Best Practices for Convening a GRAS Panel

Contains Nonbinding Recommendations

Best Practices for Convening a GRAS
Panel:
Guidance for Industry
Additional copies are available from:
Office of Food Additive Safety
Center for Food Safety and Applied Nutrition
Food and Drug Administration
5001 Campus Drive
College Park, MD 20740
240-402-1200
https://www.fda.gov/FoodGuidances
You may submit either electronic or written comments regarding this guidance at any time.
Submit electronic comments to https://www.regulations.gov. Submit written comments to the
Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852. All comments should be identified with the docket number FDA2017-D-0085.
For questions regarding this document as it relates to substances used in human food, contact the
Center for Food Safety and Applied Nutrition (CFSAN) at 240-402-1200.
For questions regarding this document as it relates to substances used in animal food, contact the
Center for Veterinary Medicine (CVM) at 240-402-7002.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Food Safety and Applied Nutrition
Center for Veterinary Medicine
December 2022
OMB Control No. 0910-0911
Current expiration date available at https://www.reginfo.gov.
*See additional PRA statements in Section VI of this guidance document.

Contains Nonbinding Recommendations

I.

Introduction

II.

Background

Table of Contents

A. Statutory and Regulatory Framework for Substances Added to Food
B. GRAS Notification Procedure
C. Evidence for General Recognition
1. General Availability
2. General Acceptance

D. 2010 Report of the Government Accountability Office

III.

Key Ideas Relevant to Our Recommendations

A. Bias
B. Balance of Expertise
C. Procedures for Organizing a Scientific Panel and Managing Its
Deliberations
D. Conflict of Interest and Appearance Issues
1. Federal Regulations and FDA Guidances
2. Policies and Literature Regarding Conflict of Interest and Appearance Issues

IV. Definitions
V.

Recommendations

A. Introduction
1. Recommendations Related to Selecting GRAS Panel Members

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2. Recommendations Related to the Operation of the GRAS Panel and to the Submission of a Notice
to FDA
3. Other Recommendations

B. Appropriate and Balanced Expertise in a GRAS Panel
1. General Considerations When Convening a GRAS Panel
2. Appropriate Expertise in a GRAS Panel
3. Number of Members of a GRAS Panel

C. Assessment and Management of Procedural Issues Associated with the
Organization and Deliberations of a GRAS Panel
D. Assessment and Management of Conflict of Interest and Appearance
Issues of Potential GRAS Panel Members
1. Overview
2. Identifying Conflict of Interest and Appearance Issues
3. Criteria for Evaluating Identified Conflicts of Interest and Appearance Issues and Strategies for
Managing Identified Conflicts of Interest and Appearance Issues
4. Documentation of Conflicts of Interest, Appearance Issues, and Rationales for Waivers
5. Format of a Written GRAS Panel Policy

E. Information Provided to a GRAS Panel
F. Documenting the Deliberations and Conclusions of a GRAS Panel
G. Considerations When a GRAS Notice is Submitted to FDA
H. Considerations When a GRAS Notice is Not Submitted to FDA
I.

Honoraria Provided to Members of a GRAS Panel

VI. Paperwork Reduction Act of 1995
VII. References
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Best Practices for Convening a GRAS
Panel:
Guidance for Industry1
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this
topic. It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public. You can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate telephone number listed on the title page
of this guidance.

I.

Introduction

This guidance document is intended to provide our recommendations on best practices for
convening a “GRAS panel.” By “GRAS,” we mean “generally recognized as safe.” See section
II.A for a discussion of the GRAS provision of the Federal Food, Drug, and Cosmetic Act
(FD&C Act). By “GRAS panel,” we mean a panel of qualified experts who independently
evaluate whether the available scientific data, information, and methods establish that a
substance is safe under the conditions of its intended use in human food or animal food as part of
an evaluation of whether adding that substance to food is lawful under the GRAS provision of
the FD&C Act.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe FDA’s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements are cited. The use of the
word should in FDA guidances means that something is suggested or recommended, but not
required.
In this document, we refer to a person who is responsible for a conclusion that a substance may
be used in food on the basis of the GRAS provision of the FD&C Act as the “proponent” of
This guidance has been prepared jointly by the Division of Food Ingredients in the Office of Food Additive Safety
in the Center for Food Safety and Applied Nutrition, and the Division of Animal Feeds in the Office of Surveillance
and Compliance in the Center for Veterinary Medicine at the U.S. Food and Drug Administration.

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GRAS status for that substance under the conditions of its intended use. In many cases, the
process whereby the proponent evaluates whether the available data and information support a
conclusion that a substance is GRAS under the conditions of its intended use need not include a
GRAS panel. However, in some cases, the proponent might decide that the opinion of a GRAS
panel may be useful. Depending on the outcome of the GRAS panel’s analysis, the proponent
could either reach a conclusion regarding the safety of the substance under the conditions of its
intended use, or be advised of one or more issues (such as gaps in the data and information, or
alternative interpretations of the available data and information) that warrant investigation before
a conclusion can be drawn about whether the substance is safe under the conditions of its
intended use.
Importantly, the outcome of a panel’s deliberations does not create or confer general recognition
of the safety of the use of an ingredient. Rather, it could provide evidence supporting the
proponent’s contention that there is general acceptance based on generally available information
among relevant scientific communities. When the outcome of the GRAS panel’s analysis
supports the proponent’s conclusion that a substance is safe under the conditions of its intended
use, in essence the proponent is relying on the members of the GRAS panel to act as a
representative sample 2 of the larger scientific community knowledgeable about the safety of
substances directly or indirectly added to food. In so doing, the proponent relies on the outcome
of the GRAS panel’s analysis to support the proponent’s conclusion that the safety of the
intended use is “generally recognized” by qualified experts. Whether a GRAS panel is a
sufficiently representative sample with respect to the larger scientific community depends on a
number of factors, such as the subject matter expertise of the members of the GRAS panel and
whether the members of the GRAS panel are representative of experts qualified by scientific
training and experience to evaluate the safety of the substance under the conditions of its
intended use. For example, a “GRAS panel” opinion published by scientists without expertise
appropriate to address the applicable safety questions could not provide evidence that the
conclusions in the publication are “generally accepted.” Unless both criteria, i.e., “generally
available” and “generally accepted,” are satisfied, there would be no basis for a conclusion of
GRAS status based on a “GRAS panel” opinion (see Response 11, 81 FR 54960 at 54974,
August 17, 2016).
A GRAS panel is just one mechanism that proponents have used to provide evidence of general
acceptance in support of their GRAS conclusion. In most cases, a well-supported GRAS
conclusion will not require an analysis by a GRAS panel (see Figure 1). We suggest that
proponents considering whether a GRAS panel would be useful in supporting their GRAS
conclusion consult with FDA before embarking on such an effort. In addition, we realize that it
can be challenging to identify, screen, and select a comprehensive panel of qualified experts
when specialized expertise applicable to the scientific considerations associated with the
intended conditions of use of a food substance is needed, given the potentially finite number of
In other words, the panel functions as a sample of the scientific community, and thus the views of the panel
members can provide evidence of their respective disciplines’ generally accepted views on a particular question.
However, if there is reason to believe that the sample is unrepresentative in some way, the credibility of the panel’s
views as evidence of general acceptance could be significantly reduced.

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experts who would be both qualified and available to serve on a GRAS panel. Thus, it may be
worth considering whether the effort to convene a GRAS panel is warranted in any particular
case before allocating resources to it.
This guidance document is intended for and directed to:
•

Those proponents who intend to consider the opinion of a GRAS panel in reaching a
conclusion that the intended use of a substance in human food or animal food is GRAS;

•

Those persons who assemble a GRAS panel and provide the framework for its
deliberations (“organizers”); and/or

•

Those persons who are interested in our views and recommendations on best practices for
convening a GRAS panel.

The recommendations in this guidance address best practices for convening a GRAS panel to:
•

Identify GRAS panel members who have appropriate and balanced expertise;

•

Take steps to reduce the risk that bias (or the appearance of bias) will affect the
credibility of the GRAS panel’s output (often called a “GRAS panel report”), including
the assessment of potential GRAS panel members for conflict of interest and the
appearance of conflict of interest; and

•

Limit the data and information provided to a GRAS panel to public information (e.g., by
not providing the GRAS panel with information such as trade secret information).

The recommendations in this guidance reiterate certain statutory and regulatory considerations
that we have previously discussed regarding the use of a GRAS panel in addressing the GRAS
provision of the FD&C Act related to food and food additives (81 FR 54960 at 54966, 54994,
and 55000). However, this guidance document is not intended to address the statutory and
regulatory criteria that govern eligibility for classification of a substance as GRAS under the
conditions of its intended use or to describe the proponent’s responsibilities for complying with
those statutory and regulatory criteria. For the most recent discussions of those statutory and
regulatory criteria, see the final rule entitled “Substances Generally Recognized as Safe” (81 FR
54960 (the GRAS final rule)) and our guidances entitled “Regulatory Framework for Substances
Intended for Use in Human Food or Animal Food on the Basis of the Generally Recognized as
Safe (GRAS) Provision of the Federal Food, Drug, and Cosmetic Act: Guidance for Industry”
(the regulatory framework guidance) (Ref. 1) and “Frequently Asked Questions About GRAS for
Substances Intended for Use in Human or Animal Food: Guidance for Industry” (the GRAS
FAQs) (Ref. 2).
Rather, this guidance includes recommendations for GRAS panels that are informed by federal
law, regulations, and FDA guidance documents related to FDA advisory committee members.
Our reference to these requirements and guidances is solely for the purpose of discussing
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concepts that are relevant to conflict of interest issues for GRAS panels (the topic of this
guidance), rather than to imply that FDA bears the same organizing role in relation to a GRAS
panel as it does for an FDA advisory committee or to imply that the processes are wholly
analogous. In addition, for more background and information, this guidance notes some
available conflict of interest policies from other organizations. This guidance is intended to
support the organizers of GRAS panels in their own development of procedures for convening
GRAS panels.

II.

