6

Societal and Policy Implications

Aprobiotic is only as effective as its ability to remain viable until it reaches a place in the human gastrointestinal (GI) tract where it can exert its effects, David Julian McClements explained (see a summary of his presentation in Chapter 5). If the viability of a probiotic is lost during storage within a food product or in the human body en route to its destination, then the beneficial health effects may not be realized. The challenge doesn’t end there. In the final speaker session of the workshop, participants addressed other, nonbiological challenges—consumer, regulatory, and industry challenges—to realizing the potential of food as a primary modulator of the microbiome for health. This chapter summarizes that discussion.

HOW AMERICANS EAT AND DRINK TO IMPROVE HEALTH1

Research conducted by the NPD Group shows that consumer behavior is stable over time. The NPD Group collects data both on usage, that is, food preparation and consumption (e.g., What did you eat? What were the ingredients? Did the product have any kind of health claim?) and on the planning and acquisition of food (e.g., What did you have on hand in your pantry? Why was a certain item on your grocery list?). Darren Seifer noted that even during difficult economic times when people are watching their budgets, consumer behavior remains mostly stable. For example, NPD data indicate that the top breakfasts consumed in the United States, based on annual eatings per capita, were more or less the same in 2011 as

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1 This section summarizes the presentation of Darren Seifer.



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6 Societal and Policy Implications A probiotic is only as effective as its ability to remain viable until it reaches a place in the human gastrointestinal (GI) tract where it can exert its effects, David Julian McClements explained (see a summary of his presentation in Chapter 5). If the viability of a probiotic is lost during storage within a food product or in the human body en route to its destina- tion, then the beneficial health effects may not be realized. The challenge doesn’t end there. In the final speaker session of the workshop, participants addressed other, nonbiological challenges—consumer, regulatory, and indus- try challenges—to realizing the potential of food as a primary modulator of the microbiome for health. This chapter summarizes that discussion. HOW AMERICANS EAT AND DRINK TO IMPROVE HEALTH1 Research conducted by the NPD Group shows that consumer behavior is stable over time. The NPD Group collects data both on usage, that is, food preparation and consumption (e.g., What did you eat? What were the ingredients? Did the product have any kind of health claim?) and on the planning and acquisition of food (e.g., What did you have on hand in your pantry? Why was a certain item on your grocery list?). Darren Seifer noted that even during difficult economic times when people are watch- ing their budgets, consumer behavior remains mostly stable. For example, NPD data indicate that the top breakfasts consumed in the United States, based on annual eatings per capita, were more or less the same in 2011 as 1  This section summarizes the presentation of Darren Seifer. 121

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122 THE HUMAN MICROBIOME, DIET, AND HEALTH in 2001. In 2001, the top five breakfasts were, in order, cold cereal; eggs or omelets; bread; hot cereal; and pancakes, waffles, or French toast. In 2011, the top five breakfasts were, again in order, cold cereal; eggs or omelets; hot cereal; pancakes, waffles, or French toast; and bread. According to Seifer, pancakes, waffles, and French toast have moved up to the number four spot because those products are being delivered in more easy-to-prepare fashions, such as instant or frozen. The same stability has been observed for lunch and dinner. NPD data indicate that the top five lunches consumed in the United States in 2001, again based on annual eatings per capita, were, in order, sandwiches (in- cluding burgers), soup, poultry, pizza, and salads. In 2011, the list and order were the same. The top five dinners consumed in the United States in 2001 were poultry, sandwiches (including burgers), beef, Italian dishes, and homemade or mix “variety.” In 2011, preferences shifted, but only slightly, to sandwiches (including burgers) as the top dinner, followed by poultry, beef, Italian dinners, and pizza. Seifer explained that as with breakfast pancakes, waffles, and French toast, part of the reason for pizza moving up into the top five list is that it is being sold in an easy-to-prepare frozen form. The slight shifts in consumer behavior around frozen foods suggest that underlying consumer behaviors can change, albeit slowly. Changes take years, if not decades. If one were to examine just the past several years, NPD data do not show much change in the percentage of meals with a main dish coming in frozen form. In looking back to the mid-1980s, however, there has been a noticeable increase in frozen items being served at all three main meals. For breakfast, 4 percent of main dishes served in 1984 were purchased in frozen form. That figure doubled, to 8 percent, by 2011. For lunch, 7 percent of main dishes served in 1984 were purchased in frozen form. That figure also doubled, to 14 percent in 2011. For dinner, 15 per- cent of main dishes served in 1984 were frozen. By 2011, that figure had increased to 23 percent. The growing preference for foods that do not need to be cooked is corroborated with other NPD data on the top 10 fastest-growing in-home foods and beverages. Based on point change in percentage of Americans consuming a product at least once in a 2-week period between 2001 and 2011, the top 10 fastest-growing in-home foods and beverages were yogurt (15), bars (10), chips (10), bottled water (10), nuts and seeds (9), pizza (8), fresh fruit (7), poultry sandwich (7), specialty Italian (7), and cheese (6). Seifer noted that fresh fruit is on the list because of changing demo- graphics; it is popular among older adults as well as among children. A common characteristic of these foods is that they require very little, if any, preparation.

