods comply with
the standards of the Federal Food, Drug, and Cosmetic Act (the act).
DATES: Submit written comments on the proposed rule by April 3, 2001.
Submit written comments on the information collection provisions by
February 20, 2001.
See section XIV of this document for the proposed effective date of
a final rule based on this document.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235,
Washington, DC 20503, Attn: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT:
Regarding human food issues: Linda S. Kahl, Center for Food Safety
and Applied Nutrition (HFS-206), Food and Drug Administration, 200 C
St. SW., Washington, DC 20204, 202-418-3101.
Regarding animal feed issues: William D. Price, Center for
Veterinary Medicine (CVM) (HFV-200), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-827-6652.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
A. The 1992 Policy
B. Consultations Under the 1992 Policy and the 1996 Procedures
C. Public Meetings
II. Legal Authority
III. Scope
IV. Definitions
V. Requirement for Premarket Biotechnology Notice
A. Foods That Are Subject to the Requirement
B. Origin of Data and Information
C. Timing
VI. Recommendation for Presubmission Consultation
A. Presubmission Consultation Program
B. Public Disclosure
C. Standard Procedures
VII. Premarket Biotechnology Notice: Administrative Information
A. Submissions to CFSAN for Use in Human Food, Animal Feed, or
Both
B. Paper Copies
C. Electronic Copies
D. English Language Translations, Incorporation by Reference,
and Available Guidance Documents
E. Opportunity to Withdraw
VIII. Premarket Biotechnology Notice: Required Parts
A. Part I: Letter
[[Page 4707]]
1. Statements Regarding the Notifier's Responsibility and the
Balanced Nature of the Notice
2. Statements Regarding the Availability of Data and Information
for FDA's Review
3. Statement Regarding Public Disclosure
B. Part II: Synopsis
C. Part III: Status at Other Federal Agencies and Foreign
Governments
D. Part IV: Method of Development
E. Part V: Antibiotic Resistance
F. Part VI: Substances in the Food
1. Covered Substances
2. Identity, Function, Level, and Dietary Exposure
3. Allergenicity
4. Other Safety Issues
G. Part VII: Data and Information About the Food
1. Comparable Food
2. Historic Uses of the Comparable Food
3. Comparing the Composition and Characteristics of the
Bioengineered Food to That of Comparable Food
4. Other Relevant Information
5. Narrative
IX. Agency Administration of a Premarket Biotechnology Notice
A. Filing Decision
B. Acknowledgment Letter
C. Response Letter
1. General Categories for FDA's Response
a. Letter That Extends FDA's Evaluation
b. Letter That the Notice Does Not Provide a Basis
c. Letter That FDA Has No Questions
d. Letter That a Notifier Has Withdrawn the Notice
2. Status of the Bioengineered Food at EPA
X. Public Disclosure
A. Existence of the Notice
B. Content of the Notice
C. Disclosure of FDA's Evaluation of, and Response to, a Notice
XI. Proposed Regulations Regarding Bioengineered Foods That Would Be
Used in Animal Feed
XII. Paperwork Reduction Act
A. Hourly Burden to Prepare a Report (Proposed Sec. 192.20(a)
through (b)(1) and Sec. 192.25
B. Hourly Reporting Burden Associated With Confidential
Information in a Report (Proposed Sec. 192.20(b)(2)(i) and
(b)(2)(ii)
C. Hourly Reporting Burden Associated With Electronic Copies of
the Report (Proposed Sec. 192.20(c)(1) and (c)(2)
D. Hourly Reporting Burden Associated With English Language
Translations, Authorization to Incorporate Information by Reference,
and Withdrawal (Proposed Sec. 192.20(d), (e), and (g)
E. Hourly Reporting Burden Associated With a Voluntary
Presubmission Consultation Program (Proposed Sec. 192.10(e) through
(g), (h)(2), (h)(3)(i), and (h)(3)(ii)
F. Hourly Recordkeeping Burden (Proposed Sec. 192.25(a)(2)
XIII. Analysis of Economic Impacts
A. Cost-Benefit Analysis
B. Background
1. Benefits
2. Costs
C. Regulatory Flexibility Act
D. Unfunded Mandates Reform Act
XIV. Effective Date
XV. Environmental Impact
XVI. Comments
XVII. References
I. Background
A. The 1992 Policy
In the Federal Register of May 29, 1992 (57 FR 22984), FDA
published its ``Statement of Policy: Foods Derived From New Plant
Varieties'' (the 1992 policy). The 1992 policy clarified the agency's
interpretation of the application of the act with respect to human
foods and animal feeds derived from new plant varieties, including
varieties that are developed using recombinant deoxyribonucleic acid
(rDNA) technology. This proposal refers to foods derived from plant
varieties that are developed using in vitro manipulations of DNA
(generally referred to as rDNA technology) as ``bioengineered foods.''
The 1992 policy provided guidance to industry on scientific and
regulatory issues related to plant-derived foods, including
bioengineered foods. In developing the 1992 policy as it relates to
bioengineered foods, FDA focused on modifications to foods that were
likely to result in commercial products and did not attempt to predict
future changes in foods that could result from technological advances.
Instead, FDA intended to modify its policy as circumstances warranted
(57 FR 22984 at 22985).
In announcing the 1992 policy, FDA invited interested persons to
submit written comments. Comments received from the scientific
community generally have supported the scientific guidance articulated
in the 1992 policy, including the scientific guidance as it relates to
bioengineered foods. In addition, the views expressed by the members of
FDA's Food Advisory Committee (Ref. 1) and the joint meeting of FDA's
Food Advisory Committee and Veterinary Medicine Advisory Committee
(Ref. 2), generally supported the scientific guidance in the 1992
policy.
However, many consumers, a number of public interest groups, and
some State officials have expressed concern about or opposed the
regulatory guidance articulated in the 1992 policy, particularly
regarding the ability of the regulated industry to make market entry
decisions. Frequently, those comments suggested, as an important
adjunct to the 1992 policy, that FDA require an administrative process,
such as premarket notification, to ensure that the agency remains aware
of new bioengineered foods entering commercial distribution.\1\
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\1\ This document defines ``commercial distribution'' as the
introduction, or delivery for introduction, into interstate commerce
for sale or exchange for consumption in any form by humans or other
animals.
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FDA is confident that the guidance articulated in the 1992 policy
adequately addressed both the scientific and regulatory issues raised
by the products that were approaching commercialization in 1992. FDA is
aware, however, that rDNA technology continues to evolve and that it is
not possible for the agency to anticipate all of the novel scientific
and regulatory issues that may arise as the number and types of foods
developed using this technology expands. As discussed more fully below,
this proposed rule would modify the regulatory guidance laid out in the
1992 policy by requiring the submission to the agency of data and
information regarding plant-derived bioengineered foods at least 120
days prior to the commercial distribution of such foods.
B. Consultations Under the 1992 Policy and the 1996 Procedures
In the 1992 policy, FDA explained that, under the act, developers
of new foods have a responsibility to ensure that the foods they offer
to consumers are safe and in compliance with all requirements of the
act (57 FR 22984 at 22985). In light of this responsibility, FDA has
long regarded it to be a prudent practice for producers who use new
technologies in the manufacture or development of foods and food
ingredients to work cooperatively with FDA to ensure that the products
of these new technologies are safe and comply with all applicable legal
requirements (57 FR 22984 at 22991). Historically, the food industry
generally has initiated consultation with FDA during the pioneer stages
of a new technology, even if there is no legal obligation to do so.
These consultations have served to make FDA aware of foods and food
ingredients before these products are distributed commercially, and
have provided FDA with the information necessary to address any
questions regarding the safety, labeling, or regulatory status of the
food or food ingredient. As such, these consultations have provided
assistance to both industry and the agency in exercising their mutual
responsibilities under the act.
In the 1992 policy, FDA noted that the agency expected this
practice of consultation to continue with respect to bioengineered
foods (57 FR 22984 at 22991). One early example of such a
[[Page 4708]]
consultation involved FLAVR SAVRTM tomatoes.\2\ In
developing FLAVR SAVTM tomatoes, Calgene used rDNA
technology to introduce an antisense polygalacturonase gene, which was
derived from tomatoes, and the kanamycin resistance gene (the kan
r gene), which encodes the enzyme aminoglycoside-3'-
phosphotransferase II (APH(3')II). The enzyme APH(3')II confers
resistance to the clinically used antibiotics kanamycin and neomycin in
the selection of new plant varieties developed using rDNA technology.
The use of APH(3')II raised several issues that had not previously been
evaluated by the agency in the context of food safety. The initial
consultation between the agency and Calgene about the intended use of
APH(3')II, which in this instance resulted in the filing and approval
of a food additive petition (59 FR 26700, May 23, 1994), was an
effective mechanism to fully explore and resolve these issues.
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\2\ This consultation was concluded in May 1994 (59 FR 26647 at
26700, May 23, 1994).
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The resolution of these and other scientific issues entailed the
use of nontraditional approaches to the evaluation of food safety. For
example, traditional evaluation of the safety of a food additive
frequently includes toxicological tests conducted in accordance with
the principles outlined in the agency's ``Toxicological Principles for
the Safety Assessment of Direct Food Additives and Color Additives Used
in Food'' (Redbook (Ref. 3)).\3\ In addition to guidance on when
certain tests may be appropriate, the Redbook includes specific
recommendations on the protocols for conducting such tests.
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\3\ In 1993, the Center for Food Safety and Applied Nutrition
(CFSAN) released a revised Redbook for public comment (58 FR 16536,
March 29, 1993). Following its evaluation of comments on each draft
chapter of the Redbook, CFSAN is making revised chapters available
on its Internet site (Ref. 4).
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In contrast, issues raised during the consultations on APH(3')II
and the FLAVR SAVRTM tomato required evaluation of data
generated using procedures that had only rarely been used in the
evaluation of food safety. For example, Calgene used ``Southern blots''
to determine which DNA sequences had been transferred to FLAVR
SAVRTM tomatoes, ``Northern blots'' to demonstrate the
intended technical effect in FLAVR SAVRTM tomatoes, and
``Western blots'' to determine the amount of APH(3')II present in FLAVR
SAVRTM tomatoes. The use of nontraditional strategies in the
evaluation of food safety likely will become the norm as the use of
rDNA technology expands, and further consultations between industry and
the agency would foster the identification and design of reasonable
test procedures to evaluate the composition and safety of whole foods.
Consultations are an appropriate forum for industry and the agency
to address proactively issues that are relevant to bioengineered foods,
and developers have actively consulted with FDA about their products
since the issuance of the 1992 policy. In June 1996, FDA provided
guidance to industry on procedures for these consultations (the 1996
procedures (Ref. 5)).\4\ Under that process, a developer who intends to
commercialize a bioengineered food meets with the agency to identify
and discuss relevant safety, nutritional, or other regulatory issues
regarding the bioengineered food prior to marketing it. Depending on
the experience the agency and the developer have with the kind of
modification being considered, a developer may initiate such a
consultation early or late in the development of the food. When the
developer believes that it has accumulated adequate data or information
to address any issues raised during the consultation, the developer
begins the ``final consultation'' by submitting to FDA a summary of its
scientific and regulatory assessment of the food. To date, the agency
has completed its evaluation of data or other information from more
than 45 such consultations (Ref. 6). FDA believes that, to date, all
developers of bioengineered foods commercially marketed in the United
States have consulted with the agency prior to marketing the food.
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\4\ In October 1997, FDA made administrative revisions to these
procedures to reflect reorganizations within the Office of Premarket
Approval, CFSAN, and the Center for Veterinary Medicine (CVM). In
this document, FDA refers to these procedures as ``the 1996
procedures'' to reflect the year that the agency made them
available.
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FDA continues to believe that the consultation process is
appropriate for bioengineered foods. Accordingly, this proposed
rulemaking includes FDA's recommendation that developers consult with
the agency to identify and discuss relevant safety, nutritional, or
other regulatory issues regarding a bioengineered food (see proposed
Sec. 192.10 and section VI of this document).
C. Public Meetings
In 1999, FDA announced that the agency would hold three public
meetings, each in a different region of the United States (64 FR 57470,
October 25, 1999). The purpose of those meetings was for the agency to
share its current approach and experience over the past 5 years
regarding bioengineered foods, to solicit views on whether FDA's
policies or procedures should be modified, and to gather information to
be used to assess the most appropriate means of providing information
to the public about bioengineered products in the food supply. In the
notice announcing the public meetings (64 FR 57470), FDA requested
comments on specific questions regarding bioengineered foods. As a
result of those meetings and the request for comments, the agency
subsequently received more than 35,000 written comments about its
policy regarding bioengineered foods.
