[Federal Register Volume 82, Number 209 (Tuesday, October 31, 2017)]
[Proposed Rules]
[Pages 50324-50346]
[FR Doc No: 2017-23629]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket No. FDA-2017-N-0763]
RIN 0910-AH43

Food Labeling: Health Claims; Soy Protein and Coronary Heart
Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
proposing to revoke its regulation authorizing the use of health claims
on

the relationship between soy protein and coronary heart disease on the
label or in the labeling of foods. We are taking this action based on
our review of the totality of publicly available scientific evidence
currently available and our tentative conclusion that such evidence
does not support our previous determination that there is significant
scientific agreement (SSA) among qualified experts for a health claim
regarding the relationship between soy protein and reduced risk of
coronary heart disease.

DATES: Submit either electronic or written comments on the proposed
rule by January 16, 2018.

ADDRESSES: You may submit comments as follows. Late, untimely filed
comments will not be considered. Electronic comments must be submitted
on or before January 16, 2018. The https://www.regulations.gov
electronic filing system will accept comments until midnight Eastern
Time at the end of January 16, 2018. Comments received by mail/hand
delivery/courier (for written/paper submissions) will be considered
timely if they are postmarked or the delivery service acceptance
receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2017-N-0763 for ``Food Labeling: Health Claims; Soy Protein and
Coronary Heart Disease.'' Received comments, those received in a timely
manner (see DATES and ADDRESSES), will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at https://www.regulations.gov or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' We will review
this copy, including the claimed confidential information, in our
consideration of comments. The second copy, which will have the claimed
confidential information redacted/blacked out, will be available for
public viewing and posted on https://www.regulations.gov. Submit both
copies to the Dockets Management Staff. If you do not wish your name
and contact information to be made publicly available, you can provide
this information on the cover sheet and not in the body of your
comments and you must identify this information as ``confidential.''
Any information marked as ``confidential'' will not be disclosed except
in accordance with 21 CFR 10.20 and other applicable disclosure law.
For more information about FDA's posting of comments to public dockets,
see 80 FR 56469, September 18, 2015, or access the information at:
https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Crystal Rivers, Center for Food Safety
and Applied Nutrition (HFS-830), Food and Drug Administration, 5001
Campus Dr., College Park, MD 20740,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Proposed Rule
    B. Summary of the Major Provisions of the Proposed Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Commonly Used Acronyms in This Document
III. Background
IV. Legal Authority
V. Scientific Evidence Regarding the Relationship Between Soy
Protein and CHD
    A. Overview of Data and Eligibility for a Health Claim
    B. Reevaluation of the Health Claim for Soy Protein Intake and
CHD
    C. Assessment of Intervention Studies
    D. Assessment of Observational Studies
VI. Strength of the Scientific Evidence
VII. Proposal To Revoke Sec.  101.82
VIII. Economic Analysis of Impacts
IX. Proposed Effective Date
X. Analysis of Environmental Impact
XI. Paperwork Reduction Act of 1995
XII. Federalism
XIII. References

I. Executive Summary

A. Purpose of the Proposed Rule

    The proposed rule would revoke the regulation authorizing the use
of a health claim regarding the relationship between soy protein and
risk of coronary heart disease (CHD) (Sec.  101.82 (21 CFR 101.82)). In
this proposed rule, we tentatively conclude, based on our reevaluation
of the totality of the publicly available scientific evidence now
available, that the evidence does not support our previous
determination that there is SSA to support an authorized health claim
for the relationship between soy protein and reduced risk of CHD.
    In 1999, we authorized a health claim about the relationship
between soy protein and a reduced risk of CHD (Sec.  101.82). In the
Federal Register of December 21, 2007, we announced our intention to
reevaluate the scientific evidence for this health claim and provided
the opportunity for public comment (72 FR 72738). We explained that we
were reevaluating the scientific basis for the soy protein and CHD
health claim because new studies yielded

varied and inconsistent findings (beneficial effect, no effect) from
one trial to another. The results of these studies called into question
the conclusions drawn from our prior review, which had served as the
basis for authorizing the soy protein and reduced risk of CHD health
claim. This proposed rule is the next step in our reevaluation.

B. Summary of the Major Provisions of the Proposed Rule

    The proposed rule would revoke the soy protein and CHD claim in
Sec.  101.82 because it does not meet the SSA standard. Our decision
about whether to authorize a health claim represents FDA's
determination as to whether there is ``significant scientific
agreement'' among qualified experts that the publicly available
scientific evidence supports the substance/disease relationship that is
the subject of a proposed health claim. In our reevaluation of the
scientific evidence in this proposed rule, we use our approach outlined
in the ``Evidence-Based Review System for the Scientific Evaluation of
Health Claims'' (hereinafter the 2009 guidance) to evaluate the
totality of publicly available scientific evidence to determine if the
SSA standard in section 403(r)(3) of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C. (343(r)(3)) is met (Ref. 1). Our
reevaluation of the totality of the publicly available scientific
evidence indicates that, although some evidence suggests a relationship
between soy protein intake and reduced risk of CHD, the totality of the
evidence is inconsistent and not conclusive. Therefore, we have
tentatively determined that the strength of the totality of the
publicly available data does not meet the SSA standard for a
relationship between soy protein intake and CHD risk.

C. Costs and Benefits

    The costs of this proposed rule, if finalized, are relabeling the
estimated 200 to 300 products currently making the health claim. We
estimate total annualized costs of $35,000 to $81,000, when the
relabeling costs are annualized over 20 years at a 7 percent discount
rate. The initial one-time costs are $370,000 to $860,000.
    The benefit of this rule is better information for the consumers
who are considering purchasing products with soy protein. This may
generate an unknown amount of increased consumer surplus. Some
consumers may react to this new information by switching their
consumption to products that they enjoy more, or products that still
have an authorized health claim. By basing their consumption decisions
on more recent and accurate scientific information, they may get more
consumer surplus, in the form of enjoyment and/or potential health
benefits, from the bundle of products they consume.

                        Table 1--Cost and Benefit Overview, USD, Annualized Over 20 Years
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                                                                   Low estimate        Mean        High estimate
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Costs, 7 percent discount rate..................................         $35,000         $55,000         $81,000
Costs, 3 percent discount rate..................................         $25,000         $39,000         $58,000
                                                                 -----------------------------------------------
Benefits........................................................    Consumer Enjoyment and/or potential Health
                                                                                Benefits
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II. Table of Commonly Used Acronyms in This Document

                Table 2--Table of Commonly Used Acronyms
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                Acronym                           What it means
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CHD....................................  Coronary Heart Disease
DASH...................................  Dietary Approaches to Stop
                                          Hypertension
DBP....................................  Diastolic Blood Pressure
FDA....................................  Food and Drug Administration
g......................................  gram(s)
kcal...................................  kilocalorie(s)
LDL....................................  Low-Density Lipoprotein
mg.....................................  milligram(s)
NCEP...................................  National Cholesterol Education
                                          Program
NHLBI..................................  National Heart, Lung and Blood
                                          Institute
oz.....................................  ounces
SBP....................................  Systolic Blood Pressure
SSA....................................  Significant Scientific
                                          Agreement
TC.....................................  Total Cholesterol
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III. Background

    In the Federal Register of November 10, 1998 (63 FR 62977), and in
response to a petition from Protein Technologies International, Inc.
(see Docket No. FDA-1998-P-1154), we proposed to provide for health
claims on the relationship of soy protein and reduced risk of CHD
(hereinafter referred to as the 1998 soy protein proposed rule). In the
1998 soy protein proposed rule, we considered the relevant scientific
studies and data presented in the petition as part of our review of the
scientific literature on soy protein and CHD. We summarized these
studies in table 1 of the soy protein proposed rule (63 FR 62977 at
62998) and presented the rationale for a health claim on this food/
disease relationship as provided for under the significant scientific
agreement standard in section 403(r)(3)(B)(i) of the FD&C Act and Sec.
101.14(c).
    In our 1998 evaluation of the scientific evidence for a
relationship between consumption of soy protein and blood total and
LDL-cholesterol levels (two validated surrogate endpoints for risk of
CHD), we found the data suggestive, but not sufficient, to establish a
dose-response for this relationship. However, we found consistent,
clinically significant reductions of total- and LDL-cholesterol levels
in controlled trials that used at least 25 grams (g) of soy protein per
day. Thus, we proposed to base the qualifying level of soy protein on a
total daily intake of 25 g, as suggested by the petitioner. For the
purposes of health claims, we assumed there are four eating occasions a
day (i.e., three main meals and one snack). Therefore, in Sec.
101.82(c)(2)(iii)(A), we proposed the qualifying criterion for a food
to bear the claim as 6.25 g of soy protein per reference amount
customarily consumed (RACC) (i.e., 25 g divided by four eating
occasions per day).
    In the Federal Register of October 26, 1999 (64 FR 57700), we
authorized a health claim for soy protein and risk of coronary heart
disease (21 CFR 101.82). As explained in the final rule, we determined,
based on our review of evidence submitted with comments to the proposed
rule, as well as evidence described in the proposed rule, that soy
protein included in a diet low in saturated fat and cholesterol may
reduce the risk of CHD by lowering blood cholesterol levels. FDA's
requirements for use of the health claim and model health claim
language were codified at 21 CFR 101.82.

    FDA evaluates new scientific information that becomes available to
determine whether it necessitates a change to an SSA health claim. On
December 21, 2007, we published a notice in the Federal Register (72 FR
72738) (the 2007 reevaluation notice) announcing our intent to
reevaluate the scientific evidence for certain health claims, including
the authorized health claim for soy protein and risk of CHD (Sec.
101.82). We stated that we were reevaluating the scientific basis for
the soy protein and CHD health claim because numerous studies published
since we had authorized the health claim had evaluated the relationship
between soy protein and CHD, and the findings of these studies were
inconsistent from study to study. For example, the Agency for
Healthcare Research and Quality (AHRQ) released a report in July 2005
outlining the effects of soy products on health outcomes, including
cardiovascular disease, and concluded that soy products appear to exert
a small benefit on LDL cholesterol (Ref. 2). However, the AHRQ report
included studies that evaluated substances in addition to soy protein
(e.g., isolated soy isoflavones). It was not clear from the AHRQ report
whether the soy protein, or other components of soy products such as
isoflavones, were responsible for lowering LDL cholesterol. In
addition, the AHRQ report used markers of cardiac function (e.g.,
triglycerides, endothelial function, and oxidized low-density
lipoprotein) that are not surrogate endpoints recognized by FDA for CHD
risk.
    Subsequently, we received a citizen petition dated August 8, 2008
(Docket Number FDA-2008-P-0452-001) (hereinafter ``the 2008 citizen
petition''), requesting that the Commissioner of Food and Drugs revoke
Sec.  101.82. On January 4, 2016, we denied the petitioner's request
because the limited relevant evidence submitted in the petition and a
supplement to the petition did not provide sufficient grounds for us to
revoke the soy protein and CHD health claim. However, as noted in the
response to the citizen petition, we considered the relevant studies
included in the petition as part of our reevaluation.