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SOCIETAL AND POLICY IMPLICATIONS 123 Yogurt Yogurt consumption has more than doubled over the past decade, from 13 annual eatings per capita in 2001 to 30 in 2011. “Certainly it is some- thing to keep watching and monitoring,” Seifer said. However, compared to other snack categories, it is still small. People eat salty items three times more often than they do yogurt, and even though people drink less milk than they used to, they still consume more than four times as much milk as yogurt. The fast growth of yogurt consumption raises the question, Why are people choosing yogurt? NPD data show that the number one reason people choose yogurt is because it is nutritious and has a health benefit (15 percent). This is different from most food items, Seifer noted. Usually taste is the top reason for choosing a food. In the case of yogurt, however, taste is the second reason (13 percent), followed by “was hungry” (10 percent), “healthy start to day” (8 percent), “favorite snack” (6 percent), “simple and easy to eat” (6 percent), “routine or habit” (5 percent), “better than other choices” (5 percent), “hold me over until next meal” (4 percent), and “low in fat or calories” (3 percent). The Nutrition Facts Panel: What Are Consumers Looking For? When people look at a Nutrition Facts Panel, what are they looking for? NPD data indicate that consumers are looking mostly for total calo- ries (49 percent), followed by sugars (43 percent), total fat (43 percent), sodium (41 percent), calories from fat (34 percent), total carbohydrates (33 percent), serving size (33 percent), saturated fat (33 percent), servings per container (28 percent), cholesterol (28 percent), and dietary fiber (25 per- cent). Seifer remarked that even though calories are the number one thing that people look for, studies indicate that only about 10 percent of people know how many calories they should be consuming on a daily basis. More people are looking for sugar content than in the past (43 percent in 2010 compared to 39 percent in 2004). Seifer characterized the grow- ing interest in sugar as a remnant of the “Atkins and low-carb craze” and a function of the aging population with more health concerns to manage, including diabetes. People are also looking for fiber content more often than in the past (25 percent in 2010 compared to 22 percent in 2004), a trend that Seifer suggested may also be related to our aging population and the fact that dietary fiber is something that older adults are concerned about. Another trend is the growing interest in sodium (41 percent in 2010 compared to 34 percent in 2004), again probably because of chang- ing demographics and greater concern about sodium among older adults. Again, as with calories, even though people are expressing more interest

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124 THE HUMAN MICROBIOME, DIET, AND HEALTH in sodium content, they are not necessarily consuming sodium within the recommended levels. In fact, NPD Group data indicate that all age groups are consuming too much sodium. Among adults, seniors (65 years and older) consume the least amount of sodium, at an average 2,912 milligrams per day. The maximum recommended daily intake level, however, is 2,300 milligrams for the general population (the recommended average daily s ­ odium intake level is 1,500 milligrams or less, particularly for older adults; African Americans; and anyone with hypertension, diabetes, or chronic kidney disease). American consumers are not looking at fat content as often as in the past (43 percent in 2010 compared to 48 percent in 2004), according to NPD data. At one time, checking fat content was second only to checking calories. Nor are they looking at cholesterol as much as they did in the past (28 percent in 2010 compared to 32 percent in 2004). Like fats, cholesterol used to be a primary health concern (in the late 1980s). Calcium content is being checked less often as well (9 percent in 2010 compared to 10 percent in 2004). Seifer emphasized that not only are people looking for different things on the Nutrition Facts Panel, they are also looking for ways to enhance, not restrict, their diets, according to NPD data. It is easier to add ingredients to one’s diet than remove them. This may partly explain yogurt’s increasing popularity, according to Seifer. The simple act of eating yogurt provides health benefits. Consumers would rather ingest their way to health than restrict their way to health. In 2010, more people were trying to add whole grains, dietary fiber, and antioxidants to their diets than in 2004. Also in 2010, not nearly as many people were as cautious about fat, salt, choles- terol, sugar, and caffeine as have been in the past. Along the same line, dieting is also on the decline, with a smaller percentage of people reporting being on any diet in 2011 compared to 2002. Older adults report being on a diet more often than any other age group. Consumer Behavior Around Probiotics and Prebiotics When probiotics were first introduced into the marketplace, consumers were confused. According to data collected by the NPD Group, in 2006 more adults were trying to cut down on or avoid probiotics (13 percent) than get more probiotics into their diets (10 percent). The trend has shifted, with more adults trying to get probiotics into their diets (24 percent) than avoid them (10 percent) in 2010. Prebiotics are still a challenge, with only 15 percent of adults trying to get more prebiotics in their diets in 2010 and 12 percent trying to cut down or avoid prebiotics. Seifer emphasized that consumers tend to be reactive, not proactive. That is, they tend to react when there is a need, such as a medical condi-