Background
A. Statutory and Regulatory Framework for Substances Added to Food

In 1958, Congress enacted the Food Additives Amendment (the 1958 amendment) to the FD&C
Act. The 1958 amendment requires that, before a food additive may be used in food, FDA must
establish a regulation prescribing the conditions under which the additive may be safely used.
The 1958 amendment defined the terms “food additive” (section 201(s) of the FD&C Act) and
“unsafe food additive” (section 409(a) of the FD&C Act), established a premarket approval
process for food additives (section (409(b) through (g) of the FD&C Act), and amended the food
adulteration provisions of the FD&C Act to deem adulterated any food that is, or bears or
contains, any food additive that is unsafe within the meaning of section 409 of the FD&C Act
(see section 402(a)(2)(C) of the FD&C Act).
Section 201(s) of the FD&C Act defines a “food additive” as “any substance the intended use of
which results or may reasonably be expected to result, directly or indirectly, in its becoming a
component or otherwise affecting the characteristics of any food . . . if such substance is not
generally recognized, among experts qualified by scientific training and experience to evaluate
its safety, as having been adequately shown through scientific procedures (or, in the case of a
substance used in food prior to January 1, 1958, through either scientific procedures or
experience based on common use in food) to be safe under the conditions of its intended
use. . . .” 3 Under this definition, a substance that is GRAS under the conditions of its intended
use is not a “food additive” and is therefore not subject to mandatory premarket review by FDA
under section 409 of the FD&C Act.
We have established regulations implementing the GRAS provision of section 201(s) of the
FD&C Act in part 170 (21 CFR part 170) and part 570 (21 CFR part 570) for human food and
animal food, respectively. In particular, we have established criteria for eligibility for
classification as GRAS (21 CFR 170.30 and 570.30), including general criteria (21 CFR
The definition of “food additive” in section 201(s) of the FD&C Act also excepts: (1) Pesticide chemical residues
in or on a raw agricultural commodity or processed food; (2) pesticide chemicals; (3) color additives; (4) substances
used in accordance with a “prior sanction” (i.e., a sanction or approval granted prior to the enactment of the Food
Additives Amendment of 1958 under the FD&C Act, the Poultry Products Inspection Act, or the Meat Inspection
Act); (5) new animal drugs; and (6) dietary ingredients in or intended for use in a dietary supplement. Thus, use of a
substance as a dietary ingredient in a dietary supplement is not eligible for classification as GRAS. In addition,
under section 201(s) of the FD&C Act, the GRAS provision applies to the definition of a food additive only; there is
no corresponding provision in the definition (in section 201(t) of the FD&C Act) of a color additive.

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170.30(a) and 570.30(a)), specific criteria for general recognition of safety through scientific
procedures (21 CFR 170.30(b) and 570.30(b)), and specific criteria for general recognition of
safety through experience based on common use in food (21 CFR 170.30(c) and 570.30(c)).

B. GRAS Notification Procedure
In 2016, we issued a final rule establishing the GRAS notification procedure (“Generally
Recognized as Safe (GRAS) Notice”) in part 170, subpart E for a substance intended for use in
human food and in part 570, subpart E, for a substance intended for use in animal food (81 FR
54960). That final rule completed the rulemaking that we initiated through a proposed rule (62
FR 18938, April 17, 1997) and a notice reopening the comment period for the proposed rule to
update comments and to solicit comment on specific issues (“reopening notice”) (75 FR 81536,
December 28, 2010).
The GRAS final rule provides that any person may notify FDA of a view that a substance is not
subject to the premarket approval requirements of section 409 of the FD&C Act based on that
person's conclusion that the substance is GRAS under the conditions of its intended use. A
submission containing this view (a GRAS notice) must contain seven parts, including an
explanation of how the generally available data and information relied on to establish safety
provide a basis for the proponent’s conclusion that the notified substance is generally recognized,
among qualified experts, to be safe under the conditions of its intended use (21 CFR 170.250(b)
and 570.250(b)).

C. Evidence for General Recognition
For a substance to be eligible for GRAS status under the conditions of its intended use, the
publicly available data and information must satisfy the safety standard for a food additive in
accordance with section 409(c)(5)(C) of the FD&C Act. Furthermore, there must be common
knowledge throughout the expert scientific community knowledgeable about the safety of
substances directly or indirectly added to food that there is reasonable certainty that the
substance is not harmful under the intended conditions of use (see 21 CFR 170.30(a) and
570.30(a)). This requirement of “general recognition” is itself composed of both “general
availability” and “general acceptance” aspects.
1.

General Availability

As discussed in GRAS rulemaking documents, publication in a peer-reviewed scientific journal
is the usual mechanism to establish that scientific information is generally available (see
Response 8, 81 FR 54960 at 54973; 62 FR 18938 at 18940).
2.

General Acceptance

There are a variety of ways to provide evidence of general acceptance. The type of evidence
necessary in a particular case will depend on the properties and intended use of an ingredient as
well as the state of the science and the available public data.
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A GRAS panel is just one mechanism that proponents have used to provide evidence of general
acceptance, thus supporting the proponent’s GRAS conclusion (see Response 13, 81 FR 54960 at
54975). However, use of a GRAS panel is not the only mechanism for doing so. While it is true
that some GRAS notices evaluated by FDA have included statements from a GRAS panel, in our
view, the presence and conclusions of the panel were not essential evidence supporting the
proponent’s GRAS conclusion for most of these notices.
Conversely, the use of a GRAS panel does not necessarily mean that the “general acceptance”
aspect of the criteria for eligibility for GRAS status has been met (see Response 13, 81 FR 54960
at 54975).
Figure 1 illustrates the continuum of value that the output of a GRAS panel could contribute to a
proponent’s GRAS conclusion, ranging from likely unnecessary to potentially useful to likely
insufficient. Table 1, further discussed below, provides examples when a GRAS panel may be
either unnecessary – because there is likely already sufficient evidence of general acceptance -or insufficient – because it is unlikely that a GRAS panel could provide credible evidence of
general acceptance -- to satisfy the “generally accepted” aspect of the criteria for eligibility for
GRAS status. In cases where the proponent is unsure of the potential value of a GRAS panel in
helping to satisfy the “general acceptance” criteria, the proponent should consult with FDA.
Figure 1: Continuum of Value for GRAS Panels in Providing Evidence of General
Acceptance

Likely Unnecessary

Potentially useful

Likely Insufficient

Table 1: Examples of Scenarios Where GRAS Panels Are Likely Unnecessary or
Insufficient to Provide Evidence of General Acceptance
GRAS Panel Likely Unnecessary

GRAS Panel Likely Insufficient

Published results in the primary scientific
literature raise no questions that experts
would need to interpret and resolve (see “d.
Basis for concluding expert consensus,” 62

Ongoing scientific discussion or controversy
about safety concerns raised by available data
(see “d. Basis for concluding expert
consensus,” 62 FR 18938 at 18949)
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GRAS Panel Likely Unnecessary

GRAS Panel Likely Insufficient

FR 18938 at 18949; see Response 13, 81 FR
54960 at 54975)
Publication of data and information in the
primary scientific literature has been
supplemented by publication of data and
information in the secondary literature, such
as scientific review articles, textbooks, and
compendia (see “C. Elements of the GRAS
Standard,” 62 FR 18938 at 18940 through
18941; see Responses 10, 11, and 13, 81 FR
54960 at 54974 through 54975)
Publication of data and information in the
primary scientific literature has been
supplemented by the opinion or
recommendation of an authoritative body […]
on a broad or specific issue that is related to a
GRAS conclusion (see “C. Elements of the
GRAS Standard,” 62 FR 18940 through
18941; see Response 13, 81 FR 54960 at
54975)

Safe level of intake is in a narrow range (see
“1. Establishing General Recognition of
Safety,” 62 FR 18938 at 18943)

Severe conflict among experts regarding the
safety of the use of a substance (United States
v. An Article of Drug* * * 4,680 Pails, 725
F.2d 976 at 990 (5th Cir. 1984); Premo
Pharmaceutical Laboratories v. United
States, 629 F.2d 795 at 803 (2d Cir. 1980))

In most cases, a well-supported GRAS conclusion will not need an analysis by a GRAS panel as
evidence of general acceptance (the left-hand side of Figure 1; the left-hand examples in Table
1). Depending on the specifics of the intended use of a substance, peer-reviewed primary safety
studies, secondary reviews of primary literature, or the findings of an authoritative body could
provide adequate evidence of general acceptance. Each of these three types of evidence is
discussed below.
•

Published peer-reviewed primary studies. In many cases, the type of evidence provided
by published peer-reviewed primary studies consistent with generally accepted safety
assessment strategies is sufficient to satisfy both the general availability as well as the
general acceptance aspects of the GRAS criteria. We stated in the GRAS proposed rule
that “there could be a basis to conclude that there is expert consensus 4 that the published
results of a particular safety study (i.e., the primary scientific literature) establish the
safety of a substance for its intended use if the study raises no safety questions that
experts would need to interpret and resolve” (62 FR 18938 at 18943). We also noted this
point in the GRAS final rule (see Response 13, 81 FR 54960 at 54975). However,

In general, FDA describes this concept using “general acceptance” rather than “expert consensus,” a term derived
from case law, for reasons discussed in the GRAS Final Rule (81 FR 54960 at 55007). We use the term “expert
consensus” where we are quoting directly from the proposed rule within the paragraph.

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•

•

“…data published in the primary scientific literature may not provide a basis for expert
consensus if those data raise unresolved safety questions” (62 FR 18938 at 18949).
Secondary literature. In some cases, the type of evidence provided by secondary
literature, such as reviews of published primary literature, may be sufficient and
appropriate to satisfy the general acceptance aspect of the GRAS criteria. In the GRAS
proposed rule, we noted that publication of data and information in the primary scientific
literature can be supplemented by publication of data and information in the secondary
scientific literature, such as scientific review articles, textbooks, and compendia (see “C.
Elements of the GRAS Standard,” 62 FR 18938 at 18940 through 18941). In the GRAS
final rule, we further observed that there may be a body of information published in the
primary or secondary literature about a class of substances, which reflect generally
available and accepted data and information that can be called to bear on the safety
assessment of a specific substance (see Response 17, 81 FR 54960 at 54976). We also
noted that technical literature from the Joint Expert Committee on Food Additives
(JECFA, a joint committee of the Food and Agriculture Organization/World Health
Organization) can provide evidence that generally available safety data and information
are generally accepted (see section III.A.1 of Ref. 3).
Findings of an authoritative body. The findings of an authoritative body are another type
of evidence that could be used to support the general acceptance aspect of the GRAS
criteria. As an example, this could include the opinion or recommendation of an
authoritative body such as the National Academy of Sciences on a broad or specific issue
that is related to a GRAS conclusion (see “C. Elements of the GRAS Standard,” 62 FR
18938 at 18940 through 18941). The findings of an authoritative body may also be the
most appropriate type of evidence to support general acceptance in those cases where the
safe level of intake is a narrow range because the difference between the intended or
recommended dietary intake (e.g., of a nutrient) and the intake at which the substance
exhibits toxic properties is small. In such cases, the opinions or recommendations of the
authoritative body may provide evidence of general acceptance, thus supporting a
proponent’s conclusion that that the safety of a substance under the conditions of its
intended use is generally accepted by qualified experts (see Response 13, 81 FR 54960 at
54975).