IV. Legal Authority

    The Nutrition Labeling and Education Act of 1990 (NLEA) (Pub. L.
101-535) amended the FD&C Act by, among other things, adding section
403(r) to the FD&C Act. This section specifies, in part, that a food is
misbranded if it bears a claim that expressly or by implication
characterizes the relationship of a nutrient to a disease or health-
related condition unless the claim is made in accordance with section
403(r)(3) of the FD&C Act (for conventional foods) or 403(r)(5)(D) of
the FD&C Act (for dietary supplements).
    The NLEA also directed FDA to issue regulations authorizing health
claims (i.e., labeling claims that characterize the relationship of a
nutrient to a disease or health-related condition) for conventional
foods if we determine, based upon the totality of publicly available
scientific evidence (including evidence from well-designed studies
conducted in a manner that is consistent with generally recognized
scientific procedures and principles), that there is SSA, among experts
qualified by scientific training and experience to evaluate such
claims, that the claim is supported by such evidence (see section
403(r)(3)(B)(i) of the FD&C Act). FDA may reevaluate the science
related to an authorized health claim and may take action to revoke the
claim (see section 403(r)(7)(B) of the FD&C Act (21 U.S.C.
343(r)(7(B)).
    Additionally, our regulations, at 21 CFR 10.40(a), provide that we
may promulgate regulations necessary to enforce the FD&C Act as
appropriate and may initiate such action in any of the ways specified
in Sec.  10.25 (21 CFR 10.25). Specifically, Sec.  10.25(b) provides
that the Commissioner may initiate a proceeding to revoke a regulation.
Accordingly, we are acting within our statutory and regulatory
authorities to propose to revoke the authorized health claim for soy
protein and a reduced risk of CHD. If this proposed rule is finalized,
the use of an authorized health claim would be prohibited and a food
that bears the health claim on the label or in labeling would misbrand
the food (see section 403(r)(1)(B) of the FD&C Act).
    In situations where we determine that the totality of the publicly
available scientific evidence does not meet the statutory SSA standard,
we may consider whether there is credible evidence to support a
``qualified'' health claim and what qualifying statements and other
information should accompany the claim to ensure that it is truthful
and not misleading. If, when we finalize this rule, we conclude there
is not SSA, but there is some credible evidence for the use of a
qualified health claim about the relationship between soy protein and a
reduced risk of CHD, we intend to issue a statement of enforcement
discretion for the use of a qualified health claim.

V. Scientific Evidence Regarding the Relationship Between Soy Protein
and CHD

A. Overview of Data and Eligibility for a Health Claim

    Health claims characterize the relationship between a substance and
a reduction in risk of contracting a particular disease or developing a
health-related condition (Whitaker v. Thompson, 353 F.3d 947, 950-51
(D.C. Cir.) (upholding FDA's interpretation of what constitutes a
health claim), cert. denied, 125 S. Ct. 310 (2004)). The substance must
be associated with a disease or health-related condition for which the
general U.S. population, or an identified U.S. population subgroup, is
at risk (Sec.  101.14(b)(1)). We analyze the information and data
related to a health claim under the framework set out in our 2009
guidance titled, ``Evidence-Based Review System for the Scientific
Evaluation of Health Claims'' (Ref. 1). The 2009 guidance discussed our
process for evaluating the scientific evidence for a health claim and
the meaning of the significant scientific agreement (SSA) standard in
section 403(r)(3) of the FD&C Act (21 U.S.C. 343(r)(3)) and 21 CFR
101.14(c). In a review of a health claim, our first step is to identify
the substance, the disease or health-related condition that is the
subject of the claim, and the population to which the claim is targeted
(Ref. 1).
    Next, we consider the totality of publicly available data and
information to determine whether the scientific evidence could support
a relationship between the substance and the disease or health-related
condition. We begin this process by organizing the evidence into
categories, such as human studies, meta-analyses, review articles,
animal studies, and in vitro studies, so we can thoroughly and
systematically assess the evidence during the evaluation process. Each
category of evidence may offer us helpful information and a better
understanding of the topic; however, only well-designed, well-conducted
human studies provide both the level of scientific rigor and
generalizability to human populations needed to potentially support a
health claim relationship. We focus our review on reports of human
intervention studies and observational studies. Of the two types of
studies, well-conducted intervention studies provide the strongest
evidence of an effect and are the most reliable category of studies for
determining a cause-and-effect relationship (Ref. 1). In an
intervention study, subjects similar to each other are randomly
assigned to either receive the intervention or not to receive the

intervention, whereas in an observational study, the subjects (or their
medical records) are observed for a certain outcome (i.e., disease).
Observational studies lack the controlled setting of intervention
studies. In contrast to intervention studies, observational studies
cannot determine whether an observed relationship represents a
relationship in which the substance caused a reduction in disease risk
or if other factors or variables may have contributed to an outcome
(Ref. 3). In addition to individual reports of human studies, we also
consider other types of data and information such as meta-analyses,
review articles, and animal and in vitro studies. These other types of
data and information may be useful to help us understand the scientific
issues about the substance, the disease, or both, but cannot by
themselves support a health claim relationship. Reports that discuss a
number of different studies, such as meta-analyses and review articles
do not provide sufficient information on the individual studies
reviewed in order for us to determine critical elements such as the
study population characteristics and the composition of the products
used. Similarly, the lack of detailed information on studies summarized
in review articles and meta-analyses prevents us from determining
whether the studies are flawed in critical elements such as design,
conduct of studies, and data analysis. We must be able to review the
critical elements of a study to determine whether any scientific
conclusions can be drawn from it. We use meta-analyses, review
articles, and similar publications to identify reports of additional
studies that may be useful to the health claim review and as background
about the substance-disease relationship. If additional studies are
identified, we evaluate them individually.
    We use animal and in vitro studies as background information
regarding mechanisms of action that might be involved in any
relationship between the substance and the disease. In vitro studies
are conducted in an artificial environment and cannot account for a
multitude of normal physiological processes, such as digestion,
absorption, distribution, and metabolism, which affect how humans
respond to the consumption of foods and dietary substances (Ref. 4).
Further, the physiology of animals is different than that of humans.
Animal and in vitro studies can be used to generate hypotheses or to
explore a mechanism of action but cannot adequately support a
relationship between the substance and the disease.
    We evaluate the individual reports of human studies to determine
whether any scientific conclusions can be drawn from each study. The
absence of critical factors, such as a control group or a statistical
analysis, means that scientific conclusions cannot be drawn from the
study (Ref. 5-6). Studies from which we cannot draw any scientific
conclusions do not support the health claim relationship, and we
eliminate such studies from further review.
    Because health claims involve reducing the risk of a disease in
people who do not already have the disease that is the subject of the
claim, we consider evidence from studies in individuals diagnosed with
the disease that is the subject of the health claim only if it is
scientifically appropriate to extrapolate to individuals who do not
have the disease. The available scientific evidence should demonstrate
that: (1) The mechanism(s) for the mitigation or treatment effects
measured in the diseased populations are the same as the mechanism(s)
for risk reduction effects in non-diseased populations; and (2) the
substance affects these mechanisms in the same way in both diseased and
healthy people. If such evidence is not available, then we cannot draw
any scientific conclusions from studies that use diseased subjects to
evaluate the substance/disease relationship. Next, we rate the
remaining human intervention and observational studies for
methodological quality. This quality rating is based on several
criteria related to study design (e.g., use of a placebo-control group
versus a non-placebo-control group), data collection (e.g., type of
dietary assessment method), the quality of the statistical analysis,
the type of outcome measured (e.g., disease incidence versus validated
surrogate endpoint), and study population characteristics other than
relevance to the U.S. population (e.g., age, smoker versus non-smoker)
to evaluate factors such as selection bias and whether important
information about the study subjects was gathered and reported. For
example, if the scientific study adequately addressed all or most of
the criteria related to study design, we would assign a high
methodological quality rating to the study. We would assign moderate or
low quality ratings based on the extent of the deficiencies or
uncertainties in the quality criteria. As noted in our guidance
(Evidence-Based Review System for the Scientific Evaluation of Health
Claims), this quality rating is based on several factors related to
study design, data collection, the quality of the statistical analysis,
the type of outcome measured, and study population characteristics
other than relevance to the U.S. population (e.g., selection bias and
the provision of important subject information [e.g., age, smokers]).
(Ref. 1). We would not use studies that are so deficient that
scientific conclusions cannot be drawn from them to support the health
claim relationship, and we eliminate such studies from further review.
    We then evaluate the results of the remaining human studies and
then rate the overall strength of the total body of publicly available
evidence (Ref. 1). We consider the study type (e.g., intervention,
prospective cohort, case-control, cross-sectional), the methodological
quality rating previously assigned, the quantity of evidence (number of
studies of each type and study sample sizes), whether the body of
scientific evidence supports a health claim relationship for the U.S.
population or target subgroup, whether study results supporting the
proposed claim have been replicated (Ref. 7), and the overall
consistency (Ref. 8-9) of the total body of evidence (Ref. 1). Based on
the totality of the publicly available scientific evidence, we
determine whether such evidence meets that SSA standard to support an
authorized health claim (also referred to as ``SSA health claim'') for
the substance/disease relationship. If the evidence does not meet the
SSA standard, then we may consider whether such evidence is credible to
support a qualified health claim. If there is credible evidence to
support a qualified health claim, then we consider what qualifying
language should be included to convey the limits on the level of
scientific evidence supporting the relationship or to prevent the claim
from being misleading in other ways.