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SOCIETAL AND POLICY IMPLICATIONS 125 tion (e.g., diabetes, heart disease, high cholesterol, high blood pressure). For example, many people with diabetes manage their sugar intake by eating foods that either lack sugar or are higher in whole grains. Compared to the total population, they eat more bread, eggs, soup, hot cereal, crackers, and seafood, and they eat fewer cookies, Italian dishes, pizza, “mac and cheese,” bars, toaster pastries, and brownies. Seifer noted that seniors (65 years and older) and older baby boomers (55-64) are more likely to experi- ence medical conditions that drive the consumption of fruits, vegetables, and other foods perceived as nonharmful. Expanding the user base of probiotics and prebiotics beyond those who have a need for additional microbes will require a marketing effort. Seifer referred to the “four P’s” of marketing: product, price, promotion, and place. In addition to alleviating some of the confusion that still surrounds use of the words “probiotic” and “prebiotic,” consumers may have to be educated on the health benefits of adding more microbes to their diet. “Be patient,” Seifer advised. “It is going to take time for this to catch on.” CONSUMER INSIGHTS FROM THE INDUSTRY PERSPECTIVE2 The probiotic market is one of the fastest-growing sectors in the func- tional food market, according to Peggy Steele. In 2001, probiotics ac- counted for $25 billion in sales worldwide. The sector is expected to continue to grow at more than 6 percent annually, yielding an estimated $32 billion in annual sales by 2015. Regionally, North America, Latin America, Eastern Europe, and Asia Pacific are expected to see the strongest growth in coming years. Growth in the already mature markets of Western Europe and Japan will be slower. Yogurts account for the majority of new products being launched as probiotics (about 75 percent), with the remainder including baby food and baby milk powder, drinks, cheese, other dairy (milk, cream, kefir), frozen desserts, and other products. The current U.S. market for probiotic yogurt is more than $1 billion, representing about one-quarter of the overall refrigerated yogurt segment. Over the past several years, the probiotic yogurt market has grown more quickly (10 percent) than the market for nonprobiotic yogurts (6.5 percent). “Yogurt is really the dominant delivery vehicle for probiotics right now,” Steele said. She referred to Darren Seifer’s remarks on the appeal of the health benefits of yogurt to consumers. Yet as markets for probiotic yogurt and other products continue to grow, Steele observed a trend toward stricter regulation and enforcement of health claims on those products. The European Food Safety Authority (EFSA), the U.S. Food and Drug Administration (FDA), Health Canada, 2  This section summarizes the presentation of Peggy Steele.