By contrast, although unanimity among experts regarding the safety of a substance is not
required, “an ongoing scientific discussion or controversy about safety concerns raised by
available data would make it difficult to provide a basis for expert consensus about the safety of
the substance for its intended use” (see “d. Basis for concluding expert consensus,” 62 FR 18938
at 18949). While “mere conflict among experts is not enough to preclude a finding of general
recognition [of safety]” (United States v. Articles of Food and Drug (Coli-Trol 80), 518 F.2d 743
at 746 (5th Cir. 1975)), it does not exist if there is a genuine dispute among qualified experts that
the use of the substance is safe (See, e.g., Premo Pharmaceutical Laboratories v. United States,
629 F.2d 795 at 803 through 804 (2d Cir. 1980) (“genuine dispute among qualified experts”
precludes finding of general recognition, and no general recognition existed as a matter of law
where there was a “sharp difference” of expert opinion)). In such cases (the right-hand side of
Figure 1; the right-hand column of Table 1), the type of evidence provided by a GRAS panel, no
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matter how well constructed, may not be appropriate or sufficient to support the “general
acceptance” aspect of the criteria for eligibility for GRAS status through scientific procedures.
Finally, there are occasionally circumstances in which a GRAS panel may provide the
appropriate type of evidence to support the general acceptance aspect of the criteria for eligibility
for GRAS status through scientific procedures (the middle of Figure 1). For example, as noted in
the proposed rule, “the opinion of an expert panel is [...] useful when multiple studies bearing on
the safety of a substance are published but there are no secondary sources that evaluate these
studies and draw general conclusions based on this comprehensive body of knowledge” (62 FR
18938 at 18943). A GRAS panel may also be useful if “the published results of a particular
safety study […] raises safety questions that require additional data to be resolved” (62 FR
18938 at 18943). In such cases where published primary or even secondary literature might not
be sufficient, a well-constructed GRAS panel may provide the type of evidence necessary to
conclude that the published safety data are generally accepted.

D. 2010 Report of the Government Accountability Office
From 2008 to 2010, the Government Accountability Office (GAO) conducted a study related to
ingredients used in human food on the basis of the GRAS provision in section 201(s) of the
FD&C Act. In 2010, GAO issued a report (Ref. 4; the GAO report) that included a number of
recommendations for FDA. The GAO report recommended that FDA develop a strategy to
minimize the potential for conflicts of interest, including issuing guidance for companies on
conflict of interest, and we requested comment on issuing such a guidance in our reopening
notice (75 FR 81536 at 81542). In the GRAS final rule, we stated our intent to issue such
guidance (see Response 125, 81 FR 54960 at 55026). This guidance addresses conflict of
interest as part of the best practices for convening a GRAS panel.

III.

Key Ideas Relevant to Our Recommendations

As noted in the Introduction, among other things, this guidance document recommends best
practices to reduce the risk that bias (or the appearance of bias) will affect the credibility of the
GRAS panel’s output (often called a “GRAS panel report”), including the assessment of
potential GRAS panel members for conflict of interest and the appearance of conflict of interest.
In developing these recommendations, we considered federal law, regulations, and FDA
guidances, as well as published literature and conflict of interest policies from several
organizations (e.g., the National Academies of Sciences, Engineering, and Medicine (NASEM)
and the National Academy of Medicine (NAM); (see sections III.B through III.D)) that have
developed policies to address topics such as bias, balance of expertise, procedures for organizing
a scientific panel and managing its deliberations, conflict of interest, and the appearance of
conflict of interest, for use by their own organizations (or the scientific community at large)
during the conduct of scientific research. In this section, we summarize key ideas from these
sources that are relevant to our recommendations.

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A. Bias
Bias is a particular tendency, trend, inclination, feeling, or opinion, especially one that is
preconceived or unreasoned (Ref. 5) and can operate either for or against an outcome that the
sponsor of an investigation might view as the “preferred” outcome (Ref. 6). Bias can be created
both by cognitive patterns (Ref. 7 and Ref. 8) 5 and by factors such as the potential for financial
gain and can operate at both an individual level and a group level. Individuals may be more
vulnerable to bias when they have competing interests (Ref. 9 and Ref. 10).
The credibility of an opinion from a panel of scientific experts can be undermined if one or more
members is, or is perceived to be, biased. Although bias typically operates at a subconscious
level and is difficult for external observers to identify or even for individuals to self-assess (Ref.
11, Appendix D), the risk of bias can be reduced if the organizer of a scientific panel of experts
identifies and addresses sources of potential bias during the assembly and deliberations of the
panel.
In sections III.B through III.D, this document discusses the following sources of potential bias
that are particularly relevant for when a panel of scientific experts is being convened:
•

Balance of expertise 6;

•

Procedures for organizing a scientific panel and managing its deliberations; and

•

Conflict of interest and an “appearance issue” (i.e., an interest or relationship that may
create the appearance that an individual lacks impartiality on an issue).

B. Balance of Expertise
The significant omission of any required discipline or subdiscipline might seriously compromise
the quality of the panel’s analysis and judgments, even if the panel is composed of highly
qualified individuals. NASEM issued a policy (the NASEM policy) (Ref. 12) emphasizing that
the knowledge, experience, and perspectives of potential members of a committee convened by
Examples of cognitive patterns that can create bias (Ref. 7 and Ref. 8) include:
• Availability bias (i.e., the tendency to assume that the most available evidence is the most relevant);
• Confirmation bias (i.e., the tendency to look for or interpret subsequent data to support an initial
hypothesis);
• Order of effects bias (i.e., the tendency to overweigh or recall more about information received at the
beginning and end of an exchange);
• Outcome bias (i.e., the tendency to interpret data in ways that support a more benign or preferred outcome);
• Posterior probability bias (i.e., the tendency to assume that a history of certain outcomes or causes can be
extrapolated to the present assessment);
• Search “satisficing” (i.e., the tendency to stop gathering information once sufficient information has been
gathered to form a hypothesis); and
• Redundancy bias (i.e., the tendency to accord more weight to data that is greater in quantity or volume).
6
Members of a GRAS panel should have the appropriate scientific expertise in order to evaluate safety. This
discussion is focused on the need for the panel to have a balance of expertise.
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NASEM must be thoughtfully and carefully assessed and balanced in terms of the subtleties and
complexities of the particular scientific, technical, and other issues to be addressed, and the
functions to be performed by the committee. The NASEM policy points out that failure to
include an appropriate discipline can compromise the quality of a panel’s analysis and
judgments, and that, even within a particular discipline, there may be important differences and
distinctions within the field that require careful consideration in the committee composition and
appointment process.

C. Procedures for Organizing a Scientific Panel and Managing Its
Deliberations
Several organizations’ policies and publications address sources of potential bias that could
occur as a result of procedures for organizing small groups such as scientific expert panels and
managing their deliberations (Ref. 11 through Ref. 19). NAM has issued a report (the NAM
report) (Ref. 11) that discusses sources of potential bias in development of clinical practice
guidelines. 7 The NAM report states that the adoption of explicit, systematic methods for
reviewing evidence and developing and documenting practice guidelines is an important strategy
for reducing the opportunities for bias, whether the source might be intellectual and professional
preconceptions, financial interests, or something else. Immediately below, we describe some
examples from published literature of how the composition and organization of a scientific
expert panel, and procedures for managing its deliberations, could introduce potential bias into
the panel’s deliberations.
•

•

•

7

Seniority or perceived status among panel members could influence the extent to which
members are willing to volunteer information or raise objections (Ref. 13). Such effects
on the composition of the panel have the potential to introduce bias in the kinds of data
and information considered by the group.
The leader (whether formal or informal) of a panel could shape the group's norms around
evaluation of information and decision-making, moving the panel’s focus either towards
sharing and discussion of information or toward consensus (Ref. 14). Such influence has
the potential to lead to bias in the kinds of information considered and the weight
attached to various kinds of data. A consensus-focused norm can also discourage
members from voicing dissenting opinions (Ref. 13).
An effect called “illusory transactive memory” can occur when a group that does not hear
any discussion of significant issues associated with a topic assigned to a particular
member of the group later believes that they heard an actual discussion to the effect that
there were no significant issues even though the group actually did not hear any
discussion at all (Ref. 15). (In other words, the lack of discussion of a topic can translate
in the mind to an affirmation that there are no issues related to that topic.) If a panel
member does not share significant information identified in his or her discipline-specific
review, other members of the panel could later “recall” that no significant information
was found. This in turn has the potential to bias group assessments about the overall
weight of the evidence.

When NAM issued its report, the name of the organization was the “Institute of Medicine.”
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•

The way in which information is presented to a panel could create bias. Framing the
charge to the panel to emphasize potential risks or potential benefits has the potential to
create bias toward particular avenues of reasoning or a particular decision (Ref. 16 and
Ref. 17). Furthermore, the order in which information is presented to the panel has the
potential to lead to bias in the importance it is assigned by participants (Ref. 18 and Ref.
19).

