Recommendations for the Early Food Safety Evaluation of New
Non-Pesticidal Proteins Produced by New Plant Varieties Intended for
Food Use

**SUPPORTING STATEMENT**

A.  **Justification**

**1. Circumstances Necessitating Information Collection**

Number range CHAPTERThe use of bioengineered plants for food production
in the United States has increased markedly over the past decade (food
refers to both human food and animal feed). As the number and diversity
of field tests for bioengineered plants increases, the likelihood of
cross-pollination occurring due to pollen drift from field tests to
commercial fields and commingling of seeds produced during field tests
with commercial seeds or grain may also increase. This could result in
the inadvertent, intermittent, low-level presence in the food supply of
a protein that has not been evaluated in the U.S. Food and Drug
Administration's (FDA) biotechnology consultation process.[^1]

FDA first addressed the safety evaluation of new proteins in
bioengineered plants in its 1992 Statement of Policy: Foods Derived from
New Plant Varieties ("1992 policy;" 57 FR 22984, May 29, 1992)
(available at <http://www.cfsan.fda.gov/~acrobat/fr920529.pdf>). Since
FDA first issued its 1992 policy, the agency has encouraged developers
of new plant varieties, including those varieties developed through
biotechnology, to consult with FDA early in the development process to
discuss possible scientific and regulatory issues that might arise. In a
notice in the Federal Register of August 2, 2002 (67 FR 50578), the U.S.
Office of Science and Technology Policy (OSTP) proposed federal actions
to update field test requirements and to establish early voluntary food
safety evaluations for new proteins produced by bioengineered plants
("the OSTP document").

On November 24, 2004, FDA announced in the Federal Register (69 FR
68381) the availability of a draft guidance for industry entitled,
"Recommendations for the Early Food Safety Evaluation of New
Non-Pesticidal Proteins Produced by New Plant Varieties Intended for
Food Use" ("the New Protein Guidance") (draft guidance available at
http://www.cfsan.fda.gov/\~dms/bioprgui.html). The draft guidance
provides recommendations to developers of new plant varieties, in
particular bioengineered plants, on the early food safety evaluation of
new non-pesticidal proteins and on the procedures for submitting an
early food safety evaluation of such proteins to the agency.

FDA is requesting OMB approval of the voluntary information collection
provisions contained in the New Protein Guidance. The recommendations
put forward in the New Protein Guidance are consistent with the
scientific principles articulated in the 1992 policy for food safety
evaluation of a new protein. The guidance continues to foster early
communication by encouraging developers to submit to FDA their
evaluation of the food safety of their new protein. Such communication
helps to ensure that any potential food safety issues regarding a new
protein in a new plant variety are resolved early in development, prior
to any possible inadvertent introduction into the food supply of
material from that plant variety. Submission of an early food safety
evaluation for a new protein is not meant to substitute for a
biotechnology consultation with FDA about a food derived from a new
bioengineered plant variety. A developer may use the information
developed for the early food safety evaluation of a new protein in the
biotechnology consultation process.

**2. How, By Whom, Purpose of Collection**

This is a new information collection. The New Protein Guidance is for
developers of new plant varieties that are intended for food use. This
guidance provides information and recommended procedures for a
scientific evaluation of the food safety of new proteins produced by
such new plant varieties. This guidance also provides information to
developers about consulting with FDA about their evaluation and
recommended procedures for submitting an early food safety evaluation of
such proteins to the agency.

The recommended procedures contained in the New Protein Guidance are
voluntary. Developers of new plant varieties will conduct the scientific
evaluation and submit it to the agency. There has been particular
interest within the U.S. government and the food and agriculture
industries in having FDA publish this guidance. That interest stems in
part from concerns that, some day, material from bioengineered food
crops undergoing field trials might inadvertently enter the food supply
without any prior food safety evaluation. While FDA has not found and
does not believe that new plant varieties under development for food and
feed use generally pose any safety or regulatory concerns, this guidance
is consistent with FDA's policy of encouraging communication early in
the development process for a new plant variety. Such communication
helps to ensure that any potential food safety issues regarding a new
protein in such a new plant variety are resolved prior to any possible
inadvertent introduction into the food supply of material from that
plant variety.