B. Reevaluation of the Health Claim for Soy Protein Intake and CHD

    In our reevaluation of the scientific evidence for a relationship
between soy protein and reduced risk of CHD, we have used the approach
outlined in the 2009 guidance to evaluate the totality of the current
publicly available scientific evidence regarding this relationship (see
section 403(r)(3)(B) of the FD&C Act). In this section, we present our
reevaluation of the totality of the publicly available scientific
evidence, including the studies we previously reviewed in promulgating
the regulation that authorized the 1999 soy protein and CHD health
claim (64 FR 57700), as well as studies published after we authorized
the health claim in 1999. The 2009 guidance represents FDA's current

thinking on the evaluation of health claims as well as the
interpretation and meaning of SSA. Because the 1999 final rule predates
that guidance, we acknowledge that our reevaluation of studies
previously considered in the 1999 rulemaking may differ in certain
respects from the previous evaluation. For the purposes of this review,
we have identified the following disease endpoints for use in
identifying CHD risk reduction for the purposes of a health claim
evaluation: The incidence of coronary events (e.g., myocardial
infarction, ischemia), cardiovascular death, coronary artery disease,
atherosclerosis, and CHD (Ref. 1). We consider high blood pressure,
blood (serum or plasma) total cholesterol (TC), and blood LDL
cholesterol levels to be surrogate endpoints for CHD risk (Ref. 1). We
use these disease and surrogate endpoints to evaluate the potential
effects of soy protein on CHD risk.
    For the purposes of the reevaluation, we identified a total of 709
publications, drawn from studies included in the 1999 final rule,
comments submitted to the 2007 notice of reevaluation, the 2008 citizen
petition, and searches of the more recent literature. These
publications consisted of 30 in vitro studies; 85 animal studies; 27
government documents; 163 review articles, meta-analyses, letters,
abstracts, and books or book chapters; 11 Web sites; 3 articles written
in a foreign language; and 141 publications that did not evaluate the
substance/disease relationship. The publications also included 11
observational studies that evaluated the substance/disease relationship
and 238 publications describing intervention studies that evaluated the
relationship between soy protein intake and CHD risk.
1. Assessment of Review Articles, Meta-Analyses, Book Chapters,
Letters, and Government Reports
    Although useful for background information, review articles, meta-
analyses, book chapters, letters, and government reports do not contain
sufficient information on the individual studies which they reviewed
and, therefore, we could not draw any scientific conclusions from this
information. For example, we could not determine factors such as the
study population characteristics or the composition of the products
used (e.g., food, dietary supplements). Similarly, the lack of detailed
information on studies summarized in review articles, meta-analyses,
book chapters, letters, and government reports prevents us from
determining whether the studies are flawed in critical elements such as
design, conduct of studies, and data analysis. We need to be able to
review the critical elements of a study to determine whether any
scientific conclusions can be drawn from it. As a result, while the
review articles, meta-analyses, book chapters, letters, and government
reports we identified provided useful background information, they did
not provide sufficient information from which scientific conclusions
could be drawn regarding soy protein consumption and risk of CHD.
2. Assessment of Animal and In Vitro Studies
    We use animal and in vitro studies as background information
regarding mechanisms of action that might be involved in any
relationship between the substance and the disease; these studies also
can be used to generate hypotheses or to explore a mechanism of action,
but they cannot adequately support a relationship between a substance
and a disease in humans (Ref. 1, 4). Such studies cannot mimic the
normal human physiology that may be involved in the risk reduction of
CHD, nor can the studies mimic the human body's response to the
consumption of soy protein. Therefore, we cannot draw any scientific
conclusions from the animal or in vitro studies regarding soy protein
and the risk of CHD in humans, and they provide insufficient data to
support a health claim. In accordance with these principles, in our
review we considered animal and in vitro studies but determined that
they did not provide useful supportive information about the
relationship between soy protein consumption and risk of CHD.

C. Assessment of Intervention Studies

    For the purposes of this review, we categorized the intervention
studies based on whether the subjects: (1) Added soy protein to the
diet (supplement) in addition to the subjects' usual diet; (2) were
instructed to substitute soy protein for animal protein in their diet;
and (3) were provided test diets (feeding studies) with soy protein for
animal protein (usually casein) in the control diet. In studies where
soy proteins were used as a substitute for animal proteins, changes in
the total fat, saturated fat, cholesterol, and dietary fiber content of
the diet can occur. A reduced intake of total fat (Ref. 10), saturated
fat ((Ref. 10), or cholesterol (Ref. 11) has been shown to lower blood
cholesterol, and an increased intake of dietary fiber (Ref. 12) has
shown the same (Ref. 10), and we have authorized SSA health claims for
reduced risk of CHD based on these substance and disease relationships
(Sec.  101.75, Sec.  101.81). Therefore, to determine the independent
effect of soy protein intake on blood cholesterol levels, total fat,
saturated fat, cholesterol, and dietary fiber need to be controlled for
in the studies. Studies that substituted soy protein for animal protein
or feeding studies that did not properly control for these nutrients
and/or did not report these nutrients were eliminated from further
review. For studies in which soy protein was added to the usual diet,
the addition of soy protein should not result in significant changes in
the total fat, saturated fat, cholesterol, and dietary fiber in the
diet (because soy protein does not have significant amounts of these
nutrients) (Ref. 13-15). Therefore, we did not eliminate these types of
studies that did not control for and/or did not report these nutrients.
    To determine the independent effects of soy protein on blood
pressure, studies need to control for the amount of sodium and
potassium, because both nutrients influence blood pressure (Ref. 16).
Studies that substituted soy protein for animal protein or feeding
studies where subjects were provided soy protein in test diets that did
not properly control for these nutrients and/or did not report these
nutrients were eliminated from further review. For studies that added
soy protein to the diet, the addition of soy protein should not result
in significant changes in the amount of sodium and potassium in the
diet; therefore, we did not eliminate these types of studies that did
not control for and/or did not report these nutrients (Ref. 13-15).
Furthermore, because the nutrients that affect blood pressure (sodium
and potassium) and cholesterol (saturated fat, dietary fiber, and
cholesterol) are different, some studies might be appropriate for
supporting one surrogate endpoint, but not the other. Thus, for the
purposes of this assessment, we discuss some studies twice.
    Of the 238 total publications describing intervention studies that
evaluated the relationship between soy protein intake and CHD risk, 9
publications did not report data on a FDA-recognized surrogate endpoint
of CHD risk (i.e., blood total cholesterol, blood LDL cholesterol,
blood pressure) (Ref. 17-25). Because these publications did not report
data on one or more surrogate endpoints, we could not draw scientific
conclusions about the relationship between soy protein consumption and
risk of CHD from these studies (Ref. 1).
    The remaining 229 publications described 212 intervention studies
that evaluated soy protein intake and CHD

risk. Of these 212 intervention studies, scientific conclusions could
not be drawn from 154 studies due to significant flaws. These studies
are discussed in sections V.C. 1. and V.C. 2. Such studies may have
other flaws in addition to those specifically mentioned. This left 58
well-designed, well-conducted intervention studies to include in our
evaluation of the totality of the publicly available scientific
evidence.
1. Intervention Studies That Examined Soy Protein Intake and Blood
Cholesterol
    As stated previously in this section, we could not draw scientific
conclusions about the relationship between soy protein consumption and
risk of CHD from 154 intervention studies due to significant design
flaws. These studies include 17 studies that did not include a control
group or provide an appropriate control for the comparison to the
relative effects of soy protein (Ref. 26-42). Without an appropriate
control group, we could not determine if the changes in LDL cholesterol
were due to soy protein intake or uncontrolled extraneous factors (Ref.
1). Therefore, we could not draw scientific conclusions about the
relationship between soy protein consumption and risk of CHD from these
studies
    Ten studies did not conduct statistical analyses between the
control group and treatment group. The statistical analysis of the
substance/disease relationship is a critical factor because it provides
the comparison between subjects that consumed soy protein and those
that did not consume soy protein (i.e., control) to determine whether
there is a reduction in CHD risk (Ref. 43-52). Therefore, we could not
draw scientific conclusions about the relationship between soy protein
consumption and risk of CHD from these studies.
    In eight studies (Ref. 53-60), the duration of the study
intervention was too short (less than 3 weeks) to adequately determine
if changes in serum cholesterol levels were due to the consumption of
soy protein (Ref. 1, 61). Therefore, we could not draw scientific
conclusions about the relationship between soy protein consumption and
risk of CHD from these studies.
    Seventy-six studies, described in 84 publications, that substituted
soy protein for animal protein or were feeding studies reported large
differences in or did not report information on other dietary
components that have an effect on blood cholesterol (e.g., dietary
fiber, saturated fat, dietary cholesterol) (Ref. 56, 62-145). Such
large differences in nutrient intakes of dietary fiber, saturated fat,
or dietary cholesterol make it difficult to clearly delineate what may
be causing a change in serum cholesterol levels. Therefore, the results
of these studies could not be interpreted, and we could not draw
scientific conclusions about the relationship between soy protein
consumption and risk of CHD from these studies (Ref. 1).
    One study, Zittermann et al. (2004) was a randomized, crossover
study (Ref. 1) in which 14 German women consumed 5 cookies made with
soy flour or 5 cookies made with wheat flour while they remained on
their usual diet for one menstrual cycle (30.8  0.9 days).
The composition of the test cookies and of the amount of soy protein in
the cookies was not adequately described. Furthermore, while the study
reported that subjects were to consume the cookies while they remained
on their usual diet, the study reported significantly higher intake of
dietary fiber (P <0.0001) in the soy period (cookies made with soy
flour) than in the control period. When an intervention study involves
providing a whole food rather than a food component, the experimental
and control diets should be similar enough that the relationship
between the substance and disease can be evaluated (Ref. 1). Because
the composition of the test cookies were not adequately described, it
is not clear why there are differences in dietary fiber intake between
the two groups. Thus, we could not draw scientific conclusions about
the relationship between soy protein and CHD when the amounts of other
substances that are known to affect the risk of CHD (e.g. dietary
fiber) are different between the control and experimental diets (Ref.
1, 146).
    Nine studies, described in 11 publications that evaluated soy
protein intake and blood cholesterol, contained added phytosterols in
the treatment group (Ref. 131-132, 147-155). We have an existing
regulation for a SSA health claim for the relationship between plant
sterol/stanol esters and reduced risk of CHD; however, because plant
sterol/stanol esters can reduce blood cholesterol, it is not possible
to clearly delineate what may be causing a change in serum cholesterol
levels (Ref. 1). Therefore, the results of these studies could not be
interpreted, and we could not draw scientific conclusions about the
relationship between soy protein consumption and risk of CHD from these
studies.
    For the remaining 58 intervention studies from which we could draw
scientific conclusions, we used the criteria established by the
National Heart, Lung and Blood Institute (NHLBI) to sort studies that
measured blood cholesterol into 3 categories: (1) Studies that had
subjects with desirable or borderline blood cholesterol (TC <240 mg/dL
or LDL-cholesterol less than 160 mg/dL); (2) studies that had subjects
with high blood cholesterol (TC >240 or LDL cholesterol >160 mg/dL);
and (3) studies that had some subjects with desirable or borderline
cholesterol level and other subjects with high cholesterol levels (Ref.
156). Additionally, studies that measured blood pressure were sorted
based on criteria established by NHLBI into three categories: (1)
Normal (Systolic Blood Pressure (SBP) <120 mmHg or Diastolic Blood
Pressure (DBP) <80 mmHg); (2) pre-hypertension (SBP 120 to 139 mmHg or
DBP 80 to 89 mmHg); and (3) hypertension (SBP >=140 mmHg or DBP >=90
mmHg) (Ref. 157-158). Studies were further sorted by whether the
studies added (supplemented) soy protein to the diet, were feeding
studies, or were substitution studies. Because some studies measured
both blood cholesterol and blood pressure, we discussed these studies
twice (see tables 4-8 in Ref. 230).
    a. Studies in subjects with desirable or borderline cholesterol
levels that added isolated soy protein to the diet.
    Carmignani et al. (2014) was a 16-week, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 40
postmenopausal Brazilian women consumed daily 40 g/day placebo powder
of maltrodextrin (n=20) or 40 g/day protein powder containing 24 g/day
isolated soy protein (90 mg/day naturally occurring isoflavones) (n=20)
in addition to their usual diet (Ref. 159). There was no significant
difference in blood TC and LDL cholesterol between the soy protein
group and the control group.
    Liu et al. (2012) was a 6-month, randomized, double-blind, placebo-
controlled, parallel trial of moderate quality in which 120
postmenopausal Chinese women consumed daily 15 g/day milk protein plus
100 mg/day isoflavone supplement (control) (n=60) or 15 g/day isolated
soy protein plus 100 mg/day isoflavone supplement (n=60) in addition to
their usual diet (Ref. 160). There was no significant difference in the
change in blood TC and LDL cholesterol between the milk protein and
isoflavone group (control) and the soy protein and isoflavone group.
    Santo et al. (2008) was a 28-day, randomized, double-blind,
controlled parallel trial of moderate quality in