At those meetings, and in the comments, FDA heard three messages
very clearly. First, there does not appear to be any new scientific
information that raises questions about the safety of bioengineered
foods currently being marketed. Second, some of the public is concerned
about FDA's existing guidance and regulatory approach to overseeing the
safety of these products. These concerns include whether FDA's guidance
and regulatory approach will be adequate for future developments and
whether firms will continue to inform FDA about new bioengineered foods
under the present program. In addition, there was a concern that the
current regulatory process lacks transparency (e.g., because FDA
discloses each consultation about a bioengineered food only at the end
of the process). Third, there are very strongly held but divergent
views as to whether bioengineered foods should bear special labeling.
However, there was general agreement that providing more information to
consumers about bioengineered foods would be useful \5\ (Ref. 8).
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\5\ In May 2000, FDA announced that it intended to issue for
public comment draft labeling guidance to aid manufacturers who wish
to voluntarily label their products as made with or without the use
of bioengineering or bioengineered ingredients (Ref. 7). The
development of that draft guidance is outside the scope of this
document.
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II. Legal Authority
FDA is responsible for ensuring that all foods \6\ in the American
food supply conform to the applicable provisions of the law. The act
provides FDA with broad authority to regulate the safety and
wholesomeness of food. In particular, the act prohibits the
adulteration of food under section 402 of the act (21 U.S.C. 342) and
the misbranding of food under section 403
[[Page 4709]]
of the act (21 U.S.C. 343). The act also requires that all food
additives (as defined by section 201(s) of the act (21 U.S.C. 321(s)))
be approved by FDA before they are marketed (sections 409 and 402 of
the act (21 U.S.C. 348(a) and 342(a)(2)(C))). FDA is authorized to seek
sanctions against foods that do not adhere to the act's standards,
through seizure of foods that violate the act under section 304 of the
act (21 U.S.C. 334); the agency is also authorized to seek an
injunction against, or criminal prosecution of, those responsible for
introducing such foods into commerce under sections 302 and 303 of the
act (21 U.S.C. 332 and 333).
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\6\ There are certain exceptions to this jurisdiction pertaining
to meat, poultry, and egg products that are not relevant to this
rulemaking.
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All plant breeding techniques have the potential to alter food
source crops in ways relevant to the legal status of food derived from
such crops. However, rDNA technology greatly facilitates, relative to
traditional breeding techniques, both the introduction of specific new
substances into foods and the directed modification of the composition
of foods. This is in part because the technology expands the range of
sources of new substances that can be introduced into plants, relative
to those that can be introduced with traditional techniques, due
principally to rDNA technology's ability to permit the transfer to a
food crop of genetic material from virtually any organism. Similarly,
at the present time, information related to the genomes of many
organisms is rapidly expanding, with the result that newly identified
genes are now available to breeders. In addition, rDNA technology
increases the speed by which traits can be introduced into food crops,
by allowing the introduction of specific, well-characterized genetic
material and by reducing the need for backcrossing to remove
undesirable traits. Given the efficiencies of rDNA techniques, the
advances in these techniques, and the rapidly expanding information
related to genomes, FDA expects that these techniques are likely to be
utilized to an increasingly greater extent by plant breeders and that
the products of this technology are likely in some cases to present
more complex safety and regulatory issues than seen to date.
Alterations in food source plants accomplished using rDNA
technology, with resulting changes in the foods derived from such
plants, can present a range of regulatory issues (57 FR 22984 to
23005). For example, such alterations may present questions as to the
food additive status of the substances introduced into the food as a
result of the genetic transformation. As noted, bioengineering permits
the introduction into food of substances from any source, and the
number and types of genes available for use in rDNA technology are
rapidly increasing. Thus, increasingly, substances may be introduced
into food using rDNA techniques that cannot be introduced by
traditional breeding. FDA noted in the 1992 policy that a nonpesticidal
substance introduced into food by way of breeding is a food additive if
the substance is not generally recognized as safe (GRAS) within the
meaning of 21 U.S.C. 321(s). Because of the greater range of sources of
substances that can be introduced into plants via rDNA technology,
there is a greater likelihood that some of the new substances will be
significantly different from substances that have a history of safe use
in food or may otherwise not satisfy the GRAS standard in section
201(s) of the act(s). Thus, there is a greater potential for foods
developed using rDNA technology to contain substances that are food
additives.
The agency reiterates its view, as stated in the 1992 policy (57 FR
22990), that transferred genetic material can be presumed to be GRAS.
Likewise, FDA is not altering its view, as set forth in the 1992
policy, that there is unlikely to be a safety question sufficient to
question the presumed GRAS status of the proteins (typically enzymes)
produced from the transferred genetic material, or of substances
produced by the action of the introduced enzymes (such as
carbohydrates, fats, and oils), when these proteins or other substances
do not differ significantly from other substances commonly found in
food and are already present at generally comparable or greater levels
in currently consumed foods. However, FDA recognizes that because
breeders utilizing rDNA technology can introduce genetic material from
a much wider range of sources than previously possible, there is a
greater likelihood that the modified food will contain substances that
are significantly different from, or are present in food at a
significantly higher level than, counterpart substances historically
consumed in food. In such circumstances, the new substances may not be
GRAS and may require regulation as food additives (57 FR 22990).
To date, FDA has not seen multiple examples of food additive
substances introduced into food using rDNA technology. However, the
agency recognizes that the potential for introducing such substances is
real. There are, for example, certain plant-derived proteins that have
a sweetening effect but whose biochemical function is not known.\7\ In
addition, they are found in plants that have not been used for food.
Thus, in contrast to other proteins introduced into foods by genetic
engineering, which have been presumed GRAS, there is little or no
apparent basis for a GRAS presumption for such substances. Genes
encoding the protein sweetener could be introduced into a fruit to
enhance sweetness. In such circumstances, FDA should be made aware of
the intended marketing of the modified food and have access to relevant
information to evaluate whether the protein sweetener is a food
additive within the act's definition under section 201(s) of the act.
If the protein sweetener is a food additive, premarket approval of the
substance would be required under section 409 of the act before the
altered food could be lawfully marketed.
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\7\ The proteins apparently do not make the plants more
attractive to insects or animals, and thus would not likely function
as natural sweeteners in plants in the wild.
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Another potential consequence of transferring genetic material from
one source into another is the possibility of introducing a food
allergen that would not be expected to be in a particular food, a
change that would be relevant to the legal status of such food. This is
because genes code for proteins, and virtually all allergens are
proteins (although only a small subset of proteins are allergens).
Thus, by increasing the range of potential proteins that can be
introduced into food over that possible by traditional breeding, there
is an increased potential for introducing an allergen into a food
developed using rDNA technology. Also, rDNA technology can be used to
express proteins at higher concentrations than they would otherwise be
expressed; these higher concentrations may increase the potential for
such proteins to be allergenic.
One implication of being able to transfer genes between unrelated
plants using rDNA techniques is that it is possible to transfer genes
from one food plant to another quite unrelated food plant, thereby
allowing the potential transfer of an allergen from the first plant to
the second. In such a case, food from the bioengineered plant could
have an allergenic characteristic completely different from that of its
conventional counterpart. Such a change would not be evident to the
consumer. For example, a gene from a Brazil nut plant was introduced
into a soy plant to improve the protein content of soy beans for use in
animal feed. The seed was never commercialized, however, because when
the company tested the
[[Page 4710]]
soy beans for allergenicity, they found that people allergic to Brazil
nuts were also allergic to the bioengineered soy (Refs. 9 and 10).
Given the potential consequences to sensitive consumers of eating soy
products containing a Brazil nut allergen, such a food would likely be
considered misbranded within the meaning of sections 201(n) and
403(a)(1) of the act, unless the presence of the new allergen were
disclosed to consumers.
Further, in certain circumstances, labeling may not be adequate or
practical to ensure that consumers are aware of the presence of
unexpected allergens. FDA would likely consider such food containing an
unexpected allergen to be adulterated within the meaning of section
402(a)(1) of the act because the unexpected allergen rendered the food
possibly injurious to health. With alterations of this type, FDA should
be made aware of the modification and have an opportunity to assess
whether and how the food could legally be marketed. Specifically, FDA
should have the opportunity to consider whether any labeling proposed
by the developer would ensure that the engineered food is not
misbranded within the meaning of sections 201(n) and 403(a)(1) of the
act, and whether, even with labeling, the food would be adulterated
because it may be injurious to health within the meaning of section
402(a)(1) of the act.
Compositional changes in foods created through breeding may also
present regulatory status issues. Although traditional breeding
techniques can be used to alter significantly the compositional
characteristics of food, rDNA technology enhances that ability because
rDNA technology enables breeders to make targeted changes in plant
components such as proteins and other constituents. For example, rDNA
techniques would facilitate a breeder's ability to modify a soy plant
so that the composition of oil derived from the plant would more
closely resemble that of a tropical oil than that of conventional soy
oil. In these circumstances, the name ``soy oil'' would likely not be
suitable for the oil derived from the altered soy plant because the
composition of the new oil is significantly different from what is
customarily understood to be ``soy oil''. Thus, a new common or usual
name would likely be required for this new oil to ensure that the oil
is not misbranded under section 403(i)(1) of the act. FDA should be
made aware of compositional changes of this type so that the agency may
consider whether a new common or usual name is required and, if so,
what that new name should be.
Additionally, rDNA technology has recently begun to be used to
introduce multiple genes to generate new metabolic pathways (Ref. 11).
New metabolic pathways are intended to result in the synthesis of
substances not normally present in the host plant. Such modifications
may alter the composition of the food in a significant manner that may
raise nutritional or safety issues or that would require use of a new
common or usual name.
In addition to enabling breeders to introduce desired new
characteristics into foods, all breeding methods used to develop new
plant varieties have a potential for unintentionally introducing
undesired new characteristics into foods (57 FR 22986). Broadly
speaking, a breeding method's potential for introducing unintended
changes to the characteristics of a food results either from bringing
into a food plant extraneous genetic material encoding trait(s)
additional to the desired trait(s), or from introducing mutations (such
as deletions, amplifications, insertions, rearrangements, or DNA base-
pair changes) into the plant's native genetic material that alter some
characteristic(s) of the food.
The most commonly used breeding method is a ``narrow cross,'' which
is hybridization between varieties of the same species. Hybridization
between related species or genera that cannot be cross-fertilized is a
``wide cross.'' Wide crosses are useful for expanding the range of
genetic source material that can be introduced into food crops, but are
performed relatively infrequently because of technical and logistical
difficulties. Both wide and narrow crosses will introduce into plants
extraneous genetic material along with the genetic material encoding
the desired traits. Breeders then attempt to remove any undesired
traits through extensive backcrossing.
Plant breeders also use mutagenic techniques to modify plants.
These techniques include random mutagenesis using a mutagenic agent and
somaclonal variation. (Somaclonal variation refers to the process of
growing a plant up from tissue culture and observing for phenotypic
changes, which are often due to chromosomal rearrangements or other
mutations.) Both techniques can introduce undesirable mutations along
with possible desirable mutations. As with hybridization, breeders
perform backcrosses to eliminate any undesirable traits. Cell fusion
poses similar issues to those posed by wide crosses (because it
generally is performed between cells of different species of plants)
and posed by somaclonal variation (because it involves growing a plant
up from tissue culture).
Recombinant DNA technology greatly reduces the likelihood of
introducing extraneous genetic material, as compared with
hybridization, because it enables breeders to introduce only the gene
or genes of interest, with little or no extraneous deoxyribonucleic
acid (DNA). However, it shares with mutagenesis techniques a potential
for introducing unintended effects through mutations. In part, this is
because rDNA technology involves growing plants from tissue culture,
which can exhibit somaclonal variation, and, more significantly,
because breeders using this technology generally cannot control the
location in the plant genome at which genetic material will insert when
introduced into a plant. Thus, with rDNA technology, the introduced
genetic segment may insert into a genetically active chromosomal
location. Such insertion may disrupt or inactivate an important gene or
a regulatory sequence that affects the expression of one or several
genes, thereby potentially affecting adversely the safety of the food
or raising other regulatory issues. Such an occurrence is referred to
as an insertional mutation.