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126 THE HUMAN MICROBIOME, DIET, AND HEALTH and other regulatory agencies have taken considerable action to control and regulate probiotic health claims. In Steele’s opinion, the level of science being required to support certain claims is approaching “pharma” level documentation. She expressed concern that not all manufacturers will have the funding or resources needed to provide such support, resulting in con- solidation and even elimination of some competitors. While probiotics that successfully pass regulatory scrutiny will likely instill consumer confidence and acceptance of probiotic products and thereby increase their market share, those that fail regulatory scrutiny could have the opposite effect. Because of the changing regulatory pressures, major players such as Danone are softening their claim language. Previously, Danone’s claims on its probiotic products were focused on structure-function claims. Now the claims are focused on nutrition or general function, and some products make no claims at all. Interestingly, Steele noted, despite the increasing regulatory pressure and changes in claim language, the probiotic market continues to show remarkable growth. Whether that growth is sustainable is difficult to predict. In addition to regulatory restraints, other key market constraints in- clude the presence of substitutes (e.g., other functional ingredients for gut and immune health such as vitamin C); lack of awareness of the word “probiotic,” especially in the United States; and challenges with product stability (i.e., probiotics are sensitive to many food and beverage applica- tions). Key market drivers include growing benefit substantiation (i.e., clinical documentation on an expanding list of conditions); health care provider endorsements; increasing awareness as a result of companies such as Danone and Yakult promoting digestive health; a trend toward self-care; and the perceived immediate impact of probiotic products (e.g., feeling the benefit of taking Activia after only 2 weeks of regular consumption). Positioning of Probiotics: Types of Claims In the United States, there are three general categories of probiotic claims: (1) content claims, (2) structure-function claims, and (3) health claims. Examples of content claims are “contains L[actobacillus] acidophi­ lus bifidobacteria,” “contains live and active bacteria,” and “probiotic.” These require the least amount of documentation. Examples of structure- function claims are “supports good digestion,” “promotes a healthy diges- tive and immune function,” and “helps naturally regulate your digestive system.” Structure-function claims require more documentation than con- tent claims and, according to Steele, resonate very well with consumers. Examples of health claims are “reduces the risk of cancer,” “reduces IBS [irritable bowel syndrome],” and “reduces incidence and severity of chronic constipation.” These require the greatest amount of documentation. Probi-

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SOCIETAL AND POLICY IMPLICATIONS 127 otic health claims cannot make any reference to treatment or mitigation of disease or disease symptoms. If so, they are considered drug claims, which require pharmaceutical approval. The most common probiotic product claims are digestive and immune structure-function claims. In the United States, 28 percent of all probiotic yogurts make structure-function claims. About one-third of those claims are for digestive health only and another one-third for both digestive and immune health. Only 3 percent are for immune health only. U.S. consumers are becoming increasingly aware of the digestive health benefits of probiotics. In an International Food Information Council (IFIC) online survey, when asked about awareness of the digestive health benefits of probiotics, the percentage of respondents answering positively increased from 58 percent in 2007 to 81 percent in 2011.3 Steele wondered whether a similar awareness among European Union (EU) consumers might be driving growing sales in probiotic yogurt despite the softening of claim language. Steele urged manufacturers to focus on clear, relevant, and substanti- ated claims on the front of their products’ packages. A DuPont survey conducted in 2011 showed that 75 percent of consumers look at the front of the package for nutrition information. Most people tend to read the Nu- trition Facts Panel and ingredient lists only when they are making a change. What Can Industry Do? Steele identified three major activities of industry that can move the field of probiotics forward in the face of a changing regulatory landscape: (1) demonstrate efficacy and help the scientific and regulatory communi- ties to recognize the effects of probiotics on human health; (2) educate and increase dialogue with doctors, nutritionists, key opinion leaders, and journalists to communicate the results of human studies conducted on probiotics; and (3) explore new end points (i.e., different populations, new health areas). As an example of efficacy research in which Danisco and DuPont4 have been involved, Steele highlighted a study on two probiotics (Lactobacillus acidophilus NCFM and a blend of L. acidophilus NCFM and Bifidobacte­ rium lactis Bi-07) in children aged 3-5 years (Leyer et al., 2009). The study was a 26-week prospective, double-blinded trial of 326 children random- ized across three treatments (the two probiotic treatments and one placebo 3  More information on the IFIC 2011 Functional Foods/Foods for Health Consumer Trending Survey is available online at http://www.foodinsight.org/Resources/Detail.aspx?topic=2011_ Functional_Foods_Foods_For_Health_Consumer_Trending_Survey (accessed August 20, 2012). 4  In May 2011, Danisco was acquired by DuPont.