D. Conflict of Interest and Appearance Issues
1.

Federal Regulations and FDA Guidances

As noted in the Introduction, this guidance includes recommendations for GRAS panels that are
informed by federal law, regulations, and FDA guidance documents related to FDA advisory
committee members. With respect to FDA advisory committees, we use the term “conflict of
interest” when we are referring to a conflict of interest within the meaning of 5 CFR part 2640
and the term “appearance issue” when we are referring to an interest or relationship within the
meaning of 5 CFR 2635.502 (“section 502”). A GRAS panel is not a federal advisory committee
under the Federal Advisory Committee Act (FACA) (5 U.S.C. App.), and a GRAS panel and its
members are not affiliated with the federal government. Therefore, our reference to these
requirements and guidance, which generally do not apply to GRAS panels or GRAS panel
members, is solely for the purpose of discussing concepts that are relevant to conflict of interest
and appearance issues for GRAS panels.
FDA’s advisory committees provide independent expert advice to us on scientific, technical, and
policy matters related to the development and evaluation of FDA-regulated products. Although
advisory committees provide recommendations to us, we make the final decisions. FDA’s
advisory committee process has some similarities to the GRAS panel process that is the subject
of this document. For example, both processes consider scientific and technical matters and both
processes provide information to a second party (FDA or the proponent) who uses the
information to reach a decision. In addition, the credibility of the conclusions of an advisory
committee or GRAS panel can be undermined when one or more members of the committee or
panel has a conflict of interest or an appearance issue and, thus, both the FDA advisory
committee process and the GRAS panel process can benefit from established, clear, transparent
criteria for identifying and managing conflicts of interest and appearance issues. However,
FDA’s relationship to a GRAS panel is not equivalent to an FDA advisory committee. Instead,
the GRAS panel organizer (together with the proponent, if these roles are distinct) stands in an
analogous relationship to the panel as we do to an FDA advisory committee. Thus, any decisions
regarding, for example, the design or application of waivers are the responsibility of the GRAS
panel organizer or proponent.
The regulations and guidances applicable to participation in an FDA advisory committee are
intended to provide transparency, clarity, and consistency for the advisory committee process
and enhance public trust in the advisory committee process. The statutory and regulatory
requirements for determining whether an advisory committee member (a special government
employee; SGE) has a potential conflict of interest and whether participation in an advisory
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committee meeting is appropriate are found in 18 U.S.C. 208(b), 21 U.S.C. 379d-1, and 5 CFR
part 2640. Where such a conflict exists, these statutory and regulatory requirements permit us to
grant a waiver allowing SGE participation in an advisory committee meeting when statutory
criteria are met; for example, when the need for the individual's services outweighs the potential
for a conflict of interest created by the financial interest involved (5 CFR 2640.302). A draft
guidance that we issued for public comment (Ref. 20; FDA’s draft appearances guidance) will,
when finalized, describe our process for evaluating whether an advisory committee member has
potentially disqualifying interests or relationships that fall into the category of “appearance
issues” under section 502 rather than financial interests that may create a recusal obligation
under federal conflict of interest laws.
Regulations concerning the prohibition of conflicts of interest under 18 U.S.C. 208(a) explain
that an employee (including an advisory committee SGE) may not participate in any “particular
matter” 8 (5 CFR 2640.103(a)(1)) that would have a “direct and predictable effect” 9 (5 CFR
2640.103(a)(3)) on their interests. As explained in FDA’s draft appearances guidance (Ref. 20),
5 CFR 2635.502 (“section 502”) addresses interests or relationships that may create the
appearance that an individual lacks impartiality on an issue. Section 502 implements the ethical
principle that a government employee should be impartial in performing official duties, meaning
that the employee must not give preferential treatment to any private organization or individual
or use public office for private gain. To the extent that an individual’s performance of official
duties might appear to benefit the individual or certain other individuals close to the individual,
the individual should take appropriate steps to avoid even an appearance of violating these
ethical principles. Section 502 places the initial burden of identifying potential appearance
issues on the potential advisory committee member, 10 who reports interests related to the subject
matter of the meeting on Form FDA 3410 (Ref. 21). Form FDA 3410 asks for information about
current and past financial interests that directly relate to the particular matter. Form FDA 3410
also asks for information about any other interests or relationships that might give rise to an
appearance issue. The member may make a threshold judgment as to whether the information
would cause a reasonable person to question his or her participation, and so inform FDA.

The term “particular matter” includes only matters that involve deliberation, decision, or action that is focused
upon the interests of specific persons, or a discrete and identifiable class of persons. It does not cover consideration
or adoption of broad policy options directed to the interests of a large and diverse group of persons such as actions
that will affect all companies or the economy in general (5 CFR 2640.103(a)(1)).
9
A particular matter will have a “direct” effect on a financial interest if there is a close causal link between any
decision or action to be taken in the matter and any expected effect of the matter on the financial interest. An effect
may be direct even though it does not occur immediately. A particular matter will not have a direct effect on a
financial interest, however, if the chain of causation is attenuated or is contingent upon the occurrence of events that
are speculative or that are independent of, and unrelated to, the matter. A particular matter that has an effect on a
financial interest only as a consequence of its effects on the general economy does not have a direct effect for the
purposes of this guidance. See 5 CFR 2640.103(a)(3)(i).
A particular matter will have a “predictable” effect if there is a real, as opposed to a speculative, possibility that the
matter will affect the financial interest. It is not necessary, however, that the magnitude of the gain or loss be
known, and the dollar amount of the gain or loss is immaterial. See 5 CFR 2640.103(a)(3)(ii).
10
Advisory committee members are considered to be special government employees during their service.
8

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Section 502 identifies “covered relationships” 11 and specific circumstances that may cause a
reasonable person to question a member’s impartiality. 12
FDA has issued a guidance (Ref. 22; FDA’s waiver guidance) that describes the basis for public
disclosure of certain financial interests by SGEs and regular government employees participating
in an advisory committee meeting and provides a format for FDA waivers allowing participation
in these meetings. FDA’s waiver guidance also explains how and when these documents will be
made publicly available by FDA.
While the FDA advisory committee process has some similarities to the GRAS panel process,
there are some important differences. One difference is that the statutes and regulations
applicable to FDA’s advisory committee process expressly provide for circumstances in which
FDA may grant a waiver that would allow an individual to participate in an advisory committee
meeting, in either a voting or non-voting capacity, even though the individual has a conflict of
interest (18 U.S.C. 208(b)(3), 5 CFR 2640.302, 21 CFR 14.80). FDA discloses such waivers as
part of the record of the advisory committee process (Ref. 22). In contrast, if a proponent allows
an individual to participate in a GRAS panel, in either a voting or non-voting capacity, even
though the individual has a conflict of interest, there generally would not be a public process
(such as a public meeting) whereby the proponent could disclose the conflict and the reasons for
waiver; the lack of a public process to make a “waived” conflict of interest transparent presents a
challenge to the proponent of the substance for waiving a conflict of interest or an appearance
issue without undermining the credibility of the GRAS panel’s opinion.
Another difference is that the primary function of the GRAS panel from FDA’s perspective is to
reflect the views of the broader scientific community, rather than to reach a scientific judgement
on specific data and information. FDA’s advisory committees often provide advice to FDA in
cases where data are incomplete, contradictory, or preliminary, and we are seeking input on a
decision or path forward in the face of these challenges. A GRAS conclusion, on the other hand,
is meant to be based on publicly available safety data that are generally accepted by experts. The
function of a GRAS panel is bound up with the extent to which it appears likely that most other
scientists with similar training would reach a similar judgement. This is distinct from providing
advice to FDA on an unresolved scientific issue to inform our decisions, as well as from the
question of whether a scientific judgement is defensible or consistent with the available data.

Examples of “covered relationships” include those with persons in the member’s household and with persons in
certain business relationships.
12
Examples include where the particular matter coming before the advisory committee is likely to have a “direct and
predictable effect” on the current financial interest of a member of the advisory committee member’s household, and
where a person (or entity) with whom the advisory committee member has a “covered relationship” is or represents
a “party to the matter” coming before the advisory committee. Section 502 includes examples of “covered
relationship” (e.g., a person or entity for which the member has, within the last year, served as an employee, officer,
director, consultant, agent, attorney, trustee, contractor, or general partner) and “party to the matter” (in most cases,
any sponsor of the product(s) coming before the advisory committee).
11

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2.

Policies and Literature Regarding Conflict of Interest and Appearance Issues

Several organizations’ policies and literature address conflict of interest and appearance issues,
and we have summarized them below.
a. The NASEM Policy
The NASEM policy explains that the FACA includes certain specific requirements regarding
work performed by NASEM for the U.S. government, including certain requirements relating to
committee composition and balance and conflict of interest. The NASEM policy emphasizes
that conclusions by fully competent committees can be undermined by allegations of conflict of
interest or lack of balance and objectivity.
The NASEM policy addresses both conflict of interest and appearance issues. The NASEM
policy uses the term "conflict of interest" to mean any financial or other interest which conflicts
with the service of the individual because it could: (1) significantly impair the individual's
objectivity; or (2) create an unfair competitive advantage for any person or organization. Except
for those situations in which the institution determines that a conflict of interest is unavoidable
and promptly and publicly discloses the conflict of interest, no individual can be appointed to
serve (or continue to serve) on a committee of the institution used in the development of reports
if the individual has a conflict of interest that is relevant to the functions to be performed. The
NASEM policy considers that appearance issues (which the NASEM policy discusses as
questions of lack of objectivity and bias) ordinarily relate to views stated or positions taken that
are largely intellectually motivated or that arise from the close identification or association of an
individual with a particular point of view or the positions or perspectives of a particular group.
Sources of potential bias in the context of appearance issues are not necessarily disqualifying for
purposes of committee service. The existence of a possible bias would be a factor to be taken
into account in the overall composition of the committee. However, the NASEM policy notes
that some appearance issues may be so substantial that they preclude committee service (e.g.,
where one is totally committed to a particular point of view and unwilling, or reasonably
perceived to be unwilling, to consider other perspectives or relevant evidence to the contrary).
b. The NAM Report
In 2007, NAM appointed the Committee on Conflict of Interest in Medical Research, Education,
and Practice to examine conflicts of interest in medicine and to recommend steps to identify,
limit, and manage conflicts of interest without negatively affecting constructive collaborations.
The NAM report defines conflict of interest as “a set of circumstances that creates a risk that
professional judgment or actions regarding a primary interest will be unduly influenced by a
secondary interest” (Ref. 11). The committee stated that financial interests are the most readily
identified and regulated and also noted that a financial interest does not have to be great for the
influence to be undue, citing social science research on the effects of small gifts, particularly in
the context of a sustained relationship. The committee acknowledged that other secondary
interests may also influence professional decisions, including professional advancement,
personal achievement, and favors to friends, family, and colleagues. The committee noted that
conflicts are not binary, and proposed criteria for assessing both the likelihood of undue
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influence as well as the seriousness of the harm that could result. The committee also proposed
criteria for evaluating conflict of interest policies, including proportionality, transparency,
accountability, and fairness. The committee discussed the role of disclosure in such policies,
viewing it as a necessary but insufficient element and recommending that disclosures be
sufficiently specific and comprehensive (with no minimum dollar threshold) to allow others to
assess the severity of the conflict.
In addition to general principles and recommendations, the NAM report discusses conflicts of
interest in a number of different areas, including the development of clinical practice guidelines.
The NAM report recommends that groups developing such guidelines:
•