FDA is the primary user of the information to be disclosed. However, as
noted above, a developer may use the information developed for the early
food safety evaluation of a new protein in the biotechnology
consultation process. In addition, the public may use this information.
In FDA's experience, there has been a considerable interest from a broad
segment of the public, including members of the regulated industry,
other federal, state, and local government agencies, international
government agencies, and public interest groups, in bioengineered
plants. FDA plans to assign a number to each submission and create a
list of the submissions for posting on the Internet. The information on
the Internet will include a hyperlink to the text of each submission
(other than confidential commercial information) and a hyperlink to the
text of the letter issued by the agency in response to each submission.
This information will be easily accessible to the public on FDA's
Internet site. []{.mark}

**3. Consideration Given to Information Technology**

The new protein guidance does not specifically prescribe the use of
automated, electronic, mechanical, or other technological techniques or
other forms of information technology as necessary for use by
developers. Developers are free to use whatever forms of information
technology may best assist them in voluntarily conducting the scientific
evaluation and submitting it to the agency. Information for early food
safety evaluations may be collected electronically. If the evaluation is
submitted to FDA as an electronic file, one paper copy is also
requested.

**4. Identification of Duplicative Information**

FDA plans to avoid duplicative collection of this information. If a
protein has been evaluated in an early food safety evaluation and no
safety concerns are identified, we would not expect an additional early
food safety evaluation to be submitted if the same protein is introduced
into another plant species. Also, if a protein has previously been
reviewed as part of a biotechnology consultation and there were no
safety concerns identified, we would not expect the submission of an
early food safety evaluation for such a protein.

Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7
U.S.C. 136 [et]{.underline} [seq.]{.underline}), the U.S. Environmental
Protection Agency (EPA) has authority to regulate all pesticides,
regardless of how they are made or their mode of action. Thus, a plant
bioengineered to contain a pesticide will also be reviewed by EPA. No
person may sell or distribute a pesticide in the United States that is
not registered, except under certain circumstances; EPA also has the
authority to regulate unregistered pesticides, e.g., in field testing.
EPA can establish conditions for use as part of the registration and for
uses of unregistered pesticides. The EPA also sets tolerance limits for
residues of pesticides on and in food and animal feed, or establishes an
exemption from the requirement for a tolerance, under the Federal Food,
Drug and Cosmetic Act (FFDCA; the act). Under the FFDCA, FDA has
authority to regulate a non-pesticidal substance that may be introduced
into a new plant variety and that is expected to become a component of
food. This early food safety evaluation guidance applies to
non-pesticidal proteins and is not duplicative with EPA
responsibilities.

Many plants developed using recombinant DNA (rDNA) technology are
considered \"regulated articles\" under regulations of USDA's Animal and
Plant Health Inspection Service (APHIS) (7 CFR Part 340), which
regulates the introduction of certain \"genetically engineered\" plants
into the environment. A developer must obtain authorization from APHIS
to field test such crops and, depending on the nature of the crop, a
developer files either a permit application or a notification. A
developer's submission to APHIS includes information on the plant from
which the food is derived, and details of the genetic changes to the
plant. APHIS considers issues of agricultural and environmental safety
during field trials, such as whether the crop could cause harm to plants
or plant products, non-target organisms, or threatened and endangered
species. After a period of research and development to gather safety
data, a developer may request that APHIS grant "non-regulated" status to
the genetically engineered plant, meaning that the agency has determined
that the plant is as safe as similar conventionally bred varieties and
as such will no longer be subject to APHIS oversight. In contrast, FDA
requests a submission of data and information concerning the food safety
of a specific new protein produced in a new plant variety. Therefore,
although a submission to APHIS would include some information, such as
the name of the company and the identity of the protein, that would be
included in the information requested under FDA's guidance for the early
food safety evaluation of new proteins, the submission is not
duplicative.