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128 THE HUMAN MICROBIOME, DIET, AND HEALTH control). The children were administered 5 × 109 colony-forming units (CFUs) twice a day. The study was conducted during the cold and flu season (i.e., from November to May). Researchers observed a significant reduction in respiratory tract infections in both treatment groups. Also, children who received the blended probiotic demonstrated an 82 percent reduction in an- tibiotic use and a 46 percent reduction in number of sick days. The findings were corroborated by a more recent (manuscripts in preparation) efficacy study of 474 adult athletes showing that the same blended probiotic led to a 33 percent reduction in respiratory infections and a 35 percent reduction in medication use over a 150-day period during the cold and flu season. As an example of how DuPont5 has contributed to education, Steele noted the national media coverage of the company’s HOWARU product launch. She also commented on Danone’s pioneering work in educating consumers about probiotic yogurt and the company’s role in promoting d ­ igestive health, including its use of a celebrity (Jamie Lee Curtis) to pro- mote the digestive benefits of probiotic yogurt. With respect to exploring new end points, Steele identified the need to address different age groups and adapt probiotic formulations accordingly. For example, older adults might require different probiotic blends than younger adults or infants and children. Reiterating some of what Julian McClements covered during his presentation, Steele explained that a pro- biotic must remain viable and in sufficient quantity until it actually delivers its benefit. A whole host of food factors could impact viability, including formulation, processing, storage or distribution, and shelf life. As just one example, she referred to data on the survival of an L. casei strain in orange juice. Over the course of its 60-day shelf life, the probiotic population decreased in size about 10-fold. DuPont scientists are also testing different food matrices both in simulated GI tract conditions and in the clinic to see which matrices are most protective of a probiotic as food is digested (­brahim et al., 2010; Makelainen et al., 2009). I Finally, DuPont scientists are investigating new health end points. For example, Amar and colleagues (2011) reported that B. lactis 420 can re- verse high-fat diet-induced diabetes in mice. In addition to impacting blood glucose, insulin secretion, and insulin sensitivity, the probiotic also reduced fat mass. The researchers linked the effects to reduced plasma lipopolysac- charide (LPS) levels and reduced tissue inflammation. As another example, Shu et al. (2000) reported significantly improved survival rates among mice that were administered Danisco’s HOWARU Bifido (B. lactis HN019) and then challenged with a single dose of Salmonella typhimurium. The results have implications for pathogen-induced diarrheal disease in humans. 5  The HOWARU product line was launched by Danisco.

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SOCIETAL AND POLICY IMPLICATIONS 129 PROBIOTIC AND PREBIOTIC HEALTH CLAIMS IN EUROPE: SCIENTIFIC ASSESSMENT AND REQUIREMENTS6 EFSA has responsibility across all EU countries for regulating nutrition and health claims on foods including probiotic and prebiotic products. EFSA is not a decision maker, Seppo Salminen explained. Rather, it is an independent risk assessment and scientific advice authority. The role of EFSA in the scientific substantiation of nutrition and health claims is based on a 2006 European Parliament regulation.7 Prior to the 2006 regulations, claims were regulated through directives, with each member state acting independently. While the new EU claim regulation addresses free and fair trade of goods, including foods, and promotion of innovation, its most important principle is consumer protection: “Nutrition and health claims on food must be substantiated by scientific evidence.” The regulation creates several new challenges for claim applicants. First, evidence should be collected from a population that is representative of the generally healthy popula- tion or from which results can be extrapolated to the general population, which Salminen noted varies even within Europe (e.g., there are significant differences in microbiota composition and activity in individuals from northern versus southern Europe). Second, the evidence must be considered “generally accepted science,” which Salminen noted is a difficult criterion for microbiota research. Finally, scientific assessment of proposed claims must address causality. Salminen referred to the comments of many previ- ous speakers and workshop participants on the issue of causality (i.e., that most of the evidence on diet-microbiome-health relationships is associa- tional, not causal). Because of these challenges, EFSA issued a guidance document to assist applicants in preparing and presenting their applications for authorization (EFSA, 2011a). The guidance document addresses both format and criteria for substantiation. Salminen noted that it is constantly being reviewed and updated and that EFSA also conducts stakeholder consultations. EFSA also published an additional and more specific guidance document on the sci- entific requirements for claims on gut health and immunity (EFSA, 2011b). The document summarizes experience from earlier assessments, gives guid- ance on factors associated with gut health and immunity, summarizes ben- eficial effects or beneficial implications that have already been considered, attempts to explain why some studies are applicable and others are not, and provides some outcome measures. The guidance is not exhaustive, Salminen ­ warned. That would be impossible. Evaluations are conducted on a case- 6  This section summarizes the presentation of Seppo Salminen. 7  Regulation on Nutrition and Health Claims Made on Foods, EC No. 1924/2006 of the European Parliament and of the Council (December 20, 2006).