Appoint a chair without a conflict of interest;

•

Limit members with conflicting interests to a distinct minority of the panel; and

•

Publicly disclose relevant conflicts of interest.
c. Other Published Reports

A report (Ref. 23) by a joint task force of the American College of Cardiology Foundation and
the American Heart Association discusses codes of conduct in human subjects’ research,
including both financial and non-financial conflicts of interest. The report notes that many nonfinancial incentives exist and are well recognized within the academic community.
A systematic review (Ref. 24) of conflict of interest in the development of clinical practice
guidelines defines such conflicts in accordance with the 2009 NAM report (primary versus
secondary interests); states that such conflicts are an important potential source of bias in
guideline development; and notes that the secondary interest in such conflicts may be financial or
non-financial. The authors observe that intellectual interests are increasingly recognized and
may be powerful motivators for researchers, systematic reviewers, and guideline authors.
A report (Ref. 25) by members of the American College of Chest Physicians involved in
development of clinical practice guidelines recommends placing equal emphasis on both
financial and intellectual conflicts of interest. The report defines intellectual conflicts as
academic activities that create the potential for an attachment to a specific point of view that
could unduly affect an individual's judgment about a specific recommendation. Such activities
include receipt of a grant or participation in research or commentary directly related to that
recommendation.
The National Comprehensive Cancer Network (Ref. 26) considers conflicts of interest, or the
appearance of such conflicts, as a source of potential bias in the development of treatment
guidelines that could compromise or diminish the integrity of such guidelines. Conflicts
encompass financial interests as well as organizational affiliations, activities, or other interests
that could impair objectivity or create an unfair competitive advantage. Recommendations and
practices include the following, with additional restrictions on the interests and activities of
chairs and vice-chairs:
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•

Public disclosure of all conflicts by guideline development panel members;

•

Exclusion of potential members with financial conflicts above a threshold;

•

Recusal of members from specific matters as warranted; and

•

Removal of members if no longer able to serve effectively due to the number of recusals.

IV. Definitions
For purposes of this document, we define the following terms below.
Ad hoc GRAS panel – A GRAS panel that is convened on a temporary basis.
Appearance issue – An interest or relationship that may create the appearance that an individual
lacks impartiality on an issue (see 5 CFR 2635.502 for guidance on the process used by federal
agencies for analyzing and resolving appearance issues). Whereas conflicts of interest include
financial interests that can be directly and predictably affected by the work of the GRAS panel,
appearance issues include a broader and more complex set of interests and relationships that
could cause a reasonable person to question impartiality.
Conclusion of GRAS status/GRAS conclusion – A conclusion that a substance is GRAS under
the conditions of its intended use.
GRAS – Generally recognized as safe.
GRAS panel – A panel 13 of qualified experts who independently evaluate whether the available
scientific data, information, and methods establish that a substance is safe under the conditions of
its intended use in human food or animal food as part of an evaluation of whether adding that
substance to food is lawful under the GRAS provision of the FD&C Act. The panel may be
convened for evaluation of a single ingredient (ad hoc panel) or for longer periods of time to
evaluate multiple substances (standing panel).
Notifier – The person (e.g., an individual, partnership, corporation, association, or other legal
entity) who is responsible for a GRAS notice submitted to FDA, even if another person (such as
an attorney, agent, or qualified expert) prepares or submits the notice or provides an opinion
about the basis for a conclusion of GRAS status.
Organizer – The party (such as a proponent, an employee of the proponent, or an attorney or
agent who acts on behalf of a proponent) who assembles a GRAS panel.
Proponent – The party who takes responsibility for a conclusion of GRAS status.

A panel is “[a] group of persons selected for some service (such as investigation or arbitration).” MerriamWebster.com. Accessed on October 31, 2019.

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Qualified expert – An individual who is qualified by scientific training and experience to
evaluate the safety of substances under the conditions of their intended use in food.
Standing GRAS panel – A GRAS panel that is convened on a permanent (or extended) basis.
Written GRAS panel policy – A written policy to govern procedures for assembling and
managing a GRAS panel, including an assessment of the potential for bias created by a conflict
of interest or an appearance issue in an individual under consideration for selection as a member
of a GRAS panel and including strategies for managing conflicts and appearance issues.

V.

Recommendations
A. Introduction

Convening a GRAS panel and relying on the GRAS panel as a representative sample of the
larger scientific community knowledgeable about the safety of substances directly or indirectly
added to food is one mechanism that proponents have used to support their conclusion that the
safety of a substance under the conditions of its intended use in human food or animal food is
generally recognized. However, the use of a GRAS panel is not the only mechanism for doing
so, and the use of a GRAS panel does not necessarily mean that the GRAS criteria have been
met. As discussed in section II.A, we have established criteria for eligibility for classification as
GRAS in 21 CFR 170.30 and 21 CFR 570.30 for substances intended for use in human food and
animal food, respectively. A GRAS panel is not a required element of these criteria.
In the remainder of the recommendations section of this guidance, we discuss detailed
recommendations related to selecting GRAS panel members, the operation of a GRAS panel,
submitting a GRAS notice to FDA, and other recommendations as summarized immediately
below. As noted previously, a GRAS panel is just one mechanism that proponents have used to
demonstrate that the safety of a substance under the conditions of its intended use is generally
accepted by qualified experts. It may be worth considering whether the effort to convene a
GRAS panel is warranted in any particular case before allocating resources to it.
1.

Recommendations Related to Selecting GRAS Panel Members

To convene a GRAS panel that can effectively evaluate the available scientific data, information,
and methods and act as a representative sample with respect to the larger scientific community of
qualified experts, and to reduce the risk that bias (or the appearance of bias) will affect the
credibility of the GRAS panel report, as discussed in more detail in sections V.B through V.D,
we recommend that the organizer (whether it be a proponent who has identified a need for a
GRAS panel or a third party in the business of convening such panels) establish and implement a
written GRAS panel policy 14 that includes general principles and procedures for:
A proponent who intends to convene the panel themselves and does not expect to convene further panels in the
foreseeable future could also consider documenting the ways in which they identified and managed sources of
potential bias described in this guidance as part of their documentation of the overall GRAS conclusion.

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•

Assessing and balancing the knowledge, experience, and perspectives of potential GRAS
panel members in terms of the subtleties and complexities of the particular scientific and
technical issues applicable to a food substance and its intended use in human food or
animal food;

•

Considering and taking steps to address procedural issues associated with the
organization and deliberations of the GRAS panel;

•

Considering and taking steps to assess potential GRAS panel members for conflicts of
interest and appearance issues;

•

Documenting how the organizer applied the written GRAS panel policy to the selection
and vetting of each member of the GRAS panel; and

•

Taking steps to provide transparency and clarity regarding the selection and vetting of
each member of the GRAS panel.
2.
Recommendations Related to the Operation of the GRAS Panel and to the
Submission of a Notice to FDA

As discussed in section II.B, we have established a GRAS notification procedure (in 21 CFR part
170, subpart E and part 570, subpart E for substances intended for use in human food and animal
food, respectively) through which any interested person may notify us of a conclusion that a
substance is GRAS under the conditions of its intended use in food. Our experience with GRAS
notices in which the person who submitted the GRAS notice (“notifier”) reported the findings of
a GRAS panel, as well as comments we received during the rulemaking to establish the GRAS
notification procedure, 15 have informed the recommendations in sections V.E through V.H for:
•

The information that the proponent of a GRAS conclusion would provide to the GRAS
panel;

•

Documenting the deliberations and output of a GRAS panel;

•

Considerations when a GRAS notice is submitted to FDA; and

•

Considerations when a GRAS notice is not submitted to FDA.
3.

•

Other Recommendations

In section V.I, we provide our recommendations regarding honoraria provided to a GRAS
panel.

See, e.g., the discussion in section I.E of the GRAS final rule and Comment/Response 8, 11 through 13, 58, 69,
and 78 in the GRAS final rule (81 FR 54960).

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We received fewer than a dozen GRAS notices where the statutory basis for the notifier’s
conclusion of GRAS status was through experience based on common use in food (Ref. 27).
Therefore, in this guidance, we focus on best practices applicable to a GRAS panel that is
convened when the statutory basis for the proponent’s conclusion of GRAS status is through
scientific procedures.

B. Appropriate and Balanced Expertise in a GRAS Panel
1.

General Considerations When Convening a GRAS Panel

We recommend that the organizer, the proponent’s attorney or agent, or employees of the
proponent, organizer, or the proponent’s attorney or agent not be members of a GRAS panel,
because such individuals generally would have a conflict of interest due to a direct and
predictable financial interest in the outcome of the panel’s deliberations (see the examples of
conflict of interest in Table 3). However, if such an individual has specialized experience that
could be helpful to a GRAS panel, the proponent or organizer could consider whether that
individual could act as a scientific advisor to the GRAS panel by providing factual information
to the GRAS panel without participating in any of the GRAS panel’s deliberations.
Alternatively, the proponent or organizer could consider having that individual participate in
deliberations of the GRAS panel without providing an opinion that would be included in any
report generated by the GRAS panel; such participation would be analogous to “non-voting
members” who are granted a waiver per 5 CFR part 2640 when necessary to afford essential
expertise to an FDA advisory committee. The potential value of such an individual’s
participation, even in an advisory or non-voting capacity, should be carefully weighed against
the introduction of another significant source of potential bias, which could reduce the credibility
of the GRAS panel as a representative sample with respect to the views of the broader expert
community.
2.