FDA believes that in the future, plant breeders will increasingly
use rDNA techniques to achieve more complicated compositional changes
to food, sometimes introducing multiple genes residing on multiple
vectors to generate new metabolic pathways. FDA expects that with the
increased introduction of multiple genes, unintended effects may become
more common. For example, rice modified to express pro-vitamin A was
shown to exhibit increased concentrations of xanthophylls (Ref. 11),
and rice modified to reduce the concentration of a specific protein was
found to exhibit an increased concentration of prolamine (Ref. 12).
FDA believes that the use of rDNA techniques in plant breeding may
lead to unintended changes in foods that raise adulteration or
misbranding questions. These unintended changes may cause a food to be
adulterated because the food may be rendered injurious to health within
the meaning of section 402(a)(1) of the act, or, in the absence of a
new common or usual name, cause the food to be misbranded under section
403(i)(1) of the act. Because of its role in ensuring the safety of the
U.S. food supply, FDA needs to be aware of the modifications to food
source plants from the application of rDNA technology and any
unintended effects in food that result so that the agency can evaluate
whether the foods
[[Page 4711]]
from such plants are adulterated or misbranded.
Because some rDNA-induced unintended changes are specific to a
transformational event (e.g., those resulting from insertional
mutagenesis), FDA believes that it needs to be provided with
information about foods from all separate transformational events, even
when the agency has been provided with information about foods from
rDNA-modified plants with the same intended new trait and has had no
questions about such foods. Similarly, the agency believes that it
needs to be provided with information about foods from rDNA-modified
plants whose intended change is the introduction of a pesticidal
protein subject to oversight by the Environmental Protection Agency
(EPA) rather than by FDA, because the transformational event that is
used to introduce the pesticidal trait may also cause unintended
changes to the food that would raise adulteration or misbranding
questions subject to FDA jurisdiction.
In contrast, the agency does not believe that it needs to receive
information about foods from plants derived through narrow crosses
(including narrow crosses between different rDNA-modified lines).
Narrow crosses, because they generally are performed between varieties
that are themselves used in food or are very closely related to
varieties used in food, are unlikely to introduce extraneous DNA that
encodes traits that have not been in food before. In addition, plant
lines used for narrow crosses generally have been subject to extensive
backcrossing and field testing to ensure genetic stability (including
lack of any active transposons that could cause insertional
mutagenesis). Finally, because the plant lines are closely related to
each other, crosses between them will involve homologous recombination
and thus are unlikely to be subject to insertional mutagenesis.
Therefore, narrow crosses are unlikely to result in unintended changes
to foods that raise safety or other regulatory questions.
The agency recognizes that unintended changes associated with other
non-rDNA breeding methods may pose regulatory questions similar to
those posed by rDNA methods. For example, wide crosses, especially
between a food plant variety and an undomesticated nonfood plant
variety, have much greater potential than do narrow crosses for
introducing unintended traits that may alter the safety of the food;
undomesticated plants frequently produce toxins at levels unsafe for
human consumption, and may also produce substances not found in food.
The agency has not found it necessary to assess routinely the safety of
foods derived from such breeding methods, because over the last 50 to
60 years that some of these techniques have been used in plant
breeding, breeders have used well-established practices successfully to
identify and eliminate, prior to commercial use, plants that exhibit
unexpected adverse traits. The agency is not aware of a basis for
additional FDA oversight of foods derived from plants modified by such
techniques, given that there has not been such a need in the past and
that there do not appear to be any significant changes in breeders' use
of such techniques that would warrant new FDA oversight. Rather,
because of the technical advantages of rDNA methods over these other
techniques, FDA anticipates that, in the future, breeders will likely
use non-rDNA methods less frequently to introduce new characteristics
into food plants as they increasingly utilize rDNA techniques.
Likewise, despite the similar potential for unintended effects, FDA
believes that declining to propose a requirement that the agency be
notified about the commercialization of food source plants transformed
using techniques other than rDNA is consistent with its current
conclusion that, unexpected effects aside, rDNA techniques have a
greater potential, relative to conventional methods of breeding, to
result in the development of foods that present legal status questions.
The agency therefore is not proposing to include foods from crops
modified by methods other than rDNA techniques within the scope of this
proposed notification rule. The agency requests comment as to whether
it should include foods from crops developed by wide crosses or other
breeding methods in the scope of any final rule based upon this
proposal.
FDA recognizes that whether there is a change in the legal status
of a food resulting from a particular rDNA modification depends almost
entirely on the nature of the modification, and that not every
modification accomplished with rDNA techniques will alter the legal
status of the food. In other words, many modifications will result in a
food that does not contain an unapproved food additive, does not
contain an unexpected allergen, and does not differ significantly in
its composition compared with its traditional counterpart or otherwise
require special labeling. For this reason, FDA is neither proposing to
require premarket approval for all foods developed using rDNA
technology nor is the agency proposing an across-the-board requirement
that all such foods bear special labeling.
There is substantial basis to conclude, however, that there is
greater potential for breeders, using rDNA technology, to develop and
commercialize foods that are more likely to present legal status issues
and thus require greater FDA scrutiny than those developed using
traditional or other breeding techniques. It was in part for this
reason that, in 1994, the agency initiated a consultation process.
Since that time, developers have actively consulted with FDA regarding
their new plant varieties; under this process, the agency has completed
its evaluation of data and other information from some 45
consultations.
As noted, FDA believes that, to date, the developer of each rDNA
variety commercially marketed in the United States has consulted with
the agency prior to marketing food from the new variety. But these
products represent only a small fraction of the potential products of
rDNA technology.\8\ Additionally, in general, the introduced traits
have been agronomic in nature (i.e., directed at the characteristics of
the plant and not at the characteristics of the food produced by the
plant). However, this picture is rapidly changing. The current list,
which is provided by the Animal and Plant Health Inspection Service
(APHIS) in the U. S. Department of Agriculture (USDA), of field tests
of plants being developed using rDNA technology shows that the plants
under development have a broader variety of introduced traits (Ref.
13). Additionally, that list shows that many such traits are not simply
agronomic, but are intended to modify the food itself, and thus would
be more likely than in the past to raise regulatory issues falling
under FDA's purview.\9\ Finally, as noted previously, FDA believes
that, given the efficiencies of rDNA techniques, the advances in these
techniques, and the rapidly expanding information related to genomes,
these techniques are likely
[[Page 4712]]
to be utilized by plant breeders to an increasingly greater extent.
---------------------------------------------------------------------------
\8\ For example, in the 45 consultations completed under the
1992 policy, only 11 different commodities are represented,
including 12 consultations on corn, 7 on canola, 6 on tomatoes, 5 on
cotton, and 4 on potatoes. Moreover, the 45 consultations do not
represent 45 separate types of modifications; rather, these 45
consultations represent only 9 general types of modifications. These
modifications were herbicide resistance, insect and virus
resistance, delayed ripening or softening, male sterility or
fertility restorer, high phosphorus availability, and modified oil.
\9\ These include modifications for altered protein quality,
increased carotenoid content, increased fruit solids, altered fiber
quality, and increased fruit sweetness, among others.
---------------------------------------------------------------------------
The confluence of the increasingly broader use of rDNA techniques
to develop foods for human and animal use and the globalization of the
world's food supply also suggest that FDA needs to be aware of the
various foods developed using rDNA technology. Currently, approximately
45 percent of the United States' plant-derived food is imported, and
that percentage continues to increase. The agency expects that rDNA
techniques may, over time, be used increasingly by plant breeders and
developers in countries that export foods to this country. In such
circumstances, the accuracy of FDA's knowledge about the presence in
the U.S. food supply of foods developed using rDNA techniques is likely
to decrease. In addition, the awareness of particular food allergies is
not uniform throughout the world because the diets of some populations
do not contain sufficiently large amounts of a food such that the
allergic potential has been demonstrated; in these circumstances, it is
particularly important that FDA be aware of imported foods modified
using rDNA techniques that may unexpectedly contain a substance that is
an allergen.
For all these reasons, FDA believes that the food products of rDNA
technology are appropriately made subject to greater regulatory
scrutiny by FDA in the form of enhanced agency awareness of all such
foods intended for commercial distribution. This increased agency
awareness will ensure that at this stage of this continuously evolving
technology, all market entry decisions about new bioengineered foods,
including those intended for import into the United States, are made
consistently and in full compliance with the law. Similarly, in order
for the agency to evaluate fully and consistently the possible
regulatory consequences of the alterations made possible using rDNA
technology, FDA must be made aware of the bioengineered foods entering
commercial distribution.
Section 701(a) of the act (21 U.S.C. 371(a)) authorizes the
Secretary of the Department of Health and Human Services (the
Secretary) to issue regulations for the efficient enforcement of the
act; under section 903(d)(2) of the act (21 U.S.C. 393(d)(2), the
Secretary is responsible for executing the act, including section
701(a), through the Commissioner of Food and Drugs. The authority under
section 701(a) of the act to issue regulations under the act extends to
both regulations that supplement a specific statutory mandate as well
as regulations that are justified by the statutory scheme as a whole.
(See National Confectioner's Association v. Califano, 569 F.2d 690, 693
(D.C. Cir. 1978), citing Toilet Goods Association v. Gardner, 387 U.S.
158, 163 (1967).) In assessing a regulation issued under section
701(a), it is important to consider both the statutory purpose as well
as the practical aspects of the situation, including the possible
enforcement problems that may be encountered by FDA. (See National
Confectioner's Association v. Califano, 569 F.2d 690, 693 (D.C. Cir.
1978), citing Toilet Goods Association v. Gardner, 387 U.S. 158, 163
(1967).)
To ensure that FDA has the maximum amount of information about
foods from bioengineered plants, the agency has tentatively concluded
that, prior to initiation of commercial distribution in the United
States of a bioengineered food, FDA must be notified of the intent to
market such food, including foods intended for import into the United
States. Notification will ensure that the agency is aware of all
bioengineered foods entering commercial distribution that are subject
to FDA's jurisdiction and will help to ensure that all market entry
decisions by the industry are made consistently and in full compliance
with the law. This will permit the agency to assess on an ongoing basis
whether foods developed using rDNA technology comply with the standards
of the act. FDA believes that it is essential that all those developing
and marketing bioengineered foods participate fully and completely in
the proposed notification program. Therefore, the agency is proposing
that the notification program that is described in this document be
mandatory.
Accordingly, for the reasons set forth above concerning the special
circumstances of bioengineered foods, to enforce the act efficiently,
and in particular, to administer efficiently the act's various
provisions that relate to food as such provisions apply to
bioengineered food, including section 301 of the act (21 U.S.C. 331)
and sections 402, 403, and 409 of the act, FDA is proposing regulations
to require that the agency be notified at least 120 days prior to the
initiation of commercial distribution in the United States of a
bioengineered food. The elements of FDA's proposed program are
discussed in detail below.
III. Scope
FDA is proposing to require the submission to the agency of data
and information regarding plant-derived bioengineered foods that would
be consumed by humans or animals. FDA's proposal also includes a
recommendation that prospective notifiers participate in a
presubmission consultation program. The regulations regarding
bioengineered foods that would be consumed by humans would be codified
in new part 192. The regulations regarding bioengineered foods that
would be consumed by animals would be codified in new part 592. The
proposed regulations regarding bioengineered foods that would be
consumed by animals parallel the proposed regulations regarding
bioengineered foods that would be consumed by humans. For ease of
discussion, in this proposed rule, FDA describes each of the
regulations that would be codified in part 192, without describing the
parallel regulations in part 592. Following this discussion, FDA
describes areas of importance in the proposed animal feed regulations
(section XI of this document).
IV. Definitions
FDA is proposing to codify five definitions that are associated
with the proposed notification program (proposed Sec. 192.1). These
terms are bioengineered food, commercial distribution, notifier,
premarket biotechnology notice (PBN or notice), and transformation
event. FDA invites comments on these proposed definitions. FDA is
particularly interested in comments on the proposed definitions of
bioengineered food and transformation event. Specifically, FDA is
requesting comment on whether these proposed definitions are consistent
with the agency's intent (described in section V of this document) that
the proposed notification program apply to a particular subset of
plant-derived foods. Such comments may result in a modification to the
proposed definitions.