which 30 American men consumed: (1) 25 g/day isoflavone-poor soy
protein isolate (1.9 mg/day isoflavones) (n=11); (2) 25 g/day
isoflavone-rich soy protein isolate (97 mg/day naturally occurring
isoflavones) (n=10); or (3) 25 g/day of milk protein (n=9) (control)
mixed with a beverage of their choice in addition to their usual diet
(Ref. 161). There were no significant differences in blood TC and LDL
cholesterol between the two soy protein isolate treatment groups and
the casein control group.
    Evans et al. (2007) was a randomized, double-blind, placebo-
controlled, crossover trial of moderate quality in which 22
postmenopausal American women consumed: (1) 25 g/day isolated soy
protein plus 20 g/day soy lecithin; (2) 25 g/day isolated soy protein
plus placebo lecithin; (3) placebo protein (50:50 calcium/sodium
caseinate) and 20 g/day soy lecithin; and (4) double placebo (protein
placebo and soy lecithin) in addition to their usual diet, for a
duration of 4 weeks each (Ref. 162). There was no significant
difference in blood TC and LDL cholesterol between the isolated soy
protein plus soy lecithin and placebo protein plus soy lecithin
treatment period (control). There was also no significant difference in
blood TC and LDL between the isolated soy protein plus placebo lecithin
and double placebo period (control).
    Maesta et al. (2007) was a 16-week, randomized, single-blind,
placebo-controlled, parallel trial of moderate quality in which 46
postmenopausal Brazilian women consumed: (1) 25 g/day isolated soy
protein (n=10); (2) 25 g/day isolated soy protein, plus resistance
exercise (n=14); (3) 25 g/day maltodextrin (control) (n=11); or (4) 25
g/day maltodextrin plus resistance exercise (n=11) (control) in
addition to their usual diet (Ref. 163). There was no significant
difference in blood TC and LDL cholesterol between the soy protein and
control groups.
    Kohno et al. (2006) was a two-part, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality (Ref. 164). In
the first part of the trial, 126 Japanese men and women, in addition to
their usual diet, consumed daily 5 g casein (control) (n=61) or 5 g of
soybean [beta]-conglycinin (storage protein component of soy protein
isolate) in the form of a candy (n=65) for 12 weeks. There was no
significant difference between the two diets for blood TC or LDL
cholesterol. In the second part of the trial, 95 Japanese men and women
consumed daily 5 g casein (n=50) or 5g soybean [beta]-conglycinin
(n=45) for 20 weeks. There was no significant difference between the
two diets for blood TC or LDL cholesterol.
    McVeigh et al. (2006) was a randomized, single-blind, controlled,
crossover trial of moderate quality in which 35 Canadian men consumed
32 g/day soy protein isolate depleted of isoflavones (1.64 mg/day), 32
g/day soy protein isolate (62 mg/day isoflavones), or 32 g/day milk
protein isolate for a duration of 57 days each (Ref. 165). There was no
significant difference between blood TC and LDL cholesterol between the
soy protein and casein groups.
    Sagara et al. (2004) was a 5-week, randomized, double-blind,
placebo-controlled parallel trial of moderate quality in which 50
Scottish men consumed 20 g/day of isolated soy protein powder in
biscuits, cereal bars, and bread rolls (n=25) or biscuits, cereal bars,
and bread rolls without added soy protein in addition to their usual
diets (n=25) (Ref. 166). There was no significant difference in blood
TC between the two groups.
    Teixeira et al. (2004) was a randomized, controlled, crossover
trial of moderate quality in which 14 men American men with type 2
diabetes with nephropathy consumed an estimated 35 g/day of soy protein
isolate and casein (control) in addition to their usual diets for a
duration of 8 weeks each (Ref. 167). There was no significant
difference in blood TC and LDL cholesterol between the soy protein and
casein group.
    Murray et al. (2003) was a 6-month, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 30
American postmenopausal women consumed: (1) 38 g/day soy protein
isolate containing (25 g soy protein) plus 1.0 mg estradiol (n=8); (2)
38 g textured milk protein plus 1.0 mg estradiol (n=7) (control); (3)
38 g/day soy protein isolate containing (25 g soy protein) plus 0.5 mg
estradiol (n=8); or (4) 38 g/day textured milk protein plus 0.5 mg
estradiol(control) (n=7) in addition to their usual diet (Ref. 168).
The baseline TC levels in the 38 g/day textured milk protein plus 1.0
mg estradiol group were significantly higher than the (25 g soy
protein) plus 1.0 mg estradiol group. If the baseline cholesterol
values between groups are significantly different, then it is difficult
to determine if differences at the end of the study were due to the
intervention or to differences observed at the beginning of the study
(Ref. 1). Thus, we could not draw scientific conclusions from this arm
of the study. For the soy protein group plus 0.5 mg estradiol and the
textured milk protein plus 0.5 mg estradiol (control) groups, the
baseline cholesterol levels were similar and conclusions could be
drawn. However, there was no significant difference in blood TC and LDL
cholesterol between the soy protein group plus 0.5 mg estradiol and the
textured milk protein plus 0.5 mg estradiol control group.
    Jayagopal et al. (2002) was a randomized, double-blind, placebo-
controlled, crossover trial of moderate quality in which 32
postmenopausal British women with type 2 diabetes consumed 30 g/day of
isolated soy protein or 30 g/day of cellulose (control) in addition to
their usual diet for a duration of 12 weeks each (Ref. 169). Blood TC
and LDL cholesterol was significantly lower (P <0.05) in soy protein
period compared to the cellulose period.
    Higashi et al. (2001) (trial one) was a randomized, controlled,
crossover trial of moderate quality in which 14 Japanese men consumed
daily milk or yogurt only (no placebo) and 20 g/day soy protein isolate
mixed in milk or yogurt in addition to their usual diet for a duration
of 4 weeks each (Ref. 26). There was no significant difference in blood
TC and LDL cholesterol between the soy protein period and the control
period (milk or yogurt only).
    Teede et al. (2001) and Dalais et al., (2003) was a 3-month
randomized, double-blind, placebo-controlled, parallel trial of
moderate quality in which 179 Australian men and postmenopausal women
consumed a casein placebo (n=93) or 40 g/day soy protein isolate (n=86)
mixed with a beverage twice a day in addition to their usual diet (Ref.
170-171). There was no significant difference in blood TC and LDL
cholesterol between the casein control group and soy protein isolate
group. In a subgroup analysis of the postmenopausal women (n=55 casein
and n=51 soy protein) by Dalais et al. (2003), there was no significant
difference in blood TC between the casein control group and soy protein
isolate group. However, blood LDL cholesterol was significantly (P
<0.05) lower in the soy protein isolate group compared to the casein
control group.
    Washburn et al. (1999) was a randomized, double-blind, placebo-
controlled, crossover trial of moderate quality in which 42
perimenopausal American women consumed daily: (1) 20 g/day complex
carbohydrate supplement mixed with a beverage (control); (2) 20 g/day
isolated soy protein (34 mg/day naturally occurring phytoestrogens)
supplement mixed with a beverage as a single dose; and (3) 20 g/day soy
protein supplement (34 mg/day naturally occurring phytoestrogens) mixed
with beverages split into two

