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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
 AGENCY: Food and Drug Administration, HHS.
 ACTION: Proposed rule.
 SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is proposing to revoke its regulation authorizing the use of health claims on 
                        ( print 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 § 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) (§ 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 (§ 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 
                    ( print 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 § 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
Low estimate
Mean
High estimateCosts, 7 percent discount rate
$35,000
$55,000
$81,000Costs, 3 percent discount rate
$25,000
$39,000
$58,000Benefits
Consumer Enjoyment and/or potential Health Benefits
 II. Table of Commonly Used Acronyms in This Document Table 2—Table of Commonly Used Acronyms
Acronym
What it meansCHD
Coronary Heart DiseaseDASH
Dietary Approaches to Stop HypertensionDBP
Diastolic Blood PressureFDA
Food and Drug Administrationg
gram(s)kcal
kilocalorie(s)LDL
Low-Density Lipoproteinmg
milligram(s)NCEP
National Cholesterol Education ProgramNHLBI
National Heart, Lung and Blood Instituteoz
ouncesSBP
Systolic Blood PressureSSA
Significant Scientific AgreementTC
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 § 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 § 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.
                    ( print 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 (§ 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 § 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 § 10.25 (21 CFR 10.25). Specifically, § 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 (§ 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 
                    ( print 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 
                    ( print 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 (§ 101.75, § 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 
                    ( print 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 
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                    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 β-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 β-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 
                    ( print 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.
                    ( print 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 
                    ( print page 50335)
                    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.
                    ( print 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 
                    ( print page 50337)
                    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 § 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 § 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 § 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 § 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 
                    ( print page 50338)
                    the soy protein and reduced risk of CHD health claim in § 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 estimateCosts, 7 percent discount rate
$35,000
$55,000
$81,000Costs, 3 percent discount rate
25,000
39,000
58,000Benefits
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 
                    ( print 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. 1. U.S. Food and Drug Administration. “Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims“, January 2009. Retrieved from: 
                        *http://www.fda.gov/​food/​guidanceregulation/​guidancedocumentsregulatoryinformation/​labelingnutrition/​ucm073332.htm.* 2. Balk E.C.M., Chew P, Ip S, Raman G, Kupelnick B, Tatsioni A, Sun Y, Wolk B, DeVine D, Lau J. “Effects of Soy on Health Outcomes. Summary, Evidence Report/Technology Assessment No. 126. (Prepared by the Tufts-New England Medical Center Evidence-Based Practice Center under Contract No. 290-02-0022.)“, AHRQ Publication No. 05-E024-1 July 2005. 3. Sempos C.T., Liu K., Ernst N.D. “Food and Nutrient Exposures: What to Consider When Evaluating Epidemiologic Evidence”. 
                        *American Journal of Clinical Nutrition.*
                         1999;69:1330S-1338S. 4. Institute of Medicine (IOM) of the National Academies. “Dietary Supplements: A Framework for Evaluating Safety, Chapter 7, Categories of Scientific Evidence—in Vitro Data.“, Washington, DC; 2005. 5. Spilker B. 
                        *Guide to Clinical Studies.*
                         New York, New York: Raven Press, 1991; pp. 59-64, 497-501, 793-800. 6. National Research Council. 
                        *Reference Manual on Scientific Evidence: Third Edition.*
                         Washington, DC: The National Academies Press, 2011; pp. 220. 7. Wilson E.B. 
                        *An Introduction to Scientific Research.*
                         New York: Dover Publications, 1990; pp. 46-48. 8. Hill A.B. “The Environment and Disease: Association or Causation?”. 
                        *Proceedings of the Royal Society of Medicine.*
                         1965;58:295-300. 9. Agency for Healthcare Research and Quality. “Systems to Rate the Scientific Evidence”, March 2002. 10. Institute of Medicine (IOM) of the National Academies. “Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients), Chapter 8: Dietary Fats: Total Fat and Fatty Acids”, Washington, DC: National Academies Press; 2002. 11. Institute of Medicine (IOM) of the National Academies. “Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients), Chapter 9: Cholesterol”, Washington, DC: National Academies Press; 2002. 12. Institute of Medicine (IOM) of the National Academies. “Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients), Chapter 7: Dietary, Functional, and Total Fiber”, Washington, DC: National Academies Press; 2002. 13. U.S. Department of Agriculture. “Soy Milk”, USDA National Nutrient Database for Standard Reference, release 28, 2016. Retrieved from: 
                        *https://ndb.nal.usda.gov/​ndb/​.* 14. U.S. Department of Agriculture. “Soy Flour”, USDA National Nutrient Database for Standard Reference, release 28, 2016. Retrieved from: 
                        *https://ndb.nal.usda.gov/​ndb/​.* 15. U.S. Department of Agriculture. “Soy Protein Isolate”, USDA National Nutrient Database for Standard Reference, release 28, 2016. Retrieved from: 
                        *https://ndb.nal.usda.gov/​ndb/​.* 16. Institute of Medicine (IOM) of the National Academies. “Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate”, Washington, DC: National Academies Press; 2005. 17. Persky V.W., Turyk M.E., Wang L., Freels S., Chatterton R., Jr., Barnes S., Erdman J., Jr., Sepkovic D.W., Bradlow H.L., Potter S. “Effect of Soy Protein on Endogenous Hormones in Postmenopausal Women”. 
                        *American Journal of Clinical Nutrition.*
                         2002;75:145-153. 18. Siefker K., DiSilvestro R.A. “Safety and Antioxidant Effects of a Modest Soy Protein Intervention in Hemodialysis Patients”. 
                        *Journal of Medicinal Food.*
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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
 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. § 101.82
 2.Remove § 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