Under the proposed definitions, a required PBN may be submitted by
any person who is responsible for the development, distribution,
importation, or sale of a bioengineered food. Based on the agency's
experience, FDA expects that it ordinarily will be the seed developers
and purveyors who notify the agency about a bioengineered food.
V. Requirement for Premarket Biotechnology Notice
FDA is proposing to require a submission to the agency of data and
information regarding a plant-derived bioengineered food at least 120
days prior to the commercial distribution of the food (proposed
Sec. 192.5). The proposed regulation would include a bioengineered food
derived from a new
[[Page 4713]]
plant variety modified to contain a pesticidal substance, and would
exclude a bioengineered food that meets three specified criteria. The
rationale for this proposed notification requirement is discussed in
section II of this document. FDA specifically requests comment on the
scope of the proposed notification requirement and on the proposed
conditions for exclusion from the notification requirement. Such
comments may result in a modification to the proposed regulation.
A. Foods That Are Subject to the Requirement
FDA is proposing that the notification requirement apply to a
bioengineered food derived from a new plant variety modified to contain
a pesticidal substance (proposed Sec. 192.2(a)). Under the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136 et
seq.), EPA has authority to regulate all pesticides, regardless of how
they are made or their mode of action. Under the act, EPA has authority
to regulate pesticide residues in foods and FDA has authority to
regulate a nonpesticidal substance that may be introduced into a new
variety and that is expected to become a component of food. Given this
statutory framework, both FDA and EPA agree that any food safety
questions beyond those associated with the pesticide, such as those
raised by unexpected or unintended compositional changes, are under
FDA's jurisdiction (57 FR 22984 at 23005). FDA's proposal to include in
its notification program new plant varieties that contain a pesticidal
substance will facilitate consultation between EPA and FDA on the
scientific and regulatory issues that are not within the scope of EPA's
authority under FIFRA and the act.
FDA is proposing to exclude from the notification requirement a
bioengineered food that satisfies three conditions. The first condition
is that the food derives from a plant line that represents a
transformation event that has been addressed in a notice previously
submitted to FDA (proposed Sec. 192.5(a)(1)). Under Sec. 192.5(a)(1), a
separate notice would be required for distinct plant lines that are
derived from separate transformed cells, even when those cells were
transformed during a single transformation procedure. The second
condition is that the use or application of the bioengineered food has
been addressed in a notice previously submitted to FDA (proposed
Sec. 192.5(a)(2)). Under Sec. 192.5(a)(2), a separate notice would be
required, for example, if herbicide tolerance introduced into a variety
of sweet corn that is used solely for human food is subsequently
transferred, using traditional plant-breeding techniques, to a variety
of field corn that would also be used in food intended for consumption
by animals. The third condition is that a letter from FDA demonstrates
that FDA has evaluated the use or application of the bioengineered food
and has no questions about it (proposed Sec. 192.5(a)(3)). Under
Sec. 192.5(a)(3), a notice would be required if, for example, a prior
notice about another use of a bioengineered food is still pending or if
the agency's response to a prior notice demonstrates that FDA did not
consider the prior notice as providing a basis to conclude that the
bioengineered food was in compliance with all applicable requirements
of the act.
As mentioned, FDA believes that all developers of bioengineered
foods that already are commercially marketed in the United States have
consulted with the agency prior to marketing the food. FDA believes
that any legal status questions that pertain to the applicable
bioengineered foods have been identified and resolved through that
consultation process. Therefore, the notification requirement would not
extend to bioengineered food obtained from a plant line (or series of
plant lines) that derives from a particular transformation event, as
long as both the applicable transformation and the use or application
of the bioengineered food has been addressed satisfactorily in a
completed consultation under the voluntary program.
It is likely that some final consultations received under the 1996
procedures would still be pending on the date of a final rule based on
this proposal. The proposed regulations include no specific provisions
regarding a bioengineered food that is the subject of a pending final
consultation under the 1996 procedures. FDA specifically requests
comment on how FDA should administer such submissions. FDA also
specifically requests comment on whether the process for administering
a final consultation that is pending on the date of a final rule based
on this proposal should be included in these regulations. Such comments
may result in a modification to the proposed regulation.
FDA specifically requests comment on the scope of proposed
notification requirement and on the proposed conditions for exclusion
from the notification requirement. Such comments may result in a
modification to the proposed regulation.
B. Origin of Data and Information
FDA is proposing that the data or information that a notifier
submits to FDA regarding a bioengineered food must be generated from a
plant line whose derivation can be traced to the transformation event
that is the subject of the notice and that contains the genetic
material introduced via the transformation event (proposed
Sec. 192.5(b)). As a practical matter, the proposed regulation will
give flexibility to producers while providing the agency with relevant
information concerning the nature of the bioengineered foods. FDA
specifically requests comment on this proposed provision. Such comments
may result in a modification to the proposed regulation.
C. Timing
FDA is proposing to require that a notifier submit a PBN at least
120 days before the bioengineered food is marketed (proposed
Sec. 192.5(c)). The proposed timeframe is consistent with contemporary
expectations of the Congress for another notification program, the
notification program for food contact substances (section 409(h) of the
act).
FDA believes that it can, in most circumstances, complete its
evaluation of a PBN within 120 days because, as discussed more fully
below, FDA is recommending that prospective notifiers participate in a
presubmission consultation program. The purpose of the presubmission
consultation program is to enable a prospective notifier to identify
and address relevant safety, nutritional, or other regulatory issues
regarding the bioengineered food before submitting a PBN. Given this
presubmission consultation program, FDA expects that a notifier will
have sufficient information to prepare a notice that adequately
addresses all issues and that scientific experts at the agency will be
familiar with the issues raised by a particular bioengineered food when
the agency receives the applicable PBN.\10\
---------------------------------------------------------------------------
\10\ The consultation procedures do not identify a timeframe for
FDA to complete its evaluation of a final consultation. As of April
2000, under that program the median time for FDA's response to a
final consultation was approximately 155 days and the average time
was approximately 175 days.
---------------------------------------------------------------------------
VI. Recommendation for Presubmission Consultation
FDA is proposing to include in the regulation a recommendation that
a prospective notifier consult with the agency, before submitting a
PBN, to identify and discuss relevant safety, nutritional, or other
regulatory issues regarding the bioengineered food
[[Page 4714]]
(proposed Sec. 192.10). The proposed recommendation describes
procedures for requesting consultation and the public disclosure
provisions that likely would apply to records that FDA maintains about
the consultation. Under Sec. 192.10(f), a notifier must state his view
as to whether the fact that he is consulting with FDA, or any or all of
the data or information that he submits to FDA, is exempt from
disclosure under the Freedom of Information Act (FOIA) and must explain
the basis for any such exemption claim. The recommendation to consult
with FDA derives from the 1992 policy, the 1996 procedures, and FDA's
experience under the 1996 procedures. FDA discusses the details of this
proposed recommendation immediately below.
Using rDNA technology, bioengineered plants such as corn are now
being developed for non-food uses. Examples of such applications
include the transfer of genes that encode pharmaceutical proteins, oral
vaccines, and enzymes that would be used for non-food industrial
applications. In some cases, such as most of the pharmaceutical
proteins, the final product would be a highly purified component of the
plant commodity. In other cases, such as some oral vaccines, the final
product would be a minimally processed plant commodity. In some cases,
there may be a potential for a bioengineered plant commodity that is
not intended for use in food to enter the food supply inadvertently.
FDA encourages developers of bioengineered plants that are not intended
for use in food or feed, but that theoretically could enter the food or
feed supply, to participate in the consultation program described in
this proposed rule. This participation would ensure that developers
have given careful consideration to the procedures needed to ensure
that their products do not inappropriately get into the food supply,
and are aware of the legal implications if their products do.
A. Presubmission Consultation Program
FDA is proposing to recommend that a prospective notifier
participate in a presubmission consultation program (proposed
Sec. 192.10(a)). Under the program (proposed Sec. 192.10(b)), a
prospective notifier would write to FDA and ask to consult about a
bioengineered food. FDA would establish an administrative file for each
consultation and would meet with a prospective notifier upon request.
Although FDA may provide written feedback during the consultation, that
feedback would not release the prospective notifier from the proposed
requirement to notify FDA about the bioengineered food at least 120
days before commercialization of the food. The proposed presubmission
consultation program derives from the 1992 policy, the 1996 procedures,
and FDA's experience under the 1996 procedures.
B. Public Disclosure
FDA is proposing to provide information about the availability for
public disclosure of: (1) The fact that a developer is consulting with
FDA (proposed Sec. 192.10(c)) and (2) the data or information in the
file that FDA would establish for a presubmission consultation
(proposed Sec. 192.10(d)). The regulations would inform all parties of
the fact that FDA must act in response to a request under FOIA for
information on presubmission consultations, and must disclose, or
protect from disclosure, the applicable record(s) in accordance with
Sec. 20.61 (21 CFR 20.61) (proposed Sec. 192.10(c)(2) and (d)(1)).
In light of the significant public interest in bioengineered foods
and in FDA's oversight of these foods, FDA believes that it is
important for developers to be informed that FOIA may entitle the
public to know that the developer has provided data or information to
FDA about a bioengineered food and to receive a copy of those data or
information. Likewise, FDA believes that it is equally important for
the public to know that the fact that a developer is consulting with
FDA may be exempt from disclosure under FOIA and that some or all of
the data or information that are submitted to FDA during a
presubmission consultation could be exempt from public disclosure.
Under FOIA, data or information that are submitted to the Federal
Government are available for public disclosure unless those data or
information fall within an established exemption of FOIA. The exemption
that is most relevant to data or information provided to FDA during a
presubmission consultation is ``exemption 4,'' which applies to ``trade
secrets and commercial or financial information obtained from a person
and privileged or confidential.'' (5 U.S.C. 552(b)(4)). FDA has issued
regulations implementing exemption 4 of FOIA in Sec. 20.61.
FDA believes that, in most cases, the fact that a developer is
consulting with FDA would not constitute confidential commercial
information. For example, most plants developed using rDNA technology
are considered ``regulated articles'' under regulations of USDA's APHIS
(7 CFR part 340), which regulates the introduction of certain
``genetically engineered'' plants. At some stage of research and
development of a regulated article, a developer requests from APHIS a
determination of the article's regulatory status, and, consistent with
FOIA requirements, APHIS discloses that request. Thus, by virtue of the
APHIS process, the fact that the developer is developing the plant and
its food product would usually already be disclosed.
FDA also believes that, in most cases, most of the data or
information provided to FDA during a presubmission consultation would
not constitute a trade secret or confidential commercial information.
For example, only a handful of the submissions that FDA has received
under its current consultation program identified specific data or
information that the developer claimed to be exempt under Sec. 20.61.
Neverthelesss, there could be circumstances where a developer initiates
a presubmission consultation about a product that has not previously
been disclosed to the public and has grounds to claim that the fact of
the consultation should not be available for public disclosure. In such
circumstances, disclosing any data or information in the applicable
submission would reveal the existence of the submission. Thus, as long
as the existence of the consultation is exempt from disclosure, all
data or information in the submission would necessarily be exempt from
disclosure.
C. Standard Procedures
FDA is proposing that a prospective notifier ask FDA in writing for
an opportunity to consult about a bioengineered food (proposed
Sec. 192.10(e)). A written request would provide clarity about the
subject of the consultation.
FDA is proposing to require that a prospective notifier who
initiates a consultation inform FDA whether, in his view, the fact of
the consultation with FDA is confidential, and whether, in his view,
any or all of the provided data or information is confidential
(proposed Sec. 192.10(f)(1)). FDA also is proposing to require that a
prospective notifier who claims confidentiality for the existence or
content of a presubmission consultation explain the basis for that
claim (proposed Sec. 192.10(f)(2)). FDA is proposing these requirements
because of the significant public interest in bioengineered foods.
These requirements would ensure that FDA is aware of the prospective
notifier's position regarding the availability for public disclosure of
the existence and content of the
[[Page 4715]]
consultation. In addition, FDA believes that these requirements would
alert a prospective notifier to the fact that the data or information
contained in a submission to FDA are available for disclosure unless
the applicable criteria for exemption are satisfied.