Appropriate Expertise in a GRAS Panel

We recommend that the organizer consider individuals with expertise that reflects the physical,
chemical, and biological properties of the food substance and the scientific questions that arise in
relation to the conditions of its intended use. At a minimum, we recommend that a GRAS panel
include members with expertise suitable to establish the identity and properties of the ingredient
(e.g., chemistry, biochemistry, protein chemistry, or microbiology) as well as expertise in
toxicology and exposure assessment, because our experience with GRAS notices demonstrates
that these scientific disciplines broadly apply to most safety evaluations. For substances
intended for use in animal food, a GRAS panel should include members with expertise suitable
to establish the identity and properties of the ingredient (e.g., chemistry, biochemistry, protein
chemistry, or microbiology), expertise in toxicology and exposure assessment, as well as
expertise suitable to evaluate the safety of the substance under the conditions of its intended use
for the target animal(s) and, when added to food for food-producing animals, for humans
consuming human food(s) derived from these animals. While one individual may have expertise
in multiple areas, it may be difficult for a single individual to represent the broader views of
multiple scientific disciplines credibly. See Table 2 for examples of additional recommended
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expertise on a GRAS panel based on the food substance and/or the conditions of its intended use.
Note that in cases where specialized expertise is appropriate, it is generally supplemental and
complementary to the core disciplines identified above. Not every GRAS panel member need be
versed in food ingredient safety assessment, as long as they are in dialogue with other members
who are.
Table 2.—Examples of Recommended Expertise on a GRAS Panel Based on the Food
Substance or the Conditions of its Intended Use
Food Substance or Conditions of its Intended Use
Enzyme produced from a microorganism
Botanically-derived substance
Substance that could have allergenic properties
Use in infant formula
Substance that has a specific physiologic effect
Complex ingredient, or ingredient defined partly by its
method of manufacture
Microbial ingredient
Substance intended to supply a nutrient
Substance intended for a technical effect (e.g., emulsifier,
binder)

Recommended Expertise
Microbiology; enzymology
Plant chemistry
Allergy
Pediatric nutrition
Expertise to address the long-term significance
of the physiological effect in the general
population or in relevant subpopulations
Chemistry; food manufacturing; food processing
Microbiology; immunology
Nutrition
Chemistry; food manufacturing; food processing

In some cases, the substance is already used in food but, for example, there has been a significant
change in the manufacturing process; there would be an increased level of the substance
compared to the levels already in use; or the intended use of the substance would be different
from existing uses. As noted elsewhere in this document, in many cases, the process whereby
the proponent evaluates whether the available data and information support a conclusion that a
substance is GRAS under the conditions of its intended use need not include a GRAS panel.
However, if a proponent decides to convene a GRAS panel in such circumstances, the emphasis
in selecting members of a GRAS panel should be on the expertise necessary to assess the change.
For example, if there has been a significant change in the manufacturing process, a chemist,
biochemist, or food technologist should evaluate the potential for toxic contaminants or
impurities associated with the new process, and a toxicologist or other scientist with expertise
applicable to the nature of those contaminants or impurities should evaluate the safety of the
substance produced using the new manufacturing process. For increased use levels, the key
expertise would be toxicology or a related scientific discipline to evaluate whether the available
data and information support the safety of an increased exposure to the substance. If the
intended use of the substance would be significantly different from existing uses, an individual
with expertise in exposure assessment should evaluate the new estimated dietary exposure and
one or more individuals with expertise in the potential toxicological or physiological effects of
the substance under the new conditions of use should evaluate whether the available data and
information support the safety of the substance under the new conditions of use. In the case of a
substance intended for use in animal food, for example, if the intended use of the substance
would be for different animal species, an individual with expertise in assessing safety for the
target animal, and potentially for human food(s) derived from the target animal, should evaluate
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animal and human exposures and possible toxicological and physiological effects of the
substance under the new conditions of use.
To optimize the applicable experience of the GRAS panel members, we recommend that an
organizer who convenes a GRAS panel convene an ad hoc GRAS panel rather than a standing
GRAS panel. However, a standing GRAS panel could be appropriate when considering a class
of substances closely related by conditions of use, function, or other properties, where the
experience and expertise of the panel members align with the scientific questions applicable to
that class of substances, or if a standing GRAS panel is supplemented with members with
additional expertise to address the physical, chemical, and biological properties of a specific food
substance and the complexity of the scientific questions that arise in relation to the conditions of
its intended use. One issue with standing GRAS panels is the potential for development of a
particular group perspective over time, 16 which may reduce the ability to credibly represent the
views of the broader scientific community. The organizer of such a panel may wish to consider
strategies for occasionally calibrating or cross-checking the panel’s perspective to ensure it
remains representative.
3.

Number of Members of a GRAS Panel

We recommend that the organizer determine the total number of GRAS panel members, as well
as the number of GRAS panel members with the same expertise, based on the substance, the
complexity of the scientific issues associated with the conditions of its intended use, and the
available data and information about the substance. As noted above, when the evidence for
safety comprises published peer-reviewed scientific literature consistent with generally accepted
safety assessment strategies, a GRAS panel of any size may be unnecessary. However, when the
available data and information relevant to the intended conditions of use of the substance involve
complex scientific issues that experts would need to interpret and resolve, we recommend that
the organizer consider having multiple representatives with expertise applicable to those
scientific issues so that there can be genuine discussion and critical analysis on those complex
scientific issues.
From FDA’s perspective, the goal of a GRAS panel, unlike a federal advisory committee, is to
provide some evidence of the generally accepted view in one or more scientific disciplines
regarding the underlying publicly available safety data. Diverse scientific views can be
extremely valuable in testing the robustness of a potential scientific acceptance, and we
encourage panel organizers to consider taking advantage of diverse scientific viewpoints to
enhance the credibility of the panel as a representative sample of the broader community.
However, the GRAS panel’s function is to adequately represent a scientific community of
qualified scientific experts rather than society as a whole, and we do not anticipate or
recommend that GRAS panel members participate as representatives of a specific societal sector.
Importantly, although general recognition of safety does not require unanimous agreement,
general recognition of safety does not exist if there is a genuine dispute among qualified experts
16

This can also be an issue if ad hoc GRAS panels are repeatedly populated from a small pool of individuals.
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Contains Nonbinding Recommendations

that the use of a substance is safe (See, e.g., United States v. Articles of Drug Consisting of
Following: 5,906 Boxes, 745 F.2d 105, 119 n. 22 (1st Cir. 1984); United States v. Articles of
Food and Drug (Coli-Trol 80), 518 F.2d 743, 746 (5th Cir. 1975)) or a severe conflict among
experts regarding the safety of the use of a substance (United States v. An Article of Drug 4,680
Pails, 725 F.2d 976, 990 (1st Cir. 1984); Premo Pharmaceutical Laboratories v. United States,
629 F.2d 795, 803 (2d Cir. 1980)). Thus, when generally available data and information
document a genuine dispute, or severe conflict, in the larger scientific community, a GRAS panel
report could not provide evidence that the available data and information are “generally
accepted” even if multiple members of a GRAS panel have expertise in a particular scientific
discipline. Instead, the GRAS panel report would more appropriately be a resource for the
proponent to use in identifying data gaps and information about ongoing scientific debate and
dispute.

C. Assessment and Management of Procedural Issues Associated with
the Organization and Deliberations of a GRAS Panel
We recommend that a written GRAS panel policy address the potential for bias that could occur
through procedures associated with the organization and deliberations of a GRAS panel by:
•

Establishing clear roles and responsibilities for each member of the GRAS panel;

•

Establishing clear decision-making procedures that the GRAS panel will follow;

•

Specifying whether the charge to the GRAS panel will inform the members of the GRAS
panel about the potential for bias (e.g., due to cognitive patterns); and

•

Considering factors such as seniority or perceived status among panel members and the
leadership skills of an individual who would be the formal leader of the GRAS panel (or
likely to become the informal leader if the organizer does not appoint a formal leader).

We also recommend that the proponent take appropriate steps to avoid influencing the
deliberations of the GRAS panel – e.g., by formulating the charge to the panel in neutral,
unbiased language; limiting communication with the GRAS panel to the minimum necessary to
manage the affairs of the GRAS panel efficiently and effectively; and then awaiting the outcome.

D. Assessment and Management of Conflict of Interest and Appearance
Issues of Potential GRAS Panel Members
1.

Overview

We recommend that a written GRAS panel policy address the potential for conflict of interest
and appearance issues during the selection and vetting of GRAS panel members. We also
recommend that a written GRAS panel policy be publicly available and provide for transparency
by allowing outside parties to assess the process used to assess and manage conflicts of interest
26

Contains Nonbinding Recommendations

and appearance issues in members of the GRAS panel. We discuss in more detail our
recommendations for a written GRAS panel policy to address the following factors:
•

The process for identifying conflicts of interest and appearance issues;

•

Criteria for evaluating identified conflicts of interest and appearance issues, including
criteria for automatic or routine exclusion from panel membership, and strategies for
managing conflicts of interest and appearance issues; and

•

Documentation of conflicts of interest, appearance issues, and rationales for waivers.
2.

Identifying Conflict of Interest and Appearance Issues

We recommend that a written GRAS panel policy include a process for identifying competing
interests, including conflicts of interest and appearance issues. For the purposes of this
document, conflicts of interest include financial interests that can be directly and predictably
affected by the work of the GRAS panel, whereas appearance issues include a broader and more
complex set of interests and relationships that could cause a reasonable person to question
impartiality. See Table 3 for examples of sources of conflict of interest. See Table 4 for
examples of appearance issues. 17 In our view, both sources of potential bias (conflict of interest
and appearance issues) have similar significance with respect to a GRAS panel’s core function of
providing evidence of community views, as described in III.D.1. From FDA’s perspective, the
primary function of the GRAS panel is to reflect the views of the broader scientific community,
rather than to reach a scientific judgement on specific data and information. A GRAS conclusion
is meant to be based on publicly available safety data which are generally accepted by experts.
Therefore, the function of a GRAS panel is bound up with the extent to which it appears likely
that most other scientists with similar training would reach a similar judgement. This is distinct
from the question of whether a scientific judgement is defensible or consistent with the available
data. See section II.C.2.
Table 3.—Examples of Conflict of Interest
Source of Conflict of Interest
Ownership of any equity of an affected entity (excluding equity held through a publicly traded diversified (i.e.,
non-food sector specific) mutual fund)
Compensation for services, such as management or consulting services to an affected entity (excluding
honoraria for service on the GRAS panel; see section V.I for recommendations regarding honoraria)
A role as director, officer, trustee, general partner, or employee of an affected entity (including trade and
professional associations)
Examples in both tables are drawn from 18 U.S.C. 208, 5 CFR parts 2635 and 2640, and FDA’s guidance on
advisory committees (Ref. 20 and Ref. 22), as well as from our review of the NAM report (Ref. 11), the NASEM
policy (Ref. 12), the codes of conduct for the American College of Cardiology Foundation and the American Heart
Association (Ref. 23), and a sample draft guidance submitted to the public docket for FDA’s rulemaking to establish
the GRAS notification procedure (Ref. 28). As noted in section III.D, our recommendations are informed by federal
law, regulations, and FDA guidance documents related to advisory committee members and our reference to these
requirements and guidance is solely for the purpose of discussing concepts that are relevant to conflict of interest
issues for GRAS panels.
17