**5. Small Businesses**

In the guidance, the agency has established criteria as to the type of
information necessary for these submissions. The New Protein Guidance
minimizes the reporting burden on all businesses, including small
businesses, by providing that the developer submit a summary of data and
information, rather than the data and information itself. There is no
known way to minimize the burdens on a small business wishing to submit
a request for action to the agency.

Further, submitting an early food safety evaluation to the agency for
comment is voluntary. There would not be additional burden to the
developer for developing the data and information that underlie the new
protein evaluation because they would have already generated such data
and information to insure that the protein is safe and is in compliance
with all applicable requirements of the FFDCA.

**6. Less Frequent Information Collection**

FDA believes that this current evaluation reinforces statutory
requirements for foods to be safe, including foods derived from
biotechnology. The New Protein Guidance encourages earlier consultation
with FDA prior to the time that a new protein could enter the food
supply, thus ensuring that no safety issues would be raised by the
possible presence of such a protein in the food supply. This information
collection makes FDA more aware of new proteins that could enter the
food supply at low levels and gives the public more confidence in the
safety of their food. Further, as noted above, submitting an early food
safety evaluation to the agency for comment is voluntary.

**7. Information Collection Circumstances**

Allowing developers to submit an early food safety evaluation to the
agency for comment does not involve submission of information more than
quarterly to the agency, written responses to the agency in less than 30
days, submission of multiple copies, retention of records for more than
three years, or the use of statistical methods.

With regard to the confidentiality of the information or the submission
of trade secrets or proprietary information, the agency expects that it
may receive submissions containing confidential commercial information.
FDA will handle information submitted as part of a food safety
evaluation of a new protein in accord with the requirements of the
Freedom of Information Act, other applicable statutes, and FDA\'s
regulations at 21 CFR Part 20. Consistent with confidentiality
requirements, FDA will make submissions of early food safety evaluations
for new proteins, and FDA\'s responses thereto, easily accessible to the
public via the Internet. FDA believes this is consistent with the goal,
as articulated in the OSTP document, of enhancing public confidence in
the regulatory oversight of bioengineered plants.

**8. Consultations with Persons Outside the FDA**

In the Federal Register of November 24, 2004 (69 FR 68381), FDA
published a Notice of Availability with a 60-day notice requesting
public comment on the collection of information in FDA's draft guidance
document titled, "Guidance for Industry: Recommendations for the Early
Food Safety Evaluation of New Non-Pesticidal Proteins Produced by New
Plant Varieties Intended for Food Use."

[Nonresponsive comments]{.underline}

FDA received approximately 5000 letters in response to the Notice.
However, many of these letters contained comments that were not
responsive to the PRA questions. For example, several comments expressed
the opinion that the collection of information was insufficient to
ensure safety; other comments expressed concern that the agency might
not be able to commit sufficient resources to performing early food
safety reviews without having to redirect resources from other tasks;
that the decision should not be left to the developer regarding when to
submit an early food safety evaluation to the agency; and about the
objectivity and scientific expertise of the individuals reviewing the
information.

(Response) These comments are general comments directed to the adequacy
of the guidance, rather than specific comments relevant to the
collection of information; therefore, these non-responsive comments will
not be addressed in this document.

[Responsive comments]{.underline}

FDA received several letters with specific comments responsive to the
comment request concerning the proposed information collection in the
notice. The comments and FDA's responses follow.

(Comment 1) Several comments were supportive of the information
collection, stating that the information collection was necessary for
FDA to fulfill statutory requirements to protect the safety of the food
supply. Relevant to the minimization of burden, several of these
comments also noted that the information collection was appropriately
limited in scope to prevent duplicative submissions among federal
agencies.

(Response) These comments provide support for the utility of the
information collection and confirm that the collection will not result
in a duplicative information collection among federal agencies.