FDA is proposing to recommend that a prospective notifier send FDA
a synopsis about the requested consultation (proposed
Sec. 192.10(f)(3)). The recommended synopsis would include the
prospective notifier's name and address, the name of the bioengineered
food and the plant species from which it is derived, a distinctive
designation(s) that the notifier uses to identify the applicable
transformation events, a list of the identity(ies) and source(s) of
introduced genetic material, a description of the purpose or intended
technical effect of the transformation event (including expected
significant changes in the composition or characteristic properties of
food derived from the plant as a result of the transformation event,
regardless of whether these changes result from the insertion of new
genes or from a modification in the expression of endogenous genes), a
description of the applications or uses of the bioengineered food, and
a description of any applications or uses of the bioengineered food
that are not suitable for the bioengineered food. FDA is proposing to
recommend this synopsis because the agency believes that the
information in the synopsis is both necessary and sufficient to
characterize the bioengineered food in a manner that will enable the
agency to engage in a meaningful dialogue with the prospective
notifier. For example, information about the identity and intended
technical effect of the transformation event would enable the agency to
address the potential issue that the food would contain an unapproved
food additive. A distinctive designation that the notifier uses to
identify the applicable transformation event would enable the agency to
efficiently locate other agency records regarding that transformation
event. It would also facilitate discussions with APHIS and EPA, if
sponsors use those same designations in information supplied to the
other agencies. Information about the sources of the genetic material
would enable the agency to identify issues associated with a known
allergenic source. Information about expected significant changes in
the composition of the food would enable the agency to discuss
suggestions for an appropriate common or usual name for the
bioengineered food. Information about the applications or uses of the
food would enable the agency to identify applicable regulatory
situations (e.g., whether the bioengineered food would likely be used
in human food, animal feed, or both). Information about any
applications or uses that the notifier believes would not be suitable
for the bioengineered food would enable the agency to identify
potential safety questions, if any, about such use of the bioengineered
food.
FDA is proposing that a prospective notifier send a request for
consultation regarding a bioengineered food to CFSAN (proposed
Sec. 192.10(g)). As necessary and appropriate, CFSAN would coordinate
the consultation process with CVM. The proposed regulation is
consistent with the approach in the 1996 procedures, which has worked
well.
FDA is proposing that a prospective notifier should send an
original and two paper copies of a written request for consultation and
of any additional materials that are sent to FDA during the
consultation process (proposed Sec. 192.10(h)(1) and (h)(2)). FDA is
proposing an original and two copies of these submissions for
efficiency in providing information about the presubmission
consultation to the agency's scientific reviewers.
Because it is likely the data or information in a presubmission
consultation would be requested under FOIA by an outside party, FDA is
proposing that a prospective notifier who claims that certain data or
information provided to FDA during the presubmission consultation are
exempt from disclosure should clearly identify, in each submission, the
data or information at issue (proposed Sec. 192.10(h)(3)(i)). When this
is the case, FDA also is proposing that the prospective notifier should
provide an additional paper copy of the submission that does not
contain such data or information (i.e., a redacted paper copy under
proposed Sec. 192.10(h)(3)(ii)). Providing a redacted copy would
communicate very clearly which data or information the prospective
notifier considers to be exempt. These recommendations are consistent
with a practice that is commonly used by firms who send FDA a food
additive petition that contains information that the petitioner claims
to be confidential, a practice that has worked well. In addition, the
practice of providing a redacted copy also has been used in a few cases
under the 1996 procedures.
FDA is proposing that the redacted paper copy be prepared in a
manner that clearly identifies the location and relative size of
deleted information. This proposed regulation is consistent with FDA's
proposed regulations (64 FR 60143, November 4, 1999) regarding
implementation of the Electronic Freedom of Information Act Amendments
of 1996 (EFOIA (Public Law 104-231)). EFOIA includes, among other
things, provisions requiring agencies to inform requesters about the
amount of information not being released to them.
FDA is proposing to specify the materials that the agency would
place in an administrative file that it establishes for a presubmission
consultation (proposed Sec. 192.10(i)(1)). These materials include any
correspondence between the prospective notifier and FDA, any written
materials that the prospective notifier provides during the
consultation process, and a memorandum of each meeting or significant
phone call between FDA and the prospective notifier during the
consultation. This part of the regulation would inform both prospective
notifiers and outside parties of the materials that ordinarily would be
in the administrative file of the consultation and thus potentially be
subject to disclosure under FOIA.
FDA's proposal includes its commitment to discuss issues associated
with a bioengineered food with any prospective notifier who asks to do
so (proposed Sec. 192.10(i)(2)). FDA is proposing to include this
commitment to both remind and encourage prospective notifiers that the
purpose of the recommended program is for a prospective notifier to
engage FDA in a discussion about the bioengineered food at an early
stage of the food's development. However, the agency realizes that
there may be circumstances where such a discussion would not be an
efficient use of resources for either the prospective notifier or for
FDA. For example, a prospective notifier may intend to notify FDA about
bioengineered foods that derive from a series of plant lines that are
the result of independent transformation events with the same genetic
construct. After FDA has completed its evaluation of one of these
bioengineered foods, the notifier likely would be aware of most or all
of the applicable safety, nutritional, or other regulatory issues that
could be associated with the food. Nevertheless, FDA would welcome the
opportunity to be informed about the notifier's plans to submit
additional notices because this information could help the agency to
plan its workload.
The proposed regulation describes a flexible process for any
discussion (e.g., by mentioning that the discussion could
[[Page 4716]]
take place through a meeting or through a telephone conference). FDA is
highlighting the opportunity to discuss the bioengineered food by a
mechanism other than a face-to-face meeting to minimize the potential
that a small business or academic research group would elect not to
participate in the program due to the cost of travel. Given the
agency's experience under the current consultation process, FDA is
confident that a meaningful dialogue can often be accomplished without
a face-to-face meeting.
VII. Premarket Biotechnology Notice: Administrative Information
FDA is proposing to codify certain administrative information that
would apply to a PBN (proposed Sec. 192.20). The proposed
administrative information includes information about where to send a
PBN, the number of copies to send, how to include information in a
foreign language, how to refer to data or information that are already
in FDA's files, how to obtain guidance on scientific issues, and the
prerogative of a notifier to withdraw a PBN from FDA's consideration.
Many of these administrative aspects of the proposed notification
program are consistent with procedures already in place for the food
additive petition program (Sec. 171.1 (21 CFR 171.1)). FDA discusses
the details of these administrative aspects of the proposed
notification program immediately below.
A. Submissions to CFSAN for Use in Human Food, Animal Feed, or Both
FDA is proposing that a notifier send a PBN regarding a
bioengineered food to CFSAN (proposed Sec. 192.20(a)). As necessary and
appropriate, CFSAN would coordinate FDA's evaluation of the PBN with
CVM. The proposed regulation is consistent with the approach that FDA
recommended in the 1996 procedures, an approach that has worked well.
B. Paper Copies
FDA is proposing that a prospective notifier send to the agency an
original paper version and one paper copy of a PBN (including any
amendments) (proposed Sec. 192.20(b)(1)). A notifier would have an
option to submit one additional paper copy or, under proposed
192.20(c)(1), to submit an electronic copy that is formatted in a
manner that makes it suitable for FDA to use while evaluating the PBN.
The number of paper copies required by the regulation is consistent
with the number of paper copies that FDA currently requires for other
premarket submissions, such as a food additive petition. A requirement
for multiple paper copies generally serves the purpose of providing a
copy of the submission to multiple scientific reviewers. However, as
discussed below, FDA also is recommending that a notifier submit an
electronic copy of a PBN that is formatted in a manner that makes it
suitable for FDA to use in evaluating a PBN. Because scientific
reviewers could accomplish their review by accessing the electronic
copy, under the proposed rule, a notifier who submits an electronic
evaluation copy would submit one less paper copy. FDA would retain the
original paper version at CFSAN, while the paper copy would be retained
at CVM. Comments may result in a modification to the proposed
requirement to submit a single paper copy.
Under the regulation, the paper copy would be the official version
at FDA. This provision would clarify the status of an electronic copy
that FDA also is proposing to require \11\ (see proposed
Sec. 192.20(c)(1) and section VII.C of this document).
---------------------------------------------------------------------------
\11\ Under 21 CFR 11.1(c), an electronic record that meets the
requirements of 21 CFR part 11 may be used in lieu of a paper
record, unless paper records are specifically required. However,
CFSAN is not prepared, at this time, to accept an electronic record
as the official record because CFSAN does not yet have specific
guidance for the submission of records only in electronic form.
---------------------------------------------------------------------------
FDA is proposing that a notifier who claims that specific data or
information in the PBN are confidential must prepare and submit one
paper copy of the PBN that does not contain any of those data or
information (proposed Sec. 192.20(b)(2)). Consistent with the EFOIA
proposed rule, the notifier would prepare this redacted paper copy in a
manner that clearly identifies the location and relative size of
deleted information. As discussed previously regarding a presubmission
consultation (see section VI.C of this document), the redacted copy
would be very useful as it would communicate very clearly which data or
information the notifier considers to be exempt from disclosure.
C. Electronic Copies
FDA is proposing to include in the regulation a recommendation that
a notifier submit an electronic copy (the evaluation copy) that is
formatted in a manner that makes it suitable for FDA to use while
evaluating the PBN (proposed Sec. 192.20(c)(1)). Because technology is
advancing at a rapid pace, the regulation would inform notifiers how to
obtain information about the appropriate format of the electronic copy
rather than specify that format. Under the regulation, a notifier would
provide such an electronic copy of both the original PBN and of any
amendments to the PBN. FDA is recommending the submission of an
electronic evaluation copy to take advantage of the fact that
contemporary technology makes it possible for notifiers to send, and
FDA to evaluate, submissions of data or information in electronic form,
and the availability of an electronic evaluation copy has the potential
to improve the efficiency of FDA's review. To encourage manufacturers
to submit an electronic evaluation copy, a notifier who submits such a
copy would submit a total of two, rather than three, paper copies.
FDA also is proposing to require that a notifier submit an
electronic copy (the disclosure copy) that is formatted in a manner
that makes it suitable for FDA to use to make a PBN available to the
public in an electronic reading room (proposed Sec. 192.20(c)(2)). As
would be the case with the electronic evaluation copy, the regulation
would inform notifiers how to obtain information about the appropriate
format of the electronic copy and a notifier would be required to
provide such an electronic copy of both the original PBN and of any
amendments to the PBN. Consistent with the EFOIA proposed rule, a
notifier would delete data or other information claimed to be
confidential from the electronic copy in a manner that clearly
identifies the location and relative size of deleted information. FDA
is proposing to require an electronic disclosure copy to facilitate the
agency's compliance with EFOIA, which includes provisions regarding the
availability of records in electronic form and the establishment of
``electronic reading rooms.'' As discussed in the EFOIA proposed rule,
section 4 of EFOIA (5 U.S.C. 552(a)(2)(D)) adds a new category of
records that agencies must make available in their public reading
rooms. This new category consists of copies of records that have been
released to any person under FOIA and that, because of their subject
matter, the agency determines have become or are likely to become the
subject of subsequent requests for substantially the same records. In
light of the significant public interest in bioengineered foods and in
FDA's oversight of these foods, FDA has tentatively concluded that it
is likely that each submitted PBN would be requested under FOIA
multiple times.
The preparation of an electronic copy formatted in a manner that
makes it suitable for FDA to use to make a PBN available to the public
in an electronic reading room will require use of computer technology.
Although the use
[[Page 4717]]
of this technology is widespread, it is possible that a firm that
develops a bioengineered food would not have access to the particular
technology that will be needed. For this reason, under the proposed
regulation a notifier may request a waiver from the requirement to
submit an electronic disclosure copy. FDA would grant or deny the
notifier's request on its merits.
FDA requests comments on its proposal to require an electronic
disclosure copy of a PBN and to provide a notifier with an opportunity
to request a waiver from this requirement. Such comments may result in
a modification to the proposed requirement to submit such a copy.
D. English Language Translations, Incorporation by Reference, and
Available Guidance Documents
FDA is proposing that a notifier who submits any material in a
foreign language provide an English translation that is verified to be
complete and accurate (proposed Sec. 192.20(d)). This proposed
regulation is necessary for the agency's efficient evaluation of a PBN
and is consistent with other agency regulations regarding the
submission of information in a foreign language (see e.g.,
Sec. 171.1(a) and the agency's recent proposal for a premarket
notification program for food contact substances (65 FR 43269, July 3,
2000)).