equal doses in addition to their usual diets for 6 weeks each (Ref.
172). Blood TC and LDL cholesterol were significantly (P <0.05) lower
in the soy protein groups compared to the control group.
    Gooderham et al. (1996) was a 28-day randomized, controlled,
parallel trial of moderate quality in which 20 Canadian men consumed
daily a supplement containing 60 g/day of soy protein isolate (n=10) or
a supplement containing 60 g/day of casein (control) (n=10) in addition
to their usual diet (Ref. 173). There was no significant difference in
blood TC and LDL cholesterol between the soy protein isolate group and
casein group.
    b. Studies in subjects with desirable or borderline cholesterol
levels that were feeding studies or substitution studies with isolated
soy protein.
    Mangano et al. (2013) was a 1-year, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 97
postmenopausal American women consumed: (1) 18 g/day isolated soy
protein plus 105 mg/day isoflavone tablets (n=25); (2) 18 g/day
isolated soy protein plus placebo tablets (n=24); (3) 18 g/day control
protein (casein, whey, and egg protein) plus 105 mg/day isoflavone
tablets (n=26); or (4) control protein and placebo tablets (n=22) in a
beverage or food. Subjects were counseled to reduce animal protein
foods by approximately 3 oz/day, which is an amount equivalent to the
protein powder provided in the study (Ref. 174). There was no
significant difference in blood TC or LDL cholesterol between any of
the soy protein groups and the control groups.
    Steinberg et al. (2003) was a randomized, double-blind, controlled,
crossover trial of moderate quality in which 28 postmenopausal American
women consumed: (1) 25 g/day of isolated soy protein (107 mg/day
naturally occurring isoflavones); (2) 25 g/day of isolated soy protein
depleted of isoflavones (2 mg/day isoflavones); and (3) 25 g/day total
milk protein (control) for a duration of 6 weeks each (Ref. 175).
Subjects mixed the protein powders with a beverage and were instructed
to incorporate the protein into their diet without increasing protein
or energy intake. There was no significant difference in blood TC and
LDL cholesterol between soy protein groups and milk protein control
group.
    Bakhit et al. (1994) was a randomized, controlled, crossover trial
of moderate quality in which 21 American men consumed muffins
containing: (1) 25 g/day isolated soy protein plus 20 g/day of dietary
fiber from cellulose; (2) 25 g/day isolated soy protein plus 20 g/day
of soybean cotyledon fiber; (3) 25 g/day casein plus 20 g/day soybean
cotyledon fiber (control); and (4) 25 g/day casein plus 20 g/day of
dietary fiber from cellulose (control) for a duration of 4 weeks each
(Ref. 176). Subjects were counseled to incorporate the muffins into a
low-fat, low-cholesterol diet. There were no significant differences
between isolated soy protein groups and control groups for blood TC and
LDL cholesterol.
    van Raaji et al. (1981) was a 4-week, controlled, parallel trial of
moderate quality in which 69 Dutch men and women were fed an average
Western diet with different types of dietary protein incorporated into
specifically developed products. The dietary protein groups were: (1)
54 g/day of isolated soy protein (n=24); (2) 17 g/day soy
(approximately a 2:1 mixture of casein:soy) (n=20); or (3) 55 g/day
casein (control) (n=25) (Ref. 177). Participants were matched for
initial serum cholesterol, energy intake, and sex. There was no
significant difference in blood TC between the isolated soy protein
groups and casein control group. However, blood LDL was significantly
lower (P <0.05) in the isolated soy protein group compared to the
casein control group.
    c. Studies in subjects with desirable or borderline cholesterol
levels that added soy foods to the diet.
    Takatsuka et al. (2000) was a 60-day, randomized, controlled,
parallel trial of moderate quality in which 52 premenopausal Japanese
women consumed approximately 16 g/day of soy protein from soy milk
(n=27) in addition to their usual diet or followed their usual diet as
a control diet (n=25) (Ref. 178). The control diet was a usual diet and
therefore not a true placebo. The change in blood TC was significantly
lower (P = 0.022) in the soy milk group compared to the control group.
However, there was no significant difference in the change in blood LDL
cholesterol between the two groups.
    Mitchell and Collins (1999) was a 4-week, randomized, controlled,
parallel trial of moderate quality in which 10 British men consumed:
(1) One liter of soy milk (n=4); (2) one liter of rice milk (control)
(n=3); or (3) one liter of semi skimmed cow's milk (control) (n=3) in
addition to their usual diets. There was no significant difference in
blood TC between groups (Ref. 179).
    Murkies et al., (1995) was a 12-week randomized, double-blind,
controlled parallel trial of moderate quality in which 47
postmenopausal Australian women consumed 45 g/day of wheat flour with
an estimated 4.6 g/day wheat protein (control) (n=24) or 45 g/day soy
flour with an estimated 15 g/day of soy protein (n=23) in addition to
their usual diet (Ref. 180). There was no significant difference in
blood TC between the two groups.
    d. Studies in subjects with desirable or borderline cholesterol
levels that were feeding studies or substitution studies with soy
foods.
    Matthan et al. (2007) was a randomized, controlled, crossover trial
of moderate quality in which 28 American subjects were fed four diets:
(1) Animal protein (control), (2) soybean diet (~37.5 g/day soy
protein), (3) soy flour (~37.5 g/day soy protein), and (4) and soy milk
(~37.5 g/day soy protein) for a duration of 6 weeks each (Ref. 181).
Blood LDL cholesterol was significantly lower (P <0.05) in the soymilk
diet period compared to the animal protein diet period (control).
However, there was no significant difference in blood TC between the
soymilk diet period and the animal protein diet period. Furthermore,
there was no significant difference in blood TC or LDL cholesterol
between the animal protein diet period (control) and the soybean diet
period or the soy flour diet period.
    Jenkins et al. (1989) was a controlled, crossover trial of moderate
quality in which 11 obese Canadian women who consumed a low calorie
diet (1,000 kcal) had 2 meals replaced by soy-based liquid formula made
from soy flour and soy protein isolate, and a milk-based liquid formula
for a duration of 4 weeks each. The soy formula provided approximately
17 g/day soy protein, and the cow's milk formula provided 18 g/day milk
protein (control) (Ref. 182). There was no significant difference in
blood TC and LDL cholesterol between the soy formula and the cow's milk
formula groups.
    Bosello et al. (1988) was a 75-day, controlled, parallel trial of
moderate quality in which 24 obese Italian subjects were fed a very low
calorie diet (375 kcal/day) for 15 days (Ref. 183). The very low
calorie diets were then integrated with a commercial textured
preparation that provided approximately 27 g/day of casein (control) or
approximately 28 g/day soy protein that was consumed daily for 60 days.
The 60-day hypocaloric diet provided a total of 800 kcal/day (375 kcal/
day from the very low calorie diet and 425 kcal/day from commercial
textured preparation). Blood TC and LDL cholesterol was significantly
lower (P <0.01) after consuming the soy protein diet compared to the
casein diet.

    e. Studies that include subjects with normal, borderline, and high
cholesterol that were fed or substituted isolated soy protein in the
diet.
    Greany et al. (2004) was a randomized, controlled, crossover trial
of moderate quality in which 33 postmenopausal American women consumed:
(1) 26 g/day of soy protein isolate; (2) 26 g/day soy protein isolate
plus probiotic capsules; (3) 26 g/day milk protein; and (4) 26 g/day
milk protein plus probiotic capsules for a duration of 6 weeks each
(Ref. 184). Subjects were counseled to substitute the protein powders
in two divided doses for other protein containing foods in their diet.
For the analysis, the soy protein and milk protein diets (control),
with or without probiotics, were combined. Blood TC and LDL cholesterol
was significantly lower (P <0.05) after consuming the soy protein
isolate compared to the milk protein control period.
    Wong et al. (1998) was a randomized, controlled, crossover trial of
high quality in which 13 American subjects with normal or borderline
high cholesterol and 13 American subjects with high cholesterol
consumed a National Cholesterol Education Program (NCEP) Step 1 soy
protein diet that provided approximately 50 g/day isolated soy protein
or an NCEP Step 1 animal protein diet that provided approximately 50 g/
day animal protein (control) for a duration of 5 weeks each (Ref. 185).
Blood LDL cholesterol was significantly lower (P <0.05) after the soy
protein period compared to the animal protein period for both the
normal and borderline high subjects and high cholesterol subjects.
However, there was no significant difference in blood TC between the
soy protein diet and the control diet for both the normal and
borderline high subjects and high cholesterol subjects.
    Goldberg et al. (1982) was a randomized, controlled, crossover
trial of moderate quality in which 12 American subjects with high
cholesterol and 4 American subjects with normal or borderline high
cholesterol consumed daily: (1) An animal protein diet (control); and
(2) an isolated soy protein diet for a duration of 6 weeks each. The
soy protein diet contained an estimated 99 g/day of isolated soy
protein (Ref. 186). Blood TC and LDL cholesterol in the 12 subjects
with high cholesterol was significantly lower (P <0.025) after the soy
protein diet compared to the animal protein diet. However, there was no
significant difference in blood TC and LDL between the two diets in the
four subjects with normal or borderline high cholesterol.
    f. Studies in subjects with high cholesterol levels that added
isolated soy protein to the diet.
    Hoie et al. (2007) was an 8-week, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 88
German subjects consumed: (1) 25 g/day of isolated soy protein in its
native, non-denatured form (n=28); (2) 25 g/day of isolated soy protein
(n=32); or (3) 25 g/day of milk protein (derived from caseinate and
skimmed milk powder) (n=28) (control) in addition to their usual diets
(Ref. 187). Blood TC and LDL cholesterol was significantly lower (P
<0.001 and P = 0.002, respectively) after consuming the non-denatured
isolated soy protein compared to milk protein group. Blood TC
cholesterol was also significantly lower (P = 0.008) after consuming
isolated soy protein compared to milk protein group. However, there was
no significant difference for blood LDL cholesterol after consuming
isolated soy protein compared to milk protein group.
    Hoie et al. (2006) was a 4-week, randomized, double-blind, placebo-
controlled, parallel trial of moderate quality in which 80 German
subjects consumed daily: (1) Ultra-heat-treated chocolate-flavored milk
containing 24.4 g/day isolated soy protein and 30.4 g/day milk protein
(n=20); (2) 43.3 g/day milk protein (control) (n=20); (3) ultra-heat-
treated chocolate flavored milk containing 12.2 g/day isolated soy
protein and 15.2 g/day milk protein (n=20); or (4) 21.7 g/day milk
protein (control) (n=20) (Ref. 188). There was no significant
difference in blood TC or LDL cholesterol between the group that
consumed the ultra-heat-treated chocolate-flavored milk containing 24.4
g/day isolated soy protein and 30.4 g/day milk protein group and the
control milk protein group. There was also no significant difference in
blood TC and LDL cholesterol between the group that consumed ultra-
heat-treated chocolate-flavored milk containing 12.2 g/day soy protein
and 15.2 g/day milk protein per day (n=20) or the control milk protein
group.
    Hoie et al. (2005a) was an 8-week, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 77
German subjects consumed 25 g/day soy protein (n=39) or 25 g/day milk
protein (derived from caseinate and skimmed milk powder) (control)
(n=38) in addition to their usual diets (Ref. 189). Blood LDL
cholesterol was significantly lower (P <0.05) in the soy protein group
when compared to the casein group. There was no difference in blood TC
between the soy protein group and casein group.
    Hoie et al. (2005b) was an 8-week, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 117
German subjects consumed: (1) 25 g/day soy protein (n=39); (2) 15 g/day
soy protein plus 10 g/day milk protein (derived from caseinate and
skimmed milk powder) (n=39); or (3) 25 g/day milk protein (derived from
caseinate and skimmed milk powder) (control) (n=39) in addition to
their usual diets (Ref. 190). Blood LDL cholesterol was significantly
lower (P = 0.002) after consumption of 25 g/day soy protein compared to
the 25 g/day casein group. TC was also significantly lower (P = 0.002)
after consumption of 25 g/day soy protein compared to the 25 g/day
casein group. In the 15 g/day soy protein plus 10 g/day casein group
blood LDL cholesterol was significantly lower (P = 0.011) compared to
25 g/day casein control group. TC was also significantly lower (P =
0.001) after consumption of 15 g/day soy protein plus 10 g/day casein
compared to 25 g/day casein control group.
    Teede et al. (2005) was a 3-month, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 40
postmenopausal Australian women consumed 40 g/day isolated soy protein
(n=19) or a casein placebo in addition to their usual diet (n=21) (Ref.
191). There was no significant difference in blood TC or LDL
cholesterol between the soy protein and casein group.
    Harrison et al. (2004) was a 5-week, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 112
British men and women consumed foods (bread, cracker biscuits, and
snack bars) that provided 25 g/day isolated soy protein (n=59) or the
same foods without soy protein as a control (n=53) in addition to their
usual diet (Ref. 192). There was no significant difference in blood TC
and LDL cholesterol between the soy protein and control groups.
    Blum et al. (2003) was a randomized, double-blind, placebo-
controlled, crossover trial of moderate quality in which 24
postmenopausal Israeli women consumed 25 g/day milk protein (control)
and 25 g/day isolated soy protein in addition to their usual diets for
a duration of 6 weeks each (Ref. 193). Blood TC and LDL cholesterol was
significantly lower (P <0.05) after consuming soy protein isolate
compared to milk protein period.
    Cuevas et al. (2003) was a randomized, double-blind, controlled,
crossover trial of moderate quality in which 18 postmenopausal Chilean
women consumed diets providing 40 g/

