Food Labeling: Health Claims; Soy Protein and Coronary Heart Disease, 50324-50346 [2017-23629]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 82, Number 209 (Tuesday, October 31, 2017)]
[Proposed Rules]
[Pages 50324-50346]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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

[[Page 50325]]

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, 240-402-1444.

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

[[Page 50326]]

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
------------------------------------------------------------------------
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
------------------------------------------------------------------------

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.

[[Page 50327]]

    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

[[Page 50328]]

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

[[Page 50329]]

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

[[Page 50330]]

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

[[Page 50331]]

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

[[Page 50332]]

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.

[[Page 50333]]

    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/

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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

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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.

[[Page 50336]]

    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

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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

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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

[[Page 50339]]

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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List of Subjects in 21 CFR Part 101

    Food labeling, Nutrition, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 101 be amended as follows:

PART 101--FOOD LABELING

0
1. The authority citation for part 101 continues to read as follows:

    Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 342, 
343, 348, 371; 42 U.S.C. 243, 264, 271.


Sec.  101.82  [Removed]

0
2. Remove Sec.  101.82.

    Dated: October 26, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-23629 Filed 10-30-17; 8:45 am]
 BILLING CODE 4164-01-P