FDA is proposing that a notifier may incorporate by reference data
or information that are already retained in FDA's files (proposed
Sec. 192.20(e)). The proposed regulation specifies that a notifier may
simply incorporate by reference a file that the notifier previously
submitted. If the notifier wishes to incorporate by reference a file
that someone else previously submitted to FDA, the procedure to
incorporate that file into the PBN depends on whether the file is
publicly available (e.g., the file is in an electronic reading room or
is otherwise available under FOIA). If the file is publicly available,
a notifier may incorporate that file by referring FDA to it. If the
file is not publicly available, a notifier may incorporate that file by
referring FDA to it if the person who submitted the file authorizes the
notifier to do so in a signed statement and the notifier includes that
signed statement in the PBN. This proposed provision is similar to that
described for incorporating previously submitted information into a
food additive petition (Sec. 171.1(b)) and to that described in the
agency's recent proposal for a premarket notification program for food-
contact substances (65 FR 43269, July 13, 2000).
FDA is proposing to inform notifiers that they can obtain current
guidance regarding specific technical issues by writing to FDA or by
looking on FDA's site on the Internet (proposed Sec. 192.20(f)). FDA is
adding this provision to assist notifiers in addressing common
technical issues, such as the estimation of dietary exposure to
substances that are present in food. FDA expects that this provision
will minimize the time spent, by the agency and the notifier, on
routine technical issues.
E. Opportunity to Withdraw
FDA is proposing to codify a provision that a notifier may request,
at any time during FDA's evaluation of a PBN, that FDA cease to
evaluate that PBN (proposed Sec. 192.30(g)). Under the regulation, the
notifier could submit a future PBN about the same bioengineered food.
FDA would retain the PBN in its files and would classify it as
``withdrawn.'' A notifier could choose to withdraw a notice for several
reasons. For example, it is possible that discussions between the
notifier and FDA would result in a decision by the notifier to
substantially revise the notice to provide data or information that
address the applicable legal status questions in a more thorough manner
than the submitted PBN.
The proposed regulation is consistent with the provisions of the
food additive premarket review program (Sec. 171.7). Although a
notifier does not need explicit authorization to withdraw a notice, a
notifier may not be aware of this fact. Likewise, a notifier may not be
aware that a notice that is ``withdrawn'' remains an agency record that
could be requested under FOIA. Thus, the regulation would both clarify
a prerogative accorded to a notifier and inform the notifier of
consequences associated with that prerogative.
VIII. Premarket Biotechnology Notice: Required Parts
FDA is proposing that a PBN be separated into seven parts (proposed
Sec. 192.25). These would include a letter (proposed Sec. 192.25(a)); a
synopsis (proposed Sec. 192.25(b)); administrative statements about the
status of review of the bioengineered food by other Federal agencies or
by foreign governments (proposed Sec. 192.25(c)); data or information
about the method of development (proposed Sec. 192.25(d)); a discussion
of any newly inserted genes that encode resistance to an antibiotic
(proposed Sec. 192.25(e)); data or information about substances
introduced into, or modified in, the food (proposed Sec. 192.25(f));
and data or information about the food (proposed Sec. 192.25(g)). The
proposed regulation fosters a case-by-case approach to addressing
relevant scientific and regulatory issues rather than a single set of
tests that likely would not be applicable in all circumstances. In
general, the proposed requirements derive from the 1992 policy, the
1996 procedures, and FDA's experience under the 1996 procedures. In
proposing these requirements, FDA also has drawn on its experience in
administering a proposed notification program for GRAS substances (62
FR 18938, April 17, 1997).\12\
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\12\ FDA has not yet issued a final rule based on the GRAS
proposal. However, in the GRAS proposal, FDA invited interested
persons who determine that a use of a substance is GRAS to notify
FDA of such GRAS determinations during the interim between the
proposed and final rules (the interim period). During this interim
period, FDA has received several dozen GRAS notices, which provided
practical experience both with theoretical issues raised by that
rulemaking and with practical issues associated with establishing an
efficient program.
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The proposed regulation reflects FDA's current judgment based on
contemporary scientific methods for development of bioengineered foods
and the types of bioengineered foods that are now under development.
Accordingly, the proposed regulation focuses on modifications to foods
that are likely to result in commercial products and does not attempt
to predict future changes in foods that may result from technological
advances. In this field of rapid scientific development, if
circumstances warrant, FDA would propose to revise any regulation that
results from this proposal. FDA requests comment on technological
advances in rDNA technology that are likely to result in commercial
products and that would not be addressed by the proposed submission
requirements. Such comments may result in a modification to the
proposed submission requirements.
A. Part I: Letter
FDA is proposing to require that a responsible official of the
notifier's organization, or the notifier's attorney or agent, date and
sign a letter that informs FDA that the notifier is submitting a PBN
under proposed Sec. 192.25. In the letter, this official, attorney, or
agent would state his position or title and attest to five statements.
1. Statements Regarding the Notifier's Responsibility and the Balanced
Nature of the Notice
FDA is proposing to require that a notifier inform FDA that it is
the
[[Page 4718]]
notifier's view that the bioengineered food is as safe as comparable
food and that the intended use of the bioengineered food is in
compliance with all applicable requirements of the act (proposed
Sec. 192.25(a)(1)). Applicable requirements of the act would include,
for example, the requirement under section 409(a) and 402(a)(2)(C) of
the act for FDA review and approval of a food additive and the
requirement under section 201(n) and 403 of the act that labeling for
the food be appropriate. FDA also is proposing that a notifier state
that to the best of the notifier's knowledge, the PBN is a
representative and balanced submission that includes information,
unfavorable as well as favorable, pertinent to the evaluation of the
safety, nutritional, or other regulatory issues that may be associated
with the bioengineered food (proposed Sec. 192.25(a)(2)). FDA is
proposing that the notifier attest to these statements because, under
the act, developers of new foods have a responsibility to ensure that
the foods they offer to consumers are safe and in compliance with all
requirements of the act (57 FR 22984 at 22985).
FDA is proposing the standard ``as safe as'' because this is the
standard that the agency currently uses to evaluate a notice that is
submitted under the 1996 procedures. Because the proposed standard is a
comparative standard (``as safe as''), it takes into account
circumstances such as the existence of naturally occurring toxicants in
many plants (e.g., solanine that occurs naturally in potatoes). As
discussed below (see section VIII.G.1 and proposed Sec. 192.25(g)(1)),
FDA also is proposing that the notifier provide a justification for
selecting a particular food or foods as the ``comparable food'' to
which the notifier will compare the bioengineered food.
2. Statements Regarding the Availability of Data and Information for
FDA's Review
FDA is proposing to require that a notifier agree to make relevant
data or information that are not included in the PBN available to FDA
upon request while FDA is evaluating the PBN or for cause (proposed
Sec. 192.25(a)(3)). FDA is proposing this requirement to ensure that
the agency will have access to relevant data or other information if
safety questions arise after the bioengineered food enters commercial
distribution. This proposed requirement will also continue a practice
that began under the 1996 procedures.
FDA also is proposing that a notifier agree to two procedures for
making such data or information available to FDA (proposed
Sec. 192.25(a)(4)). The first procedure is to allow FDA to review and
copy these data or information at a specified address during customary
business hours. The second procedure is to send these data or
information to FDA. FDA is proposing that a notifier agree to both of
these two procedures to provide flexibility and efficiency to both the
notifier and the agency.
3. Statement Regarding Public Disclosure
FDA is proposing that a notifier inform FDA as to whether the
notifier claims that the existence of a PBN, or any or all of the data
or information in the PBN, is exempt from disclosure under the FOIA and
explain the basis for that claim (proposed Sec. 192.25(a)(5)). FDA is
proposing these requirements in light of the significant public
interest in bioengineered foods. These requirements would ensure that
FDA is aware of the notifier's position regarding the availability for
public disclosure of the existence and content of a PBN. In addition,
FDA believes that these requirements would alert a notifier that the
data or information contained in a PBN are available for disclosure
unless the applicable criteria for exemption are satisfied.
As discussed more fully below, this proposed rule assumes that the
existence and content of a PBN is available for public disclosure
unless the notifier establishes that the existence of the notice
constitutes confidential commercial information or that specific data
or information in the PBN constitute a trade secret or confidential
commercial information. Thus, the proposed rule acknowledges that there
could be circumstances in which the existence or content (or a portion
of the content) of a PBN would be eligible for an exemption from public
disclosure.
B. Part II: Synopsis
FDA is proposing that the first section of a PBN be a synopsis
(proposed Sec. 192.25(b)) that includes the same information that FDA
is recommending for inclusion in a presubmission consultation (see
proposed Sec. 192.10(f)(3) and section VI.C of this document). The
synopsis would be a concise document that describes the bioengineered
food in a manner that is suitable for preparing a publicly accessible
list of PBN's (see proposed Sec. 192.40(c)(1)(i) and section X.A of
this document).
C. Part III: Status at Other Federal Agencies and Foreign Governments
FDA is proposing that a notifier inform FDA of the status of any
prior or ongoing evaluation of the bioengineered plant, or food derived
from such a plant, by USDA/APHIS and EPA (proposed Sec. 192.25(c)(1)
and (c)(2)). The proposed regulation is consistent with the
recommendations in a report issued in April 2000 by the National
Research Council (the 2000 NRC Report) (Ref. 14). That report
recommended, among other things, that FDA, EPA, and USDA/APHIS
establish a process to ensure appropriate and timely exchange of
information between agencies about bioengineered pest-protected plants.
Under the regulation, FDA would be aware of any issues still pending at
those agencies, that are relevant to FDA's evaluation of the
bioengineered food in question. When necessary and appropriate, FDA
would contact APHIS, EPA, or both agencies about their evaluation of
the bioengineered plant.
In addition, as discussed previously in this notice, the purpose of
this notification program is to provide FDA with the information
necessary to determine whether there are legal status questions
concerning a bioengineered food so as to permit FDA to carry out its
enforcement responsibilities. This would include its responsibilities
to enforce section 402(a)(2)(B) of the act, which addresses foods
containing illegal pesticide residues.\13\ If the EPA regulatory
process regarding the bioengineered food is not yet complete and a
tolerance or exemption from tolerance has not been established, the
food would not be in full compliance with the law. Accordingly, in
these circumstances, FDA would inform a notifier that the agency does
not consider the notifier's PBN to satisfy the requirement for
premarket notice (see proposed Sec. 192.30(e) and section IX.C.5 of
this document).
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\13\ Under the Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA), EPA registers pesticides, including those introduced
into food via bioengineering; under section 408 of the act (21
U.S.C. 346a), EPA sets a tolerance or grants an exemption from a
tolerance for pesticide residues in food. FDA has the statutory
responsibility to enforce these tolerances or exemptions; under
section 402(a)(2)(B), a food is adulterated if it contains a
pesticide residue that exceeds an established tolerance or for which
there is no tolerance or exemption from the requirement for a
tolerance.
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FDA also is proposing that a notifier inform FDA as to whether the
bioengineered food is or has been the subject of review by any foreign
government and, if so, describe the status of that review (proposed
Sec. 192.25(c)(3)). Foreign countries have instituted various
regulatory requirements for bioengineered foods. Information about the
status of a notifier's submission(s) to foreign
[[Page 4719]]
countries could be pertinent to FDA's review. For example, some issues
raised by a foreign country could be relevant to the legal status of
the bioengineered food under the act.
D. Part IV: Method of Development
FDA is proposing that a PBN include data or information about the
method of development (proposed Sec. 192.25(d)). Specifically, FDA is
proposing that the data or information that a notifier provides
regarding the method of development include: (1) Characterization of
the parent plant including scientific name, taxonomic classification,
mode of reproduction, and pertinent history of development (proposed
Sec. 192.25(d)(1)); (2) construction of the vector used in the
transformation of the parent plant, with a thorough characterization of
the genetic material intended for introduction into the parent plant
and a discussion of the transformation method, open reading frames, and
regulatory sequences (proposed Sec. 192.25(d)(2)); (3) characterization
of the introduced genetic material, including the number of insertion
sites, the number of gene copies inserted at each site, and information
on DNA organization within the inserts; and information on potential
reading frames that could express unintended proteins in the
transformed plant (proposed Sec. 192.25(d)(3)); and (4) data or
information related to the inheritance and genetic stability of the
introduced genetic material (proposed Sec. 192.25(d)(4)). The proposed
requirement derives from the 1992 policy, the 1996 procedures, and
FDA's experience under the 1996 procedures. FDA requests comment on
technological advances in rDNA technology that are likely to result in
commercial products and that would not be addressed by the proposed
submission requirements. Such comments may result in a modification to
the proposed submission requirements.