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Contains Nonbinding Recommendations

Source of Conflict of Interest
Funding for research purposes from an affected entity, regardless of whether there is post-grant oversight
A debt relationship of any kind with an affected entity, whether as lender, borrower, holder of debentures, or
the like
Any of the above examples with respect to a spouse, minor child, general partner, or prospective employer

Table 4.—Examples of Appearance Issues
Appearance Issue
Direct and predictable effect on the current financial interest of a household member, including adult children
and parents, as well non-relatives in residence
Having or seeking a business, contractual, or other financial relationship with an affected entity
Having a household member, or relative with a close personal relationship who is an affected entity
Serving in the last year as an employee, officer, director, consultant, agent, attorney, trustee, contractor, or
general partner for an affected entity
Having a spouse, parent, or dependent child who currently serves or is seeking to serve as an employee, officer,
director, consultant, contractor, agent, attorney, trustee, or general partner of an affected entity
Being an active participant in an organization that is an affected entity
Consistently and strongly advocating specific views or positions on a scientific issue relevant to safety
assessment
Having one’s own work as a key element of the relevant evidence for safety of the substance under the
conditions of its intended use

3.
Criteria for Evaluating Identified Conflicts of Interest and Appearance Issues and
Strategies for Managing Identified Conflicts of Interest and Appearance Issues
We recommend that a written GRAS panel policy establish pre-existing criteria for evaluating
the significance of conflicts of interest and appearance issues. Conflicts of interest are ordinarily
financial. Some policy frameworks, including FDA guidance (Ref. 22) discussed above, as well
as other policies from certain organizations (Ref. 26), ordinarily exclude members with
significant financial conflicts of interest from a committee or panel. These frameworks assess
the significance of a conflict in terms of the dollar value, although other factors such as the
duration of the interest or value relative to overall assets could also be considered. Appearance
issues, on the other hand, are often more complex and less clear-cut and may not be amenable to
quantification in the same way. Factors that could potentially be considered in assessing the
significance of an appearance issue include:
•
•
•
•

The nature of a relationship of interest, including history and current status of the
relationship;
The effect that a particular conclusion would have upon the financial interests of a person
involved in a relationship of interest;
The extent to which a person has committed to or is associated with a particular point of
view on a matter relevant to the decision; and
The degree to which research conducted by the person bears on the specific questions
before the GRAS panel.

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Contains Nonbinding Recommendations

We recommend that a written GRAS panel policy include strategies for managing conflicts and
appearance issues. These strategies could include:
•

Establishing pre-existing criteria for excluding an individual from service on a GRAS
panel based on a conflict of interest or appearance issue of sufficient significance, such
as those listed in Table 3 and Table 4; 18

•

Establishing pre-existing criteria for waiving an exclusion triggered by a conflict of
interest or appearance issue;

•

Including “balancing” viewpoints on a particular issue where one or more members is
strongly associated with a particular viewpoint;

•

Disclosing conflicts of interest and appearance issues to all panel members to allow them
to weigh this information in their assessment of the perspectives and contributions of
various panel members; and

•

Including some panel members who have a conflict of interest or an appearance issue as
non-voting members who can still contribute to deliberations, albeit in an advisory
capacity only.

Waivers and monetary thresholds for acceptable conflicts are two commonly used strategies in
assembling expert panels. We are not recommending specific criteria for administering waivers
or defining specific monetary thresholds, in part because, unlike a federal advisory committee,
GRAS panels are not organized by and do not report to FDA. These decisions are the GRAS
panel organizer’s responsibility, and we recommend that each organizer clearly document their
rationale for whatever waiver or threshold criteria they establish.
We realize that it can be challenging to identify, screen, and select a comprehensive panel of
qualified experts in light of the need for specialized expertise applicable to the scientific
considerations associated with the intended conditions of use of a food substance and the finite
number of experts who are both qualified and available to serve on a GRAS panel. There may
be circumstances in which the need for the individual's services outweighs the potential for a
conflict of interest or appearance issue in order to provide the GRAS panel essential expertise. 19
For this and other reasons it may be useful to prepare strategies of the types discussed above.
However, it is also important to remember that a GRAS panel is just one mechanism that can be
used to provide evidence of general acceptance, and in many cases a panel may not be necessary.
In the limited number of cases where there are alternative interpretations of the available data
and the proponent seeks the type of evidence of general acceptance that a GRAS panel could
provide, successful management of sources of potential bias associated with the panel becomes a
18
As discussed in section V.I., FDA recognizes that GRAS panel members are generally compensated for their time;
we are not suggesting that such compensation represents an unacceptable conflict of interest, provided that the
compensation is independent of the outcome.
19
See, e.g., the discussion in FDA’s draft appearances guidance (Ref. 21) regarding the criteria for granting a
section 502 authorization enabling participation of a Special Government Employee in an FDA advisory committee.

29

Contains Nonbinding Recommendations

pressing concern. In such cases, it may be necessary to find ways to address the challenges
acknowledged above.
4.
Documentation of Conflicts of Interest, Appearance Issues, and Rationales for
Waivers
We recommend that a written GRAS panel policy describe how to document that the process
used for identifying and managing conflicts of interest and appearance issues was implemented
in the case of a particular GRAS panel. We also recommend that the policy address
documentation of all conflicts of interest and appearance issues identified in the process of
forming a GRAS panel and how these issues were managed, whether through waivers or some
other method. This may include a discussion of the rationale for each waiver, along with the
views of the organizer or proponent on the net effect of each conflict or appearance issue on the
ability of the panel to serve as a credible representative sample of the larger scientific
community. As noted elsewhere in this guidance, from FDA’s perspective, a key criterion for
evaluating a GRAS panel’s conclusion is whether qualified scientists with similar training and
experience would likely reach the same conclusion. This documentation may help in the
interpretation of the significance and strength of a GRAS panel conclusion where the type of
evidence of general acceptance that a panel could provide is necessary to support the common
knowledge element of a GRAS conclusion.
5.

Format of a Written GRAS Panel Policy

The format of a written GRAS panel policy should promote clarity and transparency. For
example, the policy could be structured as a series of individual questions followed by a chart
that organizes the flow of the individual questions.

E. Information Provided to a GRAS Panel
As noted in section V.A, in this guidance, we focus on best practices applicable to a GRAS panel
that is convened when the statutory basis for the proponent’s conclusion of GRAS status is
through scientific procedures. When a conclusion of GRAS status is through scientific
procedures, general recognition of safety is based upon the application of generally available and
accepted scientific data, information, or methods, which ordinarily are published, as well as the
application of scientific principles, and may be corroborated by the application of unpublished
scientific data, information, or methods (21 CFR 170.30(b) and 570.30(b)).
Although general recognition of safety through scientific procedures may be corroborated by the
application of unpublished scientific data, information, or methods, to satisfy GRAS criteria
qualified experts need to be able to conclude that the substance is not harmful under the
conditions of its intended use without access to “corroborative” information (81 FR 54960 at
54973). For example, there could be no basis for a conclusion of GRAS status if trade secret
information (or other non-public information) is necessary for qualified experts to reach a
conclusion that the notified substance is safe under the conditions of its intended use (81 FR
54960 at 55000). Therefore, we recommend that the organizer minimize the amount of non30

Contains Nonbinding Recommendations

public information provided to a GRAS panel because access to unpublished or restricted
information can make it more difficult to credibly identify what outcome the GRAS panel would
have reached without that information. In cases where a proponent has identified a need for a
GRAS panel, the proponent should carefully consider the value that the GRAS panel’s exposure
to confidential information would bring relative to the potential for reducing confidence that the
GRAS panel’s conclusion reflects general acceptance of public data.
An exception relates to data and information that could raise a question about the safety of the
substance under the conditions of its intended use. We recommend that the data and information
that the organizer provides to a GRAS panel include a description of all data and information that
could raise such a safety question, regardless of whether those data and information are publicly
available. Doing so is appropriate to make the data and information provided to the GRAS panel
complete, representative, and balanced and would be consistent with the requirements we have
established for a GRAS notice (see 21 CFR 170.250(c) and 570.250(c)).
In some cases, the proponent chooses to make the opinion of a GRAS panel public – e.g., by
publishing the GRAS panel opinion in the peer reviewed scientific literature. Whether a
published GRAS panel opinion that discusses data and information that are not generally
available could support an independent GRAS conclusion would depend on factors such as
whether the published opinion includes details similar to details that would be included in a
publication in the primary scientific literature; the subject matter expertise of the members of the
GRAS panel; and whether the members of the GRAS panel would be considered representative
of experts qualified by scientific training and experience to evaluate the safety of the substance
under the conditions of its intended use (81 FR 54960 at 54966).

F. Documenting the Deliberations and Conclusions of a GRAS Panel
The organizer should consider how to document the deliberations and conclusions of a GRAS
panel. We recommend clear and explicit documentation of: (1) the available data and
information that the GRAS panel reviewed; (2) how the GRAS panel handled its deliberations;
and (3) the basis for the conclusion of the GRAS panel.
As noted in section I of this document, when the members of a GRAS panel agree that the
generally available data and information demonstrate that a substance is safe under the
conditions of its intended use, the members of the GRAS panel are serving as a representative
sample of the larger scientific community knowledgeable about the safety of substances directly
or indirectly added to food. Therefore, the deliberations and GRAS panel report should address
this threshold question of whether the panel members agree that the generally available data and
information demonstrate that substance would be safe under the conditions of its intended use
rather than the subsequent question of whether the substance would be GRAS under the
conditions of its intended use. It is the proponent’s responsibility to subsequently draw a
conclusion on whether the intended conditions of use of the substance satisfy the criteria for
eligibility for classification as GRAS.