day caseinate (control) and 40 g/day isolated soy protein in addition
to an NCEP Step 1 diet for a duration of 4 weeks each (Ref. 194). There
was no significant difference in blood TC and LDL cholesterol between
the caseinate control diet and soy protein diet.
    Gardner et al. (2001) was a 12-week, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 94
postmenopausal American women consumed: (1) 42 g/day total milk protein
(control) (n=30); (2) 42 g/day isolated soy protein with isoflavones
depleted (3 mg/day) (n=33); or (3) 42 g/day isolated soy protein (80
mg/day naturally occurring isoflavones) (n=31) in addition to their
usual diet (Ref. 195). There was no significant difference in blood TC
or LDL cholesterol between the isolated soy protein groups and the
total milk protein control group.
    Hori et al. (2001) was a 3-month, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 21
Taiwanese men consumed: (1) Casein hydrolysate (n=7); (2) 3 g/day of a
crude type of soy protein hydrolysate (n=7); or (3) 6 g/day of a crude
type of soy protein hydrolysate (n=7) in addition to their usual diet.
Blood TC was significantly lower (P <0.05) after consuming 3 g/day of a
crude type of soy protein hydrolysate group for 3 months compared to
the casein hydrolysate control (Ref. 196). Blood TC was also
significantly lower after consuming 6 g/day crude type of soy protein
hydrolysate group after 2 and 3 months compared to the casein
hydrolysate control. Blood LDL cholesterol was significantly lower (P
<0.05) after consuming 3 g/day of a crude type of soy protein
hydrolysate group after 2 and 3 months compared to the casein
hydrolysate control. Blood LDL cholesterol was also significantly lower
(P <0.05) after consuming 6 g/day a crude type of soy protein
hydrolysate group after 1, 2, and 3 months compared to the casein
hydrolysate group.
    g. Studies in subjects with high cholesterol levels that were
feeding or substitution studies with isolated soy protein.
    Chen et al. (2006) was a 12-week, randomized, double-blind,
placebo-controlled, parallel trial of high quality in which 26
Taiwanese subjects on dialysis consumed daily their usual dialysis diet
that incorporated 30 g/day milk protein (control) (n=13) or an isolated
soy protein diet containing 30 g/day soy protein (n=13) (Ref. 197).
Blood TC was significantly lower (P <0.05) in the isolated soy protein
diet compared to the milk protein control. There was no significant
difference in blood LDL cholesterol between the milk protein control
and isolated soy protein diet.
    Ma et al. (2005) was a 5-week, randomized, double-blind,
controlled, parallel trial of moderate quality in which 159 American
subjects consumed daily 28 g/day milk protein supplement (n=78)
(control) or a 32 g/day isolated soy protein supplement (n=81) in a
beverage. Subjects were counseled to modify their protein and
carbohydrate intake to account for the protein supplement intake. There
was no significant difference in blood TC and LDL cholesterol between
the two diets (Ref. 198).
    West et al. (2005) and Hilpert et al. (2005) both discuss a
randomized, double-blind, controlled, crossover trial of high quality
in which 32 American subjects were fed an NCEP Step 1 diet that
incorporated 25 g/day milk protein or 25 g/day soy protein isolate for
a duration of 6 weeks each (Ref. 199-200). On each diet, 15 g of the
protein supplement was consumed in a muffin while the remaining protein
supplement was provided to the subjects to integrate into the meals
provided. There was no significant difference in blood TC and LDL
cholesterol between the milk protein and soy protein isolate diets.
    Jenkins et al. (2002 a and b) was a randomized, single-blind,
controlled, crossover trial of moderate quality in which 41 Canadian
men and women were fed an NCEP Step 2 diet in which the main protein
containing foods were replaced with test foods made with: (1)
Approximately 60 g/day dairy and egg protein; (2) 50 g/day of soy
protein isolate (10 mg/day naturally occurring isoflavones); and (3) 50
g/day soy protein isolate (73 mg/day naturally occurring isoflavones)
for a duration of 1 month each (Ref. 201-202). The percent change in
blood TC and LDL cholesterol was significantly lower (P <0.01) after
consuming the soy protein diets compared to the dairy and egg protein
diet (control).
    Lichtenstein et al. (2002) was a randomized, double-blind,
controlled, crossover, feeding trial of moderate quality in which 42
American men and women consumed diets of: (1) Isolated soy protein
depleted of isoflavones (25 g soy protein/1,000 kcal); (2) isolated soy
protein enriched with isoflavones (25 g soy protein plus 50 mg
isoflavones/1,000 kcal); (3) animal protein with no added isoflavones
(25 g animal protein/1,000 kcal); and (4) animal protein with added
isoflavones (25 g animal protein and 50 mg isoflavones/1,000 kcal) for
a duration of 6 weeks each (Ref. 203). The mean soy intake for women
was 55 g/day and 71 g/day for men. The treatment effects for blood TC
and LDL cholesterol were significantly lower (P = 0.017 and P = 0.042,
respectively) after consuming the soy protein diets compared to the
animal protein diets. For 20 subjects with LCL-C >160 mg/dL, the
treatment effects for blood TC and LDL-C were significantly lower (P
<0.001 and P = 0.003) after consuming the soy protein diets compared to
the animal protein diets. These data were also reported in Wang et al.,
(2004) and Desroches et al., (2004) (Ref. 204-205).
    Van Horn et al. (2001) was a 6-week, randomized, controlled,
parallel trial of high quality in which 126 postmenopausal American
women consumed an NCEP Step 1 diet in which they isocalorically
substituted: (1) Oats and 29 g/day milk protein (n=31) (control); (2)
wheat and 29 g/day isolated soy protein (n=31); (3) oats and 29 g/day
isolated soy protein (n=31); or (4) wheat and 29 g/day milk protein
(n=32) (control) for other carbohydrates and dairy type foods (Ref.
206). There was no significant difference in blood TC or LDL
cholesterol between the two control and the two soy protein diets.
    h. Studies in subjects with high cholesterol that added soy foods
to the diet.
    Gardner et al. (2007) was a 4-week, randomized, single-blind,
controlled, crossover trial of high quality in which 28 American men
and women consumed daily: (1) 1 percent cow's milk (control); (2) whole
bean soy milk; and (3) soy protein isolate milk, in addition to an
American Heart Association diet (Ref. 207). The whole bean soy milk and
the soy protein isolate milk provided 25 g/day of soy protein, and the
1 percent cow's milk provided 25 g/day of milk protein. Blood LDL
cholesterol was a significantly lower (P = 0.02) after consuming whole
bean soy milk when compared to 1 percent cow's milk. Blood LDL
cholesterol was also significantly lower (P = 0.02) after consuming the
soy protein diet compared to the 1 percent cow's milk diet.
    i. Study in subjects with high cholesterol that were fed soy foods.
    Jenkins et al. (2000) was a randomized, controlled, crossover trial
of moderate quality in which 25 Canadian men and women consumed daily
an NCEP Step 2 diet that incorporated: (1) A commercial breakfast
cereal containing 8 g/day wheat protein (control); and (2) a breakfast
cereal made with 70 percent soy flour that provided 36 g/day soy
protein for a duration of 3 weeks each (Ref. 208). There was no
significant