(Comment 2) One comment suggested that FDA should minimize the burden on
developers by referencing in the guidance the availability of public
protein databases that could be useful in the evaluation of allergen or
toxin homology.

(Response) FDA does not want to reference or list the various databases
because to do so would imply that FDA is endorsing any or all of them.
FDA finds that there are several databases in the public domain that are
easily obtained through the internet, are known in the scientific
community, and are in common use by developers of bioengineered crops.

(Comment 3) One comment suggested that FDA could minimize the burden of
the proposed collection of information by clarifying that a weight of
the evidence approach is applied to the assessment of potential
allergenicity of a new protein. The comment further suggested that
alternative methods and protocols be considered in the evaluation of the
allergenicity of new proteins.

(Response) FDA's guidance does not state that a weight of the evidence
approach will be applied to the evaluation. The guidance describes a
case-by-case evaluation that recognizes that different pieces of
information may have varying importance for the food safety evaluation
depending on the characteristics of the protein. As stated in the
guidance, developers are free to use alternative approaches in their
evaluations. The comment fails to explain how a weight of the evidence
approach would reduce the burden under the PRA.

(Comment 4) One comment suggested as an approach to minimize burden on
developers that FDA treat highly similar proteins as a family of
proteins, if they differ only by a few amino acids but retain the same
function, rather than evaluating each protein individually, though the
comment further suggests that certain aspects of a protein may be
evaluated individually.

(Response) FDA notes that the guidance is intended to consider specific
proteins, not protein families. FDA further notes that even small
changes in amino acid sequence may alter a protein and these small
differences could also have implications for food safety. However, if
there is relevant information contained in a previous submission, that
information can be incorporated by reference into a current submission
for a new protein evaluation.

(Comment 5) One comment suggested as a means of minimizing burden of the
proposed collection of information that FDA provide standard forms or
formats for certain elements of the submission (e.g., bioinformatics
reports). The comment also suggested minimizing burden by making greater
use of electronic submissions.

(Response) FDA has considered the use of standardized forms or formats
and at this time does not believe that their use would reduce the burden
of the information collection. The use of standardized forms could
discourage alternative approaches for the presentation of data in an
evaluation that might more clearly or thoroughly set forth the data.
Developers will have access to the forms and formats used by previous
submitters and are free to use them; thus, at this time we do not
perceive a need for a standardized form. Based on its experience in
evaluation of submissions FDA will in the future revisit whether the use
of standardized forms and formats would be advantageous to developers.

With respect to electronic submissions, FDA states in the guidance that
electronic submissions are acceptable, but one paper copy is also
requested. Efforts are underway at FDA to convert in the future to a
submission process that is entirely electronic.

(Comment 6) One comment stated that a way to enhance the quality,
utility, and clarity of the information to be collected is to follow
guidance available from the Codex Alimentarius. Although the comment did
not specify which guidance from the Codex Alimentarius FDA should
follow, FDA believes that the comment is referring to the Codex
Alimentarius "Guideline for the Conduct of Food Safety Assessment of
Foods Derived from Recombinant-DNA Plants" (CAC/GL 45-2003) (the Codex
Plant Guideline), containing "Annex: Assessment of Possible
Allergenicity" (the Codex Allergenicity Annex). The comment also stated
that FDA should make Codex guidance a mandatory part of its guidance.

(Response) FDA agrees in part and disagrees in part. FDA notes that its
recommendations in this guidance are consistent with the approach
recommended in the Codex Plant Guideline. In fact, FDA references the
Codex Plant Guideline as a resource to be consulted by a developer in
evaluating the food safety of a new protein. However, FDA notes that the
Codex Plant Guideline addresses a broad range of issues associated with
food safety assessment of food derived from bioengineered plants. While
FDA's guidance is consistent with the Codex Plant Guideline, it does not
address the entire broad range of issues as that document. FDA's
guidance is focused on the food safety issues that might arise from the
intermittent, low-level presence of material from a plant being
developed for food and feed use. FDA believes that any potential risk
from the intermittent, low-level presence of such material in the food
supply would be limited to the food safety of the new proteins. FDA
references the Codex Plant Guideline, Paragraphs 34-43 under *Expressed
Substances (non-nucleic acid substances)* and the Codex Allergenicity
Annex, for that component of the safety review.