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Contains Nonbinding Recommendations

We recommend that each member of the GRAS panel identify the particular data or information
that form the basis for his or her opinion on whether the intended use of the substance is safe,
both during deliberations and in any written GRAS panel report. We also recommend that
GRAS panel members avoid filling a gap in the available data and information through
theoretical considerations and prior relevant experience – e.g., making overly broad inferences
(in the absence of data) about safety of the substance in question based on the properties of other
substances that are related in some way, or based on professional familiarity with a particular
class of substances. From a procedural perspective, this approach is a significant source of
potential bias. Members of the GRAS panel should limit the role of theoretical considerations
and prior relevant experience to determining which of the available data and information are
relevant to the safety of the substance under the conditions of its intended use. However, this
recommendation is not meant to discourage the use of well-established, rigorous methods of
extrapolation, such as read-across practices and quantitative structure-activity relationships (see
Ref. 29, Ref. 30).
As discussed in section I of this document, the proponent may be relying on the deliberations and
report of a GRAS panel to serve as a representative sample of the larger scientific community
knowledgeable about the safety of substances directly or indirectly added to food. Therefore, we
recommend that the organizer establish and implement a mechanism to demonstrate that the
deliberations of a GRAS panel and any GRAS panel report broadly reflect the views of the
scientific community knowledgeable about the safety of substances directly or indirectly added
to food in addition to the individual views of each panel member. For example, each panel
member could identify the basis for concluding that his or her view is representative of the views
held by most scientists in the respective discipline.

G. Considerations When a GRAS Notice is Submitted to FDA
Any person who submits a GRAS notice to FDA must include a signed statement certifying that
to the best of the notifier’s knowledge, the GRAS notice is a complete, representative, and
balanced submission that includes unfavorable information, as well as favorable information,
known to the notifier and pertinent to the evaluation of the safety and GRAS status of the
intended use of the substance (21 CFR 170.225(c)(9) and 570.225(c)(9)). The certification
statement is intended, in part, to emphasize the notifier’s responsibility to identify, discuss, and
place in context, data and information that are, or may appear to be, inconsistent with a
conclusion of GRAS status, regardless of whether those data and information are generally
available (81 FR 54960 at 54994). Thus, as already noted in section V.E, we recommend that
the data and information that organizer provides to a GRAS panel include a description of all
data and information that are, or may appear to be, inconsistent with a conclusion of GRAS
status, regardless of whether those data and information are publicly available.
The certification statement also is intended, in part, to communicate our expectation that a
notifier would describe, and place in context, unpublished data and information if the notifier
considers that the findings of the unpublished data and information warrant sharing with a GRAS
panel (81 FR 54960 at 54994). Although we recommend that the organizer minimize the amount
of non-public information provided to a GRAS panel (see the discussion in section V.E), a
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Contains Nonbinding Recommendations

notifier who does provide non-public information to a GRAS panel should describe, and place in
context, those unpublished data and information in any GRAS notice that mentions the findings
of a GRAS panel. This includes, for example, studies that the notifier considers corroborative of
safety (81 FR 54960 at 55994) as well as any trade secret information regarding the method of
manufacture (81 FR 54960 at 55000).
Any person who submits a GRAS notice must include a narrative that explains how the generally
available data and information that the notifier relies on to establish safety provide a basis for the
notifier’s conclusion that the notified substance is generally recognized, among qualified experts,
to be safe under the conditions of its intended use (21 CFR 170.250 and 570.250). For nonpublic, safety-related data and information considered in reaching a conclusion of GRAS status,
the notifier must explain how there could be a basis for a conclusion of GRAS status if qualified
experts do not have access to such data and information. If non-public information is provided
to a GRAS panel, the notifier would be required to explain how there could be a basis for a
conclusion of GRAS status if qualified experts (other than those on the GRAS panel) do not have
access to such data and information (21 CFR 170.250(e) and 570.250(e)). As noted above,
exposure to non-public data and information can sometimes make it much harder to credibly
assert that the panel’s conclusion is representative of the expert scientific community based on
public data.
In our view, most GRAS conclusions do not need a GRAS panel (81 FR 54960 at 55026).
However, in some cases, we might recommend consulting with us on whether a GRAS panel
could be useful in generating evidence of general acceptance (see Figure 1). Where a panel’s
deliberations constitute primary evidence supporting the general acceptance aspect of the GRAS
criteria for the intended use, FDA would be unable to evaluate this evidence and the significance
of the GRAS conclusion unless the composition, deliberations, and the outcome of the GRAS
panel are provided by the notifier.

H. Considerations When a GRAS Notice is Not Submitted to FDA
The GRAS criteria (21 CFR 170.30(a) to (c) and 21 CFR 570.30(a) to (c)) apply regardless of
whether a conclusion of GRAS status is submitted to us as a GRAS notice or whether it is an
independent conclusion of GRAS status that remains with the proponent. We advise any
company that intends to market a food substance on the basis of an independent conclusion of
GRAS status to carefully consider the recommendations in this guidance and to apply them to its
own assembly and management of a GRAS panel. However, as previously noted, the outcome
of a GRAS panel’s deliberations does not create or confer general recognition status on the use
of an ingredient. Rather, it can provide evidence supporting the proponent’s contention that
there is general acceptance based on generally available information among relevant scientific
communities. Ultimately, all decisions regarding the safe and lawful use of a substance in food,
including decisions about GRAS status, are subject to FDA review (see, for example 21 CFR
170.38). If a question arises, a well-constructed GRAS panel for which all sources of potential
bias are addressed and managed may be useful to support the proponent’s conclusion. When a
use of a substance does not qualify for GRAS status or other exceptions provided under section
201(s) of the FD&C Act, that use of the substance is a food additive use subject to the premarket
33

Contains Nonbinding Recommendations

approval mandated by the FD&C Act. Under Section 409 of the FD&C Act, a food additive not
approved for its intended use is deemed unsafe. Any food that is, or bears or contains, a food
additive that is unsafe is adulterated under section 402(A)(2) of the FD&C Act.

I. Honoraria Provided to Members of a GRAS Panel
We recommend that the written GRAS panel policy address the honoraria provided to a GRAS
panel. We recognize that members of a GRAS panel are generally compensated, and in our
opinion, such compensation is not itself an unacceptable conflict. However, an honorarium
provided to members of a GRAS panel should not be contingent on the outcome of deliberations
by a GRAS panel. We consider that such conditional compensation creates an unacceptable
conflict of interest that undermines the credibility of a GRAS panel report.

VI. Paperwork Reduction Act of 1995
This guidance contains information collections that are subject to review by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 35013521).
The time required to complete this information collection is estimated to average 20 hours per
response, including the time to review instructions, search existing data resources, gather the data
needed, and complete and review the information collection. There is also a one-time estimated
recordkeeping burden of 40 hours per response. Send comments regarding this burden estimate
or suggestions for reducing this burden to:
Center for Food Safety and Applied Nutrition (HFS-255), Food and Drug Administration, 5001
Campus Dr., College Park, MD 20740.
An Agency may not conduct or sponsor, and a person is not required to respond to, a collection
of information unless it displays a currently valid OMB control number. The OMB control
number for this information collection is 0910-0911 (To find the current expiration date, search
for this OMB control no. available at https://www.reginfo.gov).

VII. References
The following references marked with an asterisk (*) are on display at the Dockets Management
Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD
20852, 240-402-7500 and are available for viewing by interested persons between 9 a.m. and 4
p.m., Monday through Friday; they also are available electronically at
https://www.regulations.gov. References without asterisks are not on public display at
https://www.regulations.gov because they have copyright restriction. Some may be available at
the website address, if listed. References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of the date this
document publishes in the Federal Register, but websites are subject to change over time.

34

Contains Nonbinding Recommendations

1. U.S. Food and Drug Administration (2017). “Regulatory Framework for Substances
Intended for Use in Human Food or Animal Food on the Basis of the Generally Recognized
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Industry,” available at https://www.fda.gov/media/109117/download.*
2. U.S. Food and Drug Administration (2016). “Frequently Asked Questions About GRAS for
Substances Intended for Use in Human or Animal Food: Guidance for Industry,” available at
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3. Experience with GRAS Notices Under the 1997 Proposed Rule, Memorandum Dated
November 4, 2010, from Linda S. Kahl of FDA to Docket No. FDA–1997–N–0020. See
Reference 1 to the 2010 notice, available at http://www.regulations.gov.*
4. United States Government Accountability Office (2010). “Report to Congressional
Requestors on Food Safety: FDA Should Strengthen Its Oversight of Food Ingredients
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8. Arnott D. (2006). Cognitive biases and decision support systems development: a design
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10. Moore DA, Tanlu L, Bazerman MH. (2010). Conflict of interest and the intrusion of bias.
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11. Institute of Medicine (2009). Full Report. Conflict of Interest in Medical Research,
Education, and Practice. National Academies Press, 500 5th Street, NW, Lockbox 285,
Washington, D.C. 20055.
12. The National Academies of Sciences, Engineering, and Medicine (2003). Policy on
Committee Composition and Balance and Conflicts of Interest: For Committees Used in the
Development of Reports. The National Academies Press, 500 5th Street, NW, Washington,
D.C. 20001.
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Contains Nonbinding Recommendations

13. Pagliari C, Grimshaw J, Eccles M. (2001). The potential influence of small group processes
on guideline development. Journal of Evaluation of Clinical Practice. 7(2):165-173.
14. Van Ginkel WP, van Knippenberg D. (2012). Group leadership and shared task
representations in decision making groups. The Leadership Quarterly. 23:94-106.
15. Tschan F, Semmer NK, Gurtner A, Bizzari L, Spychiger M, Bruer M, Marsch SU. (2009).
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group medical decision making. Small Group Research. 40(3):271-300.
16. Cheng PY, Chiou WB. (2008). Framing effects in group investment decision making: role of
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17. Milch KF, Weber EU, Appelt KC, Handgraaf MJJ, Krantz DH. (2009). From individual
preference construction to group decisions: Framing effects and group processes.
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18. Jonas E, Schulz-Hardt S, Frey D, Thelen N. (2001). Confirmation bias in sequential
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19. Mancuso VF, Finomore VS, Rahill KM, Blair EA, Funke GJ. (2014). Effects of cognitive
biases on distributed team decision making. Proceedings of the Human Factors and
Ergonomics Society 58th Annual Meeting. 405-409.*
20. U.S. Food and Drug Administration (2016). Procedures for Evaluating Appearance Issues
and Granting Authorizations for Participation in FDA Advisory Committees; Guidance for
the Public, FDA Advisory Committee Members, and FDA Staff (Draft Guidance). Available
at https://www.fda.gov/media/98852/download.*
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