FDA also is proposing to require that a notifier include a
discussion, as necessary, of other relevant data or information about
the method of development (proposed Sec. 192.25(d)(5)). This
requirement would cover any issues about the method of development that
are not explicitly addressed in proposed Sec. 192.25(d)(1), (d)(2),
(d)(3), and (d)(4). FDA expects that such issues would be identified
during presubmission consultations on specific products.
E. Part V: Antibiotic Resistance
In September 1998, FDA issued for public comment a draft guidance
document regarding the use of antibiotic resistance markers in
bioengineered plants (the 1998 draft antibiotic resistance guidance
(Ref. 15)).\14\,\15\ Consistent with the thinking presented in that
document, FDA is proposing to require that a PBN include a discussion
about any newly inserted genes that encode resistance to an antibiotic
(proposed Sec. 192.25(e)). Because scientific methods to assess this
issue are evolving, in the proposed regulation FDA is recommending that
a notifier contact FDA about the agency's current thinking on this
topic.
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\14\ In the 1992 policy, FDA discussed the role of genes that
encode resistance to an antibiotic as part of the development of
some bioengineered foods (57 FR 22984 at 22987). In the APH(3')II
final rule, FDA approved the use of the enzyme expressed by one such
gene, the kanr gene encoding resistance to kanamycin, in
the development of new varieties of cotton, oilseed rape, and
tomatoes. Between November 1996, and February 1997, FDA had several
discussions with outside experts to determine whether circumstances
exist under which FDA should recommend that a given antibiotic
resistance gene not be used in crops intended for food use, and if
so, to delineate the nature of those circumstances. Based on these
discussions, FDA issued for public comment the 1998 draft antibiotic
resistance guidance. FDA intends to issue final guidance in the near
future.
\15\ A report that describes the consultations that FDA relied
on in developing this draft guidance is available (Ref. 16).
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F. Part VI: Substances in the Food
FDA is proposing that a PBN include data or information about
substances introduced into, or modified in, the food (proposed
Sec. 192.25(f)). These data or information would include data or
information about the identity and function of these substances
(proposed Sec. 192.25(f)(1)), the level of these substances in the
bioengineered food (proposed Sec. 192.25(f)(2)), dietary exposure to
these substances (proposed Sec. 192.25(f)(3)), the potential that a
protein introduced into the food will be an allergen (proposed
Sec. 192.25(f)(4)), and a discussion of other safety issues that may be
associated with these substances (proposed Sec. 192.25(f)(5)). In
general, the proposed requirements derive from the 1992 policy, the
1996 procedures, and FDA's experience under the 1996 procedures. FDA
requests comment on these proposed submission requirements. Such
comments may result in a modification to the proposed submission
requirements.
1. Covered Substances
FDA is proposing that a notifier provide data or information about
substances introduced into, or modified in, the food (proposed
Sec. 192.25(f)). Under the regulation, a ``modified substance'' would
include a substance that is present in the bioengineered food at an
increased level relative to comparable food. Because pesticidal
substances are regulated by EPA, the proposed regulation regarding data
and information about substances introduced into the plant excludes
data and information about pesticidal substances.
As discussed previously (section II of this document), a
nonpesticidal substance introduced into food by way of breeding is a
food additive if the substance is not GRAS within the meaning of 21
U.S.C. 321(s). Thus, the legal status issues raised by bioengineered
foods include the potential that the food would contain an unapproved
food additive. In the 1992 policy, FDA expressed its view that there is
unlikely to be a safety question sufficient to question the presumed
GRAS status of the expression products of the transferred genetic
material when the expression products do not differ significantly from
other substances commonly found in food and are already present at
generally comparable or greater levels in currently consumed foods (57
FR 22984 at 22990). In the 1992 policy, FDA identified proteins,
carbohydrates, and fats and oils as substances commonly found in food
because those were the substances that were being considered in
products under development in 1992.\16\ As discussed, rDNA technology
has recently begun to be used to introduce multiple genes to generate
new metabolic pathways (Ref. 11). As with proteins, carbohydrates, and
fats and oils, it is FDA's view that the substances produced by the new
pathways would be presumed to be GRAS if they do not differ
significantly from other substances that are currently present at
generally comparable or greater levels in food and, as such, are safely
consumed.
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\16\ As discussed in the 1992 policy, FDA has presumed that
transferred nucleic acids would be GRAS (57 FR 22990). Under the
proposed regulation, a notifier provides data or other information
about transferred nucleic acids in Parts IV (method of development)
and V (genes that encode resistance to an antibiotic).
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2. Identity, Function, Level, and Dietary Exposure
FDA is proposing that a PBN include data or information about the
identity and function of substances introduced into, or modified in,
the food (proposed Sec. 192.25(f)(1)) and the level in the
bioengineered food of these substances (proposed Sec. 192.25(f)(2)).
The proposed regulation derives from the fact that the quantity and
quality of scientific evidence required to establish that the use of a
substance is safe vary
[[Page 4720]]
considerably depending upon the chemical, physical, and physiological
properties of the substance and its estimated dietary exposure.
FDA is proposing that a notifier include either: (1) An estimate of
dietary exposure to substances introduced into, or modified in, the
food (proposed Sec. 192.25(f)(3)(i)); or (2) a statement that explains
the basis for the notifier's conclusion that an estimate of dietary
exposure to these substances is not needed to support safety (proposed
Sec. 192.25(f)(3)(ii)). As discussed in the 1992 policy (57 FR 22984 at
22998), many substances that would be introduced into, or modified in,
a bioengineered food would be present in the bioengineered food at a
relatively low level. For example, since 1994, developers have
completed more than 45 consultations about bioengineered foods, most of
which contain newly introduced or modified enzymes (Ref. 6). In most
cases, an estimate of dietary exposure to these enzymes was not
critical to the safety assessment. However, this is not always the
case, even for enzymes that would be present in food at a low level.
For example, in the case of the enzyme APH(3')II, FDA relied, in part,
on the estimated dietary exposure to APH(')II in concluding that active
APH(3')II in food would not interfere with the clinical efficacy of the
orally administered antibiotic, kanamycin (59 FR 26700 at 26703). Thus,
the particular circumstances will determine whether an actual estimate
of dietary exposure to a substance that is introduced into a food plant
is needed to support the notifier's view that the bioengineered food is
as safe as comparable food.
3. Allergenicity
FDA is proposing that a notifier include a discussion of the
available data or information that address the potential that a protein
introduced into the food will be an allergen (proposed
Sec. 192.25(f)(4)). The proposed regulation is consistent with the 1996
procedures, which recommend that a notifier provide FDA with
information regarding any known or suspected allergenicity and a
discussion of the available information about the potential for the
bioengineered food to induce an allergic response. Because scientific
methods to assess this issue are evolving, in the proposed regulation
FDA is recommending that a notifier contact FDA about the agency's
current thinking on this topic.
FDA is developing guidance for evaluating the potential
allergenicity of proteins introduced into bioengineered foods and
intends to make that draft guidance available for public comment in the
near future. The draft guidance will be based in part on
recommendations made by scientific experts who attended a public
scientific conference on food allergy and bioengineered foods that FDA,
EPA, and USDA jointly hosted on April 18 and 19, 1994 (the 1994
allergenicity conference (Ref. 17)).\17\
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\17\ The goal of the 1994 allergenicity conference was to foster
a scientific dialogue to assess information that was available at
that time regarding the characteristic properties of food allergens
and the methods that are available to assess allergenicity. The
scientists who participated in this conference noted that serum from
an individual who is sensitive to a known allergenic source can be
used to assess the allergenic potential of proteins derived from
that source. These scientists acknowledged that there are no direct
methods to assess allergenicity of proteins from sources that are
not known to produce food allergy. However, they suggested that the
possibility that a new protein will cause an allergic reaction can,
to some degree, be evaluated by comparing its similarity to
characteristics of known food allergens. If a protein does not have
characteristics of known food allergens, the potential that the
protein would cause an allergic reaction is minimized. Because
exceptions have been reported for the observed characteristics of
allergens, and no one factor is fully predictive, the scientists
recommended that an assessment of allergenicity be based on all
available information.
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4. Other Safety Issues
It is impracticable for FDA to either anticipate all classes of
substances that could be introduced into food or provide specific
guidance about each of those classes of substances. Therefore, FDA is
proposing that a notifier provide a discussion of data or information
relevant to other safety issues that may be associated with the
substances introduced into, or modified in, the food (proposed
Sec. 192.25(f)(5)). This requirement would cover any issues that are
not explicitly addressed in proposed Sec. 192.25(f)(1), (f)(2), (f)(3),
and (f)(4) regarding substances introduced into, or modified in, the
food. Such issues could include, for example, the digestibility or
toxicity of an introduced protein. FDA expects that such issues would
be identified during presubmission consultations on specific foods.
G. Part VII: Data and Information About the Food
FDA is proposing that a notifier provide data or information about
the bioengineered food (proposed Sec. 192.25(g)). These data or
information would include a justification for selecting a particular
food(s) as ``comparable food'' (proposed Sec. 192.25(g)(1)); a
discussion of historic uses of the comparable food(s) (proposed
Sec. 192.25(g)(2)); data or information comparing the composition and
characteristics of the bioengineered food to those of comparable
food(s), with emphasis on significant nutrients, naturally occurring
toxicants and antinutrients, and any intended changes to the
composition of the food (proposed Sec. 192.25(g)(3)); any other
information relevant to the safety, nutritional, or other regulatory
assessment of the bioengineered food (proposed Sec. 192.25(g)(4)); and
a narrative that explains the basis for the notifier's view that the
bioengineered food is as safe as comparable food(s) and that the
bioengineered food is otherwise in compliance with all applicable
requirements of the act (proposed Sec. 192.25(g)(5)). In general, the
proposed requirements derive from the 1992 policy, the 1996 procedures,
and FDA's experience under the 1996 procedures. FDA discusses the
details of this proposed regulation immediately below. FDA requests
comment on the proposed submission requirements regarding the food.
Such comments may result in a modification to the proposed submission
requirements.
1. Comparable Food
FDA is proposing that the notifier provide a justification for
selecting a particular food or foods as the ``comparable food'' to
which the notifier will compare the bioengineered food (proposed
Sec. 192.25(g)(1)). The proposed requirement is based on the 1992
policy and FDA's experience under the 1996 procedures.
Ordinarily, the comparable food would be the parental variety or
commonly consumed varieties of the parent plant (57 FR 22984 at 22996
and Ref. 5)). However, when the intended effect of the transformation
is to change the composition of the food, it may be appropriate to also
compare the composition and characteristics of the bioengineered food
to that of another commonly consumed food. For example, if an oilseed
crop is modified to produce an oil that has a higher content of a
particular fatty acid than commonly consumed varieties, it may be
appropriate to also compare the composition and characteristics of the
bioengineered food to that of a food that contains that fatty acid. FDA
expects that any issues associated with the appropriate selection of
comparable food(s) would be identified during presubmission
consultations on specific products.
2. Historic Uses of the Comparable Food
FDA is proposing that the notifier provide a discussion of historic
uses of the comparable food(s) to which the notifier will compare the
bioengineered food (proposed Sec. 192.25(g)(2)). Several
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notifiers who have consulted with FDA under the 1996 procedures have
included such a discussion (e.g., as part of their description of the
applications or uses of the bioengineered food). FDA has found that
such a discussion is particularly helpful in identifying the potential
uses of the bioengineered food, regardless of whether those uses are
specifically targeted by the notifier.
3. Comparing the Composition and Characteristics of the Bioengineered
Food to That of Comparable Food
Consistent with the 1992 policy, the 1996 procedures, and FDA's
experience under the 1996 procedures, FDA is proposing that a notifier
provide data or information comparing the composition and
characteristics of the bioengineered food to those of comparable
food(s), with emphasis on changes in the levels of significant
nutrients and naturally occurring toxicants and antinutrients (proposed
Sec. 192.25(g)(3)(i) and (g)(3)(ii)). Such changes could raise legal
status questions such as whether the name of the food adequately
describes the food or whether the food is adulterated within the
meaning of section 402(a)(1) of the act.