FDA disagrees with the comment's suggestion that the agency make the
Codex Plant Guideline a mandatory part of its guidance. While FDA
believes that the Codex Plant Guideline and the Codex Allergenicity
Annex are useful documents, it recognizes that other approaches may also
be appropriate.

(Comment 7) One comment stated that while the information to be
collected is essential and important for FDA to obtain, the information
is inadequate to fulfill FDA's "stated and mandated goals," and
therefore it is of questionable utility.

(Response) FDA disagrees. The guidance is properly focused on the food
safety assessment of a new protein produced in a new plant variety when
there might be a low-level, intermittent presence of material from a
plant being developed for food. Although the commenter would like more
information to be presented for FDA review at this stage, FDA notes that
more information is not necessary because the information that the
guidance recommends a developer collect and present to FDA as part of a
food safety evaluation of a protein is adequate for the specific
assessment that FDA is making at this stage. FDA recommends that a
broader scope of information be presented to FDA for review at
subsequent evaluation stages. For example, when a developer utilizes the
recommendations articulated in FDA's guidance entitled, "Consultation
Procedures for New Plant Varieties" (available at
<http://www.cfsan.fda.gov/~lrd/consulpr.html>), FDA expects that
significantly more information will be presented during the
consultation.

(Comment 8) Several comments challenged the accuracy of FDA's estimate
of the burden of the proposed collection of information. These comments
opined that FDA should collect more extensive information than what is
proposed in the guidance and they concluded, therefore, that FDA had
underestimated the burden of the proposed information collection. The
comments did not challenge the accuracy of the burden estimate for the
information as proposed in the guidance.

(Response) FDA notes that the comments did not challenge the accuracy of
FDA's estimate, rather they challenged what FDA recommends in the
guidance. FDA believes that the estimate of the burden of the proposed
collection of information is accurate.

**9. Payment or Gift**

This information collection does not provide for payment or gifts to
respondents.

**10. Confidentiality**

This information collection will only be used to aid developers of new
non-pesticidal proteins determine the safety of their new protein.
Consistent with confidentiality requirements, FDA will make submissions
of early food safety evaluations for new proteins, and FDA\'s responses
thereto, easily accessible to the public via the Internet.

**11. Sensitive Questions**

This information collection does not involve any questions of a
sensitive nature.

**12. Burden of Information Collection**

FDA estimates the burden for this information collection as follows:

  ---------------- ------------- ----------- ----------- -------------- -------------
  Table                                                                 
  1.\--Estimated                                                        
  Reporting                                                             
  Burden^1^                                                             

                   No. Of        Annual      Total       Hours per      Total Hours
                   Respondents   Frequency   Annual      Response       
                                 per         Responses                  
                                 Response                               

  4 easy data      20            1           20          4              80
  elements                                                              

  2 original data  20            1           20          16             320
  elements                                                              

  Annual one time                                                       400
  burden hours                                                          
  ---------------- ------------- ----------- ----------- -------------- -------------

^1^ There are no capital costs or maintenance costs associated with this
information collection.

[Burden]{.underline}: 

Hour Burden Estimate

[One Time Burden]{.underline}

Submitting an early food safety evaluation for a new plant protein will
be a one-time burden (one submission per new protein). As this guidance
is voluntary, FDA cannot know how many developers will choose to submit
an early food safety evaluation for their plant protein. Many developers
of novel plants may choose not to submit an evaluation because the field
testing of a plant containing a new protein is conducted in such a way
(e.g., on such a small scale, or in such isolated conditions, etc.) that
cross-pollination with traditional crops or commingling of plant
material is not likely to be an issue. Also, other developers may have
previously communicated with FDA about the food safety of a new plant
protein, for example, when the same protein was expressed in a different
crop.