difference between the wheat protein cereal (control) period and soy
flour cereal diet period for blood TC and LDL cholesterol.
2. Intervention Studies That Examined Soy Protein Intake and Systolic
Blood Pressure (SBP) or Diastolic Blood Pressure (DBP)
    Twenty-eight studies, described in 30 publications, either
substituted soy protein in the diet or were feeding studies. These
studies did not control for or provide information on sodium and
potassium intake in the diet (Ref. 44, 55, 66, 74, 77, 84, 91, 96-97,
99, 114, 116, 123, 125-126, 131-132, 139-140, 144, 149-151, 153-154,
181, 201-202, 208-209). Because sodium and potassium intake also
influence blood pressure, the independent effects of soy protein intake
and blood pressure could not be determined. Therefore, we could not
draw scientific conclusions about the relationship between soy protein
consumption and risk of CHD from these studies.
    Four studies did not include an appropriate control protein for a
comparison of the relative effects of soy protein (Ref. 40, 42, 210-
211). Without an appropriate control group, it cannot be determined if
the changes in SBP or DBP were due to soy protein intake or
uncontrolled, extraneous factors. Therefore, we could not draw
scientific conclusions about the relationship between soy protein
consumption and risk of CHD from these studies.
    Chiechi et al. (2002) was a 6-month, randomized, parallel trial in
which 67 subjects with pre-hypertension (SBP 120 to 139 mmHg or DBP 80
to 89 mmHg) consumed their usual diet (n=43) or their usual diet plus a
soy food serving each day (e.g. soy milk, miso soup, tofu, tempeh, or
soy beans) (n=34) (Ref. 142). Subjects in the soy group also exchanged
two meals twice a week with two meals from a study menu that was based
on traditional Mediterranean recipes and soy or soy products.
Approximately 50 percent of subjects in the soy group dropped out of
the study compared to 20 percent in the control group. Therefore, the
dropout rate in the treatment group makes the results of this study
difficult to interpret. A high dropout rate can introduce bias because
it changed the number of subjects in the treatment group and may also
have changed the group's composition compared to the control group. In
addition to a high dropout rate, the study had other quality issues
(e.g., information on study blinding was not reported, adequate
descriptions were not provided for the composition of the background
diets or the amount of soy protein in the diets), the study measured
biomarkers (SBP or DBP) instead of clinical outcomes (e.g., incidence
of CHD). Therefore, this study is so deficient in methodological
quality that it is considered to be of low-quality design (Ref. 1) and,
as a result, we could not draw scientific conclusions regarding the
relationship between soy protein intake and reduced risk of CHD.
    a. Studies in subjects with normal or pre-hypertension (SBP <139
mmHg or DBP <89 mmHg).
    Anderson et al. (2007) was a 16-week, randomized, single-blind,
controlled, parallel trial of moderate quality in which 35 obese
American women with pre-hypertension (SBP 120 to 139 mmHg or DBP 80 to
89 mmHg) were fed daily 3 meal replacement shakes containing
approximately 22 g/day of casein (control) (n=18) or 21 g/day isolated
soy protein (n=17) each (Ref. 89). There was no significant difference
in SBP or DBP between the casein and soy protein diet.
    Azadbakht et al. (2007) was a randomized, controlled, crossover
trial of moderate quality in which 42 postmenopausal Iranian women with
pre-hypertension (SBP 120 to 139 mmHg or DBP 80 to 89 mmHg) consumed
daily: (1) A Dietary Approaches to Stop Hypertension (DASH) control
diet; (2) a 30 g/day soy protein diet; and (3) a 30 g/day soy nut diet
for a duration of 8 weeks each (Ref. 65). The soy protein and soy nut
diets were the same as the DASH diet with soy protein and soy nuts
being substituted for red meat for the control diet. There was no
significant difference in SBP or DBP between the DASH control diet and
the soy protein and soy nut diets.
    Evans et al. (2007) was a randomized, double-blind, placebo-
controlled, crossover trial of moderate quality in which 22 pre-
hypertensive (SBP 120 to 139 mmHg or DBP 80 to 89 mmHg), postmenopausal
American women consumed: (1) 25 g/day isolated soy protein plus 20 g/
day soy lecithin; (2) 25 g/day isolated soy protein plus placebo
lecithin; (3) placebo protein (50:50 calcium/sodium caseinate) and 20
g/day soy lecithin; and (4) double placebo (protein placebo and soy
lecithin) in addition to their usual diet for a duration of 4 weeks
each (Ref. 162). There was no significant difference in SBP or DBP
between the soy protein plus placebo lecithin group and the double
placebo group (control) or between the soy protein plus soy lecithin
group and the placebo protein plus soy lecithin period (control).
    Harrison et al. (2004) was a 5-week, randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 112
British men and women with pre-hypertension (SBP 120 to 139 mmHg or DBP
80 to 89 mmHg) consumed foods (bread, cracker biscuits, and snack bars)
that provided 25 g/day isolated soy protein (n=59) or the same foods
without soy protein as a control (n=53) in addition to their usual diet
(Ref. 192). There was no significant difference in SBP and DBP between
the soy protein and control groups.
    Cuevas et al. (2003) was a randomized, double-blind, controlled,
crossover trial of moderate quality in which 18 pre-hypertensive (SBP
120 to 139 mmHg or DBP 80 to 89 mmHg) postmenopausal Chilean women
consumed diets providing 40 g/day caseinate (control) or 40 g/day
isolated soy protein in addition to an NCEP Step 1 diet for a duration
of 4 weeks each (Ref. 194). There was no significant difference in SBP
or DBP between the soy protein diet and caseinate control diet.
    Teede et al. (2001) was a 3-month randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 179
pre-hypertensive (SBP 120 to 139 mmHg or DBP 80 to 89 mmHg) Australian
men and postmenopausal women consumed a casein placebo (n=93) or 40 g/
day soy protein isolate mixed with a beverage twice a day (n=86) in
addition to their usual diet (Ref. 170). SBP was significantly lower (P
<0.05) in the soy protein isolate group compared to casein control
group. However, there was no significant difference in DBP between the
casein control group and soy protein isolate group.
    Washburn et al. (1999) was a randomized, double-blind, placebo-
controlled, crossover trial of moderate quality in which 42 pre-
hypertensive (SBP 120 to 139 mmHg or DBP 80 to 89 mmHg), perimenopausal
American women consumed: (1) A complex carbohydrate supplement (20 g/
day) mixed with a beverage (control); (2) 20 g/day isolated soy protein
supplement mixed with a beverage as a single dose; and (3) 20 g/day soy
protein supplement mixed with beverages split into two equal doses in
addition to their usual diet for a duration of 6 weeks each (Ref. 172).
There was no difference in SBP or DBP between the soy protein
supplement mixed with a beverage as a single dose period and the
complex carbohydrate control period. However, SBP and DBP were
significantly lower (P <0.05) after consuming the 20 g/day soy protein
supplement mixed with beverages split into two equal doses compared to
the complex carbohydrate supplement.

    b. Studies in normotensive or pre-hypertensive (SBP <39 mmHg or DBP
<89 mmHg) and hypertensive subjects (SBP =140 mmHg or DBP
=90 mmHg).
    He et al. (2005) was a 12-week, randomized, double-blind, parallel
trial of moderate quality in which 276 Chinese men and women with pre-
hypertension (SBP 120 to 139 mmHg or DBP 80 to 89 mmHg) or hypertension
(SBP >=140 mmHg or DBP >=90 mmHg) consumed cookies containing 40 g/day
complex carbohydrates from wheat (n=139) (control) or cookies with 40
g/day isolated soy protein (n=137) (Ref. 212). Subjects were instructed
to reduce other food intake to keep total energy intake constant. Most
subjects consumed the cookies in place of their usual breakfast or
usual lunch. SBP and DBP were significantly (P <0.001) lower for those
who consumed the soy protein cookies compared to the wheat cookies
(control).
    Sagara et al. (2004) was a 5-week randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 50
Scottish men with pre-hypertension (SBP 120 to 139 mmHg or DBP 80 to 89
mmHg) or hypertension (SBP >=140 mmHg or DBP >=90 mmHg) consumed 20 g/
day of isolated soy protein powder in biscuits, cereal bars, and bread
rolls (n=25) or biscuits, cereal bars, and bread rolls without added
soy protein in addition to their usual diets (n=25) (Ref. 166). There
was no significant difference in SBP or DBP between the soy protein and
control group.
    c. Studies in hypertensive subjects (SBP =140 mmHg or
DBP =90 mmHg).
    Webb et al. (2008) was a 5-day, randomized, double-blind, placebo-
controlled, parallel trial of moderate quality in which 25 hypertensive
(SBP >=140 mmHg or DBP >=90 mmHg) British men and women with CHD
consumed 25.7 g/day soy protein isolate (n=13) or 25.7 g/day milk
protein isolate (n=12) in addition to their usual diets (Ref. 60).
There was no significant difference in SBP or DBP between the soy
protein isolate group and the control milk protein isolate group.
    Jayagopal et al. (2002) was a randomized, double-blind, placebo-
controlled, crossover trial of moderate quality in which 32
hypertensive (SBP >=140 mmHg or DBP >=90 mmHg) postmenopausal British
women with type 2 diabetes consumed 30 g/day of isolated soy protein or
30 g/day of cellulose (control) in addition to their usual diet for a
duration of 12 weeks each (Ref. 169). There was no significant
difference in SBP and DBP between the control diet and the soy protein
diet.
    Rivas et al. (2002) was a 3-month randomized, double-blind,
placebo-controlled, parallel trial of moderate quality in which 40
hypertensive (SBP >=140 mmHg or DBP >=90 mmHg) Spanish men and women
consumed daily 1 liter of soy milk (18 g/day soy protein) or 1 liter of
cow's milk (15.5 g/day protein) in addition to their usual diet (Ref.
213). SBP and DBP was significantly lower (P <0.0001) in the soy milk
group compared to the cow's milk group.

D. Assessment of Observational Studies

    FDA identified 11 observational studies that evaluated soy protein
and CHD risk (Ref. 214-224). All of these observational studies
calculated soy protein intake from estimated dietary intake. In
observational studies that calculated nutrient intake from conventional
foods, measures of soy protein intake were based on recorded dietary
intake methods such as food frequency questionnaires, diet recalls, or
diet records, in which the type and amount of foods consumed were
estimated. A common weakness of observational studies is the limited
ability to ascertain the actual food or nutrient intake for the
population studied as a result of poor memory, over- or underestimation
of portion sizes, and recall bias (Ref. 225). Furthermore, the nutrient
content of foods can vary due to a number of factors, including soil
composition, food processing and cooking procedures, and storage
conditions (e.g., duration, temperature). Thus, we cannot ascertain an
accurate amount of soy protein consumed based merely on subjects'
reports of dietary intake of foods.
    In addition, soy foods contain not only soy protein, but also other
nutrients that may be associated with the metabolism of soy protein or
the pathogenesis of CHD. Therefore, because soy protein containing
foods consist of many nutrients and substances, it is difficult to
study the nutrient or food components in isolation (Ref. 3). For
studies based on recorded dietary intake of such foods, it is not
possible to accurately determine whether any observed effects of soy
protein on coronary heart disease risk were due to: (1) Soy protein
alone; (2) interactions between soy protein and other nutrients; (3)
other nutrients acting alone or together; or (4) decreased consumption
of other nutrients or substances contained in foods displaced from the
diet by the increased intake of soy protein containing foods. In some
instances, epidemiological studies based on the recorded dietary intake
of conventional foods may indicate a benefit for a particular nutrient
with respect to a disease; however, it is subsequently demonstrated in
an intervention study that the nutrient-containing dietary supplement
does not confer a benefit or actually increases risk of the disease
(Ref. 226). For example, previous epidemiological studies reported an
association between fruits and vegetables high in beta-carotene and a
reduced risk of lung cancer (Ref. 227). However, subsequent
intervention studies, the Alpha-Tocopherol and Beta Carotene Prevention
Study (ATBC) and the Carotene and Retinol Efficiency Trial (CARET),
demonstrated that beta-carotene supplements increase the risk of lung
cancer in smokers and asbestos-exposed workers, respectively (Ref. 228-
229). These studies illustrate that the effect of a nutrient provided
as a dietary supplement exhibits different health effects compared to
when it is consumed as part of a usual diet among many other food
components. Furthermore, these studies demonstrate the potential public
health risk of relying on results from epidemiological studies in which
the effect of a nutrient is based on recorded dietary intake of
conventional foods as the sole source for concluding that a
relationship exists between a specific nutrient and disease risk (i.e.,
the effect could actually be harmful).
    For the reasons provided in this section, scientific conclusions
cannot be drawn from observational studies on foods for soy protein as
a food ingredient or component of food.