Consistent with the 1992 policy, the 1996 procedures, and FDA's
experience under the 1996 procedures, FDA is proposing that a notifier
provide data or information about any intended changes to the
composition or characteristics of the food (proposed
Sec. 192.25(g)(3)). Such changes could raise legal status questions
such as the appropriate common or usual name for the food. For example,
FDA has been notified about a modification to a canola variety of
rapeseed to produce an oil with a modified fatty acid composition.
Because the name that is most often used to describe oil derived from
the parent plant (i.e., canola oil) did not accurately reflect the
characteristic properties of the bioengineered oil, the notifier
suggested a new name for the oil.
Intended changes to the composition or characteristics of the food
also could raise safety questions about the food. For example, it is
possible that a developer could modify corn so that the corn becomes a
significant dietary source of the nutrient folic acid. Folic acid is
used to fortify many foods, including breakfast cereals, because of the
relationship between consumption of folic acid and a reduced risk of
neural tube defects (21 CFR 101.79). However, excess folic acid in the
diet can mask the signs of vitamin B12 deficiency. Thus, an
increased level of folic acid in a food such as corn, which is commonly
used in breakfast cereals, could raise safety or other regulatory
issues.
Under proposed Sec. 192.25(g)(3), intended changes to the
composition of food include modifications that are intended to reduce
the level of a substance in food. For example, it is possible that a
modification would be intended to decrease the level of a substance
that is considered undesirable, such as the phytate that naturally
occurs in soybeans. It also is possible that a modification would be
intended to reduce the fat content of a food. As with intended
increases in the level of substances already in food, changes that
decrease the level of substances already in food could raise legal
status questions such as the appropriate common or usual name for the
food.
4. Other Relevant Information
Consistent with the 1992 policy, the 1996 procedures, and FDA's
experience under the 1996 procedures, FDA is proposing that a notifier
provide a discussion of any other information relevant to the safety,
nutritional, or other regulatory assessment of the bioengineered food
(proposed Sec. 192.25(g)(4)). This requirement would cover any legal
status issues about the food that are not explicitly addressed in
proposed Sec. 192.25(g)(1), (g)(2), and (g)(3). For example, under
proposed Sec. 192.25(g)(4), a notifier could discuss the basis for
proposing a specific common or usual name for a bioengineered food, or
any other proposed labeling that would accompany the bioengineered
food. FDA expects that such issues would be identified during
presubmission consultations on specific foods.
FDA requests comment on whether this rule should also include a
requirement that a premarket notice for a bioengineered food include
methods by which the food could be detected. In particular, the agency
is interested in comments on the circumstances under which such methods
should or should not be required, and the rationale for any such
requirement (e.g., the modification to the crop makes the food
acceptable for animal feed but unacceptable for human food). The agency
is also interested in comments on whether any such required methods
should be for raw agricultural commodities, representative finished
foods likely to contain the modified food, or both; and whether any
such required methods should contain sufficient information, such as
primer sequences, to enable technically-proficient non-government
laboratories to use them; and what other criteria, if any, there should
be for required methods (e.g., cost). Such comments may result in a
modification to the proposed submission requirements.
5. Narrative
FDA is proposing to require that a notifier provide a narrative
that explains the basis for the notifier's view that the bioengineered
food is as safe as comparable food and that the bioengineered food is
otherwise in compliance with all applicable requirements of the act
(proposed Sec. 192.25(g)(5)). The narrative would provide an integrated
discussion of the data and information submitted in a PBN. FDA is
proposing this requirement because the notifier has the responsibility
for determining that the intended use of the bioengineered food is as
safe as comparable food and is otherwise lawful. Absent an integrated
discussion of the underlying data and information, the basis for the
notifier's conclusion about the legal status of the bioengineered food
may not be apparent.
IX. Agency Administration of a Premarket Biotechnology Notice
A. Filing Decision
FDA is proposing to do an initial evaluation of the notice within
15 working days to see whether the notice appears to include all
elements required under Secs. 192.20 and 192.25 (proposed
Sec. 192.30(a)). FDA also is proposing to file a PBN that appears to
include all required elements, and to contact a notifier to explain
what is missing if the PBN does not appear to include all required
elements. FDA is proposing this ``filing decision'' because the
timeframe for the agency's response to the notifier (i.e., 120 days
(see proposed Sec. 192.5(c) and section V.C of this document) is
relatively short. To enable the agency to complete its evaluation in
this period, it is essential that the agency have a complete notice
when the 120-day period begins.
The proposed timeframe for the filing decision (i.e., within 15
working days) is consistent with the timeframe for the filing decision
for a food additive petition (Sec. 171.1(i)(1)). The proposed process
that ``FDA will inform the notifier'' provides flexibility for the
mechanism whereby FDA contacts a notifier. FDA expects to contact the
notifier by telephone or possibly by electronic mail and expects that a
notifier would provide the missing material promptly. However, should
circumstances warrant (e.g., FDA is unable to reach a notifier by
telephone, or the notifier does not provide the
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materials promptly), under the regulation, FDA could send a letter or
telefax to the notifier explaining that the agency had received, but
not filed, the PBN and the reasons therefor.
Under proposed Sec. 192.30(a)(1), CFSAN will inform CVM about any
PBN that it files. Regardless of whether the bioengineered food would
be used in human food, food for animals, or both, this inter-Center
communication will ensure that both Centers are aware of all
bioengineered foods that are nearing commercialization.
B. Acknowledgment Letter
FDA is proposing to send, within 15 working days of filing a
notice, a letter to the notifier (or, when applicable, the notifier's
agent) informing the notifier of the date on which FDA filed the PBN
(proposed Sec. 192.30(b)). As a practical matter, such a letter would
acknowledge receipt as well as inform the notifier of the date of
filing.
C. Response Letter
FDA is proposing to respond to a notifier within 120 days of filing
a notice (proposed Sec. 192.30(c)). Because all submissions will be
sent to CFSAN, CFSAN would issue the response to the notifier,
regardless of whether the intended use of the bioengineered food is in
human food, food for animals, or both. A response from CFSAN would make
clear that CFSAN was aware of, and thus had been notified about, all
bioengineered foods, regardless of their intended use.
As with any correspondence, the particular circumstances will
determine the full text of the agency's letter. However, the agency
believes that a letter would likely fall into one of four general
categories (proposed Sec. 192.30(d)(1), (d)(2), (d)(3), and (d)(4)).
FDA discusses each of these four categories immediately below.
1. General Categories for FDA's Response
a. Letter that extends FDA's evaluation. FDA is proposing that the
agency could inform a notifier that the agency is extending its
evaluation of the premarket notice by 120 days (proposed
Sec. 192.30(d)(1)). Under the regulation, in this letter FDA would also
inform the notifier that the agency expects that the bioengineered food
will not be marketed during the extended evaluation period.
Ordinarily, FDA expects to send a final response to a notifier
within 120 days, particularly if a prospective notifier discusses
relevant scientific and regulatory issues with FDA, prior to submitting
a PBN about a bioengineered food (see proposed Sec. 192.10 and section
VI of this document). However, there are several circumstances that
could prevent the agency from completing its evaluation within that
time period. For example, FDA may need to extend the review time if a
notifier did not participate in the presubmission consultation program;
the issues raised by a particular bioengineered food could be
particularly novel and complex; parts of a submission could require
clarification, amplification, or correction; or the submission could be
poorly written or be of such poor scientific quality that it precludes
timely evaluation by the agency.
As discussed previously, FDA is issuing this proposed rule to
ensure that it has the appropriate amount of information about
bioengineered foods and to help to ensure that all market entry
decisions by the industry are made consistently and in full compliance
with the law. The goal of this rulemaking would not be achieved if a
bioengineered food entered commercial distribution before FDA had
completed its evaluation of the applicable notice.
b. Letter that the notice does not provide a basis. FDA is
proposing that the agency have an option to inform a notifier that the
premarket notice does not provide a basis for the notifier's view that
the bioengineered food is as safe as comparable food or is otherwise
lawful (proposed Sec. 192.30(d)(2)). In so doing, FDA would inform the
notifier of the reasons for this conclusion. Under the regulation, in
this letter FDA would also inform the notifier that the agency expects
that the bioengineered food will not be marketed.
FDA has had experience with another food program, the proposed
notification program for GRAS substances, in which some submitted
notices do not provide a basis for the notifier's view that the
intended use of a substance is lawful (Ref. 18). The underlying reasons
why the applicable notices have not provided a basis for a GRAS
determination have been quite varied. Likewise, there could be various
reasons why a premarket notice does not provide a basis for the
notifier's view that the bioengineered food is as safe as comparable
food or is otherwise lawful. For example, the notice may not provide a
basis for the notifier's view that a substance introduced into the
bioengineered food is not an unapproved food additive or that the
bioengineered food would not be misbranded. As another example, the
notice may not provide a basis to conclude that a bioengineered food
that contains an unusually high level of a naturally occurring toxicant
would not be adulterated. As a third example, if the poor quality of a
notice makes it difficult for the agency to fully evaluate the notice,
regardless of the time period available, FDA may inform the notifier of
the inadequacies of the notice rather than extend its evaluation of the
notice for another 120 days.
If a notice about a bioengineered food does not provide a basis to
conclude that a bioengineered food is as safe as comparable food or is
otherwise lawful, that food could be adulterated or misbranded and
should not be marketed. If a notifier initiates commercial distribution
of a bioengineered food after being informed that the applicable notice
is not adequate, FDA will carefully and completely review the legal
status of the applicable food and will use all available options to
ensure that the food is fully in compliance with all provisions of the
act. In particular, in such circumstances, the agency fully intends to
bring to bear the complete range of its authorities and resources,
including its authority under section 704 of the act (21 U.S.C. 374) to
conduct inspections and investigations, collect samples, and perform
analyses, as well as its authority under sections 705 and 903 of the
act (21 U.S.C. 375 and 393) to engage in publicity and public
education. When the agency concludes through the application of these
resources that a food is adulterated, misbranded, or otherwise not in
full compliance with the act, FDA will utilize the act's legal
sanctions, as appropriate, including in rem seizure of violative foods
and injunction proceedings against, or criminal prosecution of, those
responsible for distributing such foods.
c. Letter that FDA has no questions. If, based on its evaluation of
a notice, FDA has no questions regarding the notifier's view that the
bioengineered food is as safe as comparable food and is otherwise
lawful, FDA would inform a notifier of that fact (proposed
Sec. 192.30(d)(3)). Because the evaluation of food safety is a time-
dependent judgment that is based on general scientific knowledge as
well as specific data and information about the food, FDA would qualify
its statement to clarify that the agency has no questions ``at this
time.'' This proposed response is similar to the letters that FDA has
issued in response to submissions received under the 1996 procedures.
d. Letter that a notifier has withdrawn the notice. Under proposed
Sec. 192.20(g), if a notifier requests that FDA cease to evaluate a
PBN, FDA would retain the PBN in its files and classify the PBN as
``withdrawn.'' In such a circumstance,
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FDA would bring the notification process to closure by sending the
notifier a letter acknowledging that the agency had received a
withdrawal letter and had ceased to evaluate the PBN, effective on the
date that FDA received the letter (proposed Sec. 192.30(d)(4)). This
proposed response is similar to responses issued by FDA under the
proposed notification program for GRAS substances when the notifier
requests that FDA cease to evaluate a GRAS notice (Ref. 18).
2. Status of the Bioengineered Food at EPA
If the bioengineered food contains a pesticidal substance, FDA is
proposing that FDA's response letter will describe the status of the
bioengineered food at EPA (proposed Sec. 192.30(e)). If all applicable
regulatory processes at EPA have come to closure (proposed
Sec. 192.30(e)(1)), FDA would say so and would respond as described
above. As discussed above, if regulatory processes at EPA regarding the
bioengineered food are still pending, FDA would inform the notifier
that FDA does not consider the PBN to satisfy the requirement for
premarket notice (proposed Sec. 192.30(e)(2)).
X. Public Disclosure
FDA is proposing to inform notifiers about: (1) The public
disclosure provisions that apply to the existence and content of a PBN;
(2) procedures that a notifier should use to inform FDA of the
notifier's view about whether the existence or content of a PBN is
exempt from public disclosure; and (3) the criteria that FDA uses to
evaluate the notifier's view (proposed Sec. 192.40(a) through (d)). FDA
also is proposing the procedures that FDA will use to disclose the
agency's evaluation of, and response to, each PBN (proposed
Sec. 192.40(e)). This part of the regulation would ensure that both
n