FDA scientists predict that this guidance will generate about 20 to 150
early food safety evaluations yearly. While there is uncertainty as to
the number of evaluations that developers will choose to submit, FDA
estimates that the annual number of early food safety evaluations will
be closer to the lower bound estimate of 20 evaluations rather than the
upper bound estimate of 150 evaluations. This estimation is supported by
the fact that on average there have been nine initial biotechnology
consultations per year. An initial biotechnology consultation has
traditionally been the first discussion between a developer and FDA
about a food made from a new bioengineered plant variety; it is usually
bioengineered varieties of plants that are the subject of a consultation
with FDA.

[Evaluation Components]{.underline}

The early food safety evaluation for new proteins from new plant
varieties includes six main data components. Four of these data
components are easily and quickly obtainable, having to do with the
identity and source of the protein. FDA estimates that completing these
data elements will take about 4 hours per evaluation. In table 1 of this
document, row 1 shows that for 20 evaluations, the total burden for
these four data requirements is 80 hours.

Two data components ask for original data to be generated. One data
component consists of a bioinformatics analysis which can be performed
using publicly available databases. The other data component involves
\'wet\' lab work to assess the new protein's stability and the
resistance of the protein to enzymatic degradation using appropriate in
vitro assays (protein digestibility study).

These data components will be completed in the course of study on the
new protein whether or not the company submits an early food safety
evaluation to FDA. Therefore, the paperwork burden of these two data
elements consists only of the time it takes the company to put together
the information on these two data elements to submit to FDA. Given that
the 4 easy data elements are expected to take 4 hours to prepare per
evaluation, it is reasonable to assume that the two more involved data
elements will each take twice as long to complete for the early food
safety evaluation. Therefore, for each evaluation, these two data
components will take 16 hours to complete (8 hours for each component,
doubled from the 4 hours it takes to complete the simpler components of
the early food safety evaluation). Table 1 row 2 shows that for 20
evaluations, the total burden for these two data requirements is 320
hours.

**13. Capital Costs (Maintenance of Capital Costs)**

The data components generated for an early food safety evaluation of a
new protein will be completed in the course of study on the new protein
whether or not the company submits an early food safety evaluation to
FDA. Therefore, there are no additional capital costs or operating and
maintenance costs associated with this collection.

**14. Annual Cost to Federal Government**

FDA estimates that the staffing burden for review of early food safety
evaluations will be 80 hours per submission.  We estimate that we will
receive approximately 20 submissions annually.  Thus, we estimate 1600
hours will be needed to review early food safety evaluation
submissions.  The cost to the Federal government is estimated as being
equivalent to the number of hours of review per year at an average
hourly salary rate of \$48.18, which is the hourly salary rate for a
GS-13/Step 10 for the Washington-Baltimore locality pay area for year
2006 (1600 hours x \$48.18/hour = \$77,088).   This estimate also
presumes that overhead will be equal to salary for a total cost to the
Federal government of approximately \$154,176 per year (\$77,088 x 2 =
154,176).

**15. Reason for Change**

This is a new collection.

**16. Statistical Reporting**

FDA plans to assign a number to each submission and create a list of the
submissions for posting on the Internet. The information on the Internet
will include a hyperlink to the text of each submission (other than
confidential commercial information) and a hyperlink to FDA's response.

**17. Display of OMB Approval Date**

There are no reasons why display of the expiration date for OMB approval
of the information collection would be inappropriate.

**18. Exceptions to "Certification for Paperwork Reduction Act
Submissions" of OMB Form 83I**

No exceptions to the certification statement identified in Item 19 of
the instructions for completing OMB Form 83-I have been identified.

[^1]: The document entitled, "Guidance on Consultation Procedures: Foods
    Derived from New Plant Varieties," can be found at
    <http://www.cfsan.fda.gov/~lrd/consulpr.html>.