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130 THE HUMAN MICROBIOME, DIET, AND HEALTH by-case basis. Furthermore, the guidance is a living document and will be updated as appropriate. Types of Nutrition and Health Claims That Can Be Made About Probiotic and Prebiotic Food Products As in the United States, three types of nutrition and health claims are allowed in the European Union: (1) nutrition claims based on scientific as- sessment of a benefit, (2) function claims about the maintenance or improve- ment of a function, and (3) disease risk reduction claims about the reduction of a risk factor for a human disease and claims concerning children. With respect to disease risk reduction claims, disease risk reduction must be dem- onstrated using a commonly accepted risk factor and changes in relevant biomarkers that relate to the risk of the particular disease. These categories of claims were not decided by EFSA, but rather by “word of law.” Examples of function claims are claims about bowel function and constipation, gastrointestinal discomfort, and defense against pathogens. In order to make a function claim about bowel function and constipation, for example, one would define an average healthy consumer and then show that the probiotic or prebiotic in question can reduce or somehow improve bowel function. Salminen commented on the availability of validated ques- tionnaires for use in assessing GI discomfort and the ways to gather these data in a scientifically acceptable manner. Making a function claim about pathogen defense requires demonstrating a reduction in numbers of specific pathogens (i.e., “real” pathogens associated with the particular risk, not opportunistic pathogens). An example of a disease risk reduction claim is a claim about LDL (low-density lipoprotein) cholesterol as a recognized risk factor for heart disease. As required by the regulation, the risk factors must be physiologically relevant. Salminen emphasized that there is no exhaustive list of recognized risk factors, reiterating that EFSA conducts assessments on a case-by-case basis. Characterizing and Evaluating Probiotic and Prebiotic Products in the European Union There is no legal EU definition of either “probiotic” or “prebiotic.” According to the Food and Agriculture Organization-World Health Organi- zation (FAO-WHO, 2002) definition, probiotics are defined as “live micro- organisms which when administered in adequate amounts confer a health benefit on the host.” A prebiotic was defined by FAO as “a non-viable food component that confers a health benefit on the host associated with modu- lation of the microbiota” (Pineiro et al., 2008). On the basis of these defini- tions and other parameters laid out by FAO and WHO, ­ alminen explained S

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SOCIETAL AND POLICY IMPLICATIONS 131 that in order for something to be considered a probiotic (or prebiotic), its health effects and safety must be demonstrated, with an emphasis on data from human studies, and strains must be clearly identified and deposited in public culture collections. Because of the uniqueness of each probiotic (and prebiotic) strain, the health effects for each individual strain or strain combination should be documented separately, according to Salminen. Yet a number of bacteria currently being marketed in the European Union as probiotics have no demonstrated health-promoting properties, and different strain combinations are advertised without any proven as- sociation with health benefits. One of the goals of the 2006 health claim regulation was to improve consumer protection by more clearly identifying actual probiotic and prebiotic products and their benefits to the consumer. As part of its task, EFSA was required to assess existing health claims in each individual EU member state. These assessments required identify- ing and characterizing the probiotics in use; evaluating relevant studies, with an emphasis on controlled human intervention studies; and assessing whether the proposed health relationship is something that consumers can understand. Characterization alone has been a challenge. The purpose of charac- terization is to assure EFSA that the substance for which a claim is made is the same as that for which the evidence on efficacy is provided. Until a substance is characterized, EFSA cannot conduct a health claim assessment. Deposit to an international culture collection is key. The strain does not have to be publicly available, Salminen noted, but it should be available to regulatory officials. In its assessment of existing health claims, EFSA has identified more than 100 probiotic products that could not be characterized because of a lack of data on the strain used. The most important component of a health claim assessment is human intervention studies (van Loveren et al., 2012). For disease risk reduction claims, the manufacturer needs to show that the product causes change in a generally accepted risk factor in a normal, healthy population, Salminen noted. It is also important for human intervention studies to be supported by animal model or other mechanistic studies. Salminen acknowledged the challenge of demonstrating a change in a normal, healthy population. To illustrate the difficulty, he mentioned a study on a milk-based drink containing a combination of L. rhamnosus CG, L. rhamnosus Lc705, Propionibacterium freudenreichii ssp. shermannii ­ JS, and a Bifidobacterium strain. The goal was to see if a daily dose of 4 × 109 CFU, with equal amounts of each bacterial strain, would reduce GI discomfort in a normal, healthy population of individuals