VI. Strength of the Scientific Evidence

    In evaluating the scientific evidence using our evidence-based
review system (Ref. 1), we considered the strength of evidence for a
relationship between soy protein intake and reduced risk of CHD. When
evaluating the strength of the evidence, we consider study types,
methodological quality, quantity of evidence for and against the claim
(taking into account the numbers of various types of studies and study
sample sizes), relevance to the U.S. population or target subgroup,
replication of study results supporting the claim, and overall
consistency of the evidence (beneficial effect, no effect) (Ref. 1).
For the outcome of an intervention study to demonstrate an effect, the
validated surrogate or clinical endpoint evaluated in the intervention
group should be statistically significantly different from the same
validated surrogate or clinical endpoint evaluated in the control group
(P <0.05). After assessing the totality of the scientific evidence, we
then determine whether there is SSA to support an

authorized health claim, or credible evidence to support a qualified
health claim.
    Our decision about whether to authorize a health claim represents
our determination as to whether there is significant scientific
agreement among qualified experts that the publicly available
scientific evidence supports the substance/disease relationship that is
the subject of a proposed health claim. The SSA standard is intended to
be a strong standard that provides a high level of confidence in the
validity of the substance/disease relationship. SSA occurs well after
the stage of emerging science, where data and information permit an
inference, but does not require consensus based on unanimous and
incontrovertible scientific opinion. We explained in our 2009 guidance
(Ref. 1) that we may evaluate new information that becomes available to
determine whether it necessitates a change to an existing SSA claim to
maximize the public health benefit of our health claims review. The
2009 guidance represents our current thinking on the meaning of the SSA
standard in section 403(r)(3) of the FD&C Act and Sec.  101.14(c) and
the process for evaluating the scientific evidence for a health claim
pursuant to these authorities.
    As noted in section V, we reevaluated, consistent with the 2009
guidance (Ref. 1), the studies included in the 1999 final rule as well
as new studies that were published since the original review. As
discussed in section V.C and D, the totality of the scientific evidence
includes 58 well-designed, well-executed intervention studies. Of these
58 studies, 46 are intervention studies of high or moderate quality
that measured blood TC or LDL cholesterol, and 12 are intervention
studies of high or moderate quality that measured SBP or DBP. The
results of these studies were inconsistent and not conclusive.
    Of the 46 studies intervention studies of high or moderate quality
that measured blood TC or LDL cholesterol, 25 studies were conducted on
subjects with desirable or borderline cholesterol levels, defined as a
blood TC less than 240 mg/dL or LDL cholesterol less than 160 mg/dL; 18
were conducted on subjects with high TC levels, defined as TC levels
less than 240 mg/dL or LDL cholesterol greater than or equal to 160 mg/
dL; and 3 studies included subjects with desirable or borderline TC
levels and subjects with high TC levels. Of the 46 intervention studies
that looked at the relationship between blood TC and/or LCL cholesterol
and soy protein intake, only 19 intervention studies showed a benefit
in significantly reducing the risk of CHD, while the other 27
intervention studies did not. Study findings also were inconsistent
regardless of whether soy protein was added to diet as a supplement or
whether the studies were substitution or feeding studies. The study
findings also were inconsistent regardless of the study size (10
subjects to 179 subjects) or the dose of soy protein (3 g to 92 g/day).
Of the 12 high or moderate quality intervention studies that measured
SBP or DBP from which a conclusion could be drawn, only 4 showed a
benefit in lowering SBP or DBP with soy protein consumption, while the
other 8 studies did not show a benefit. Again, the study findings were
inconsistent regardless of baseline SBP or DBP, study size (18 subjects
to 276 subjects), or dose (18 g to 60 g/day). Consistency of findings
among similar and different study designs is important for evaluating
causation and the strength of scientific evidence (Ref. 1). The
totality of the evidence does not provide a basis on which experts
would find SSA because of the high degree of inconsistency of findings
across similar and different studies with high or moderate
methodological quality. This degree of inconsistency would not be seen
when SSA exists because, when there is SSA, we would find most of the
studies to consistently find a beneficial relationship between a
substance and a disease risk.
    Although there is some evidence that suggests a relationship
between soy protein intake and reduced risk of CHD, the strength of the
totality of the current, publicly available scientific evidence,
discussed in sections V and VI and the references cited therein, which
includes many studies that post-date the publication of our 1999 rule,
is inconsistent and not conclusive. See also tables 4-8 in Ref. 230.
The additional evidence now available to us includes a number of new
studies that do not support the relationship, and a number of studies
that are inconclusive that also do not support a relationship. This
combined body of evidence represents the totality of the scientific
evidence that is currently available. We have now evaluated this entire
body of evidence, which consists of the studies in the 1999 rule as
well as new evidence published since that time, using the evidence
based process described in our 2009 guidance. The totality of the
evidence, which includes the new, non-supportive studies, does not
support the statutory standard for authorizing a health claim. We have
determined that the totality of the scientific evidence does not
provide significant scientific agreement, among experts qualified by
scientific training and experience to evaluate such claims, that the
claim is supported. Therefore, we have tentatively concluded that,
currently, there is not significant scientific agreement among experts,
under section 403(r)(3)(B)(i) of the FD&C Act, that a health claim
about a relationship between soy protein intake and CHD risk is
supported by the evidence. We request comment and any supporting data
and information concerning this tentative conclusion. However, while
the totality of the publicly available scientific evidence does not
support a finding of SSA, if, when we finalize this rule, we conclude
there is not SSA, but there is some credible evidence for the use of a
qualified health claim about the relationship between soy protein and a
reduced risk of CHD, we intend to issue a statement of enforcement
discretion for the use of a qualified health claim.
    In the 1999 soy protein final rule authorizing the use of a health
claim regarding soy protein and the risk of CHD (64 FR 57700) (now
codified at Sec.  101.82) (the 1999 authorized soy protein health
claim), the petitioner determined that use of soy as a dietary protein
is generally recognized as safe. Under the health claim petition
process, we evaluate whether the proponent of the claim demonstrates,
to FDA's satisfaction, that the food ingredient is ``safe and lawful''
under the applicable food safety provisions of the FD&C Act. In the
1999 soy protein final rule, we concluded that there was not sufficient
evidence to challenge the petitioner's assertion that soy protein
ingredients are GRAS. The petitioner met the showing required by Sec.
101.14(b)(3)(ii) that the substance be ``safe and lawful.'' We have
reviewed the scientific evidence relative to the safety of soy protein
as a food ingredient and the evidence does not change our previous
conclusion that the use of soy protein at the levels necessary to
justify a claim has been demonstrated, to our satisfaction, to be safe
and lawful under the applicable food safety provisions of the FD&C Act.

VII. Proposal To Revoke Sec.  101.82

    As discussed above, FDA may reevaluate the science related to an
authorized health claim and may take action to revoke the claim (see
section 403(r)(7)(B) of the FD&C Act (21 U.S.C. 343(r)(7)(B)). Based on
our review of the totality of the publicly available scientific
evidence, we have tentatively concluded that the SSA standard is not
met for a relationship between soy protein and reduced risk of CHD.
Therefore, we are proposing to revoke

the soy protein and reduced risk of CHD health claim in Sec.  101.82.

VIII. Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and
13563 direct Agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 13771
requires that the costs associated with new regulations shall ``be
offset by the elimination of existing costs associated with at least
two prior regulations.'' It has been determined that this proposed rule
is an action that does not impose more than de minimis costs as
described below and thus is not a regulatory or deregulatory action for
purposes of Executive Order 13771. This proposed rule is a significant
regulatory action under Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because up to 40 small businesses could be required
to relabel one or more products, we find that the proposed rule may
have a significant economic impact on a substantial number of small
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $148 million, using the most current (2016) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in any year expenditure that meets or exceeds this amount.
    The costs of this rule are relabeling the estimated 200 to 300
products currently making the health claim. We estimate total
annualized costs of $35,000 to $81,000, when the relabeling costs are
annualized over 20 years at a 7-percent discount rate. The initial,
one-time costs are $370,000 to $860,000.
    The benefit of this rule is better information for the consumers
who are considering purchasing products with soy protein. This may
generate an unknown amount of increased consumer surplus. Some
consumers may react to this new information by switching their
consumption to products that they enjoy more, or products that still
have an authorized health claim. We request public comment on how many
consumers are likely to react to the changes in health claims caused by
this proposed rule, and what the nature of their reaction will be. By
basing their consumption decisions on more recent and accurate
scientific information, they will get more consumer surplus, in the
form of enjoyment and/or potential health benefits, from the bundle of
products they consume.

                        Table 3--Cost and Benefit Overview, USD, Annualized Over 20 Years
----------------------------------------------------------------------------------------------------------------
                                                                   Low estimate        Mean        High estimate
----------------------------------------------------------------------------------------------------------------
Costs, 7 percent discount rate..................................         $35,000         $55,000         $81,000
Costs, 3 percent discount rate..................................          25,000          39,000          58,000
rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr
Benefits........................................................     Consumer Health Benefits and/or Enjoyment
----------------------------------------------------------------------------------------------------------------

    The Economic Analysis of Impacts of the proposed rule performed in
accordance with Executive Order 12866, Executive Order 13563, the
Regulatory Flexibility Act, and the Unfunded Mandates Reform Act is
available at https://www.regulations.gov under the docket number for
this proposed rule and at: https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm.

IX. Proposed Effective Date

    We intend that the effective date for a final rule resulting from
this rulemaking be 30 days after the final rule's date of publication
in the Federal Register.
    With respect to a compliance date, we intend that any adjustments
to a product's labeling occur in a manner consistent with our uniform
compliance date (see 81 FR 85156, November 25, 2016). Thus, if we issue
a final rule before December 31, 2018, then the compliance date would
be January 1, 2020.

X. Analysis of Environmental Impact

    We have determined under 21 CFR 25.32(p) that this action, revoking
a health claim, is categorically excluded from an environmental
assessment or an environmental impact statement.

XI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no
collection of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.

XII. Federalism

    FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. Section 4(a) of the
Executive order requires Agencies to ``construe * * * a Federal statute
to preempt State law only where the statute contains an express
preemption provision or there is some other clear evidence that the
Congress intended preemption of State law, or where the exercise of
State law conflicts with the exercise of Federal authority under the
Federal statute.'' Federal law includes an express preemption provision
that preempts ``any requirement respecting any claims of the type
described in [21 U.S.C. 343(r)(1)] made in the label or labeling of
food that is not identical to the requirement of [21 U.S.C. 343(r)] * *
*.'' 21 U.S.C. 343-1(a)(5). However, the statutory provision does not
preempt any State requirement respecting a statement in the labeling of
food that provides for a warning concerning the safety of the food or
component of the food (Pub. L. 101-535, section 6, 104 Stat. 2353
(1990)). If this proposed rule is made final, the final rule would
revoke the health claim related to soy protein and coronary heart
disease in the label or labeling of food under 21 U.S.C. 343(r).

XIII. References

    The following references are on display in the Dockets Management
Staff (see ADDRESSES) and are available

for viewing by interested persons between 9 a.m. and 4 p.m., Monday
through Friday; they are also available electronically at https://www.regulations.gov. FDA has verified the Web site addresses, as of the
date this document publishes in the Federal Register, but Web sites are
subject to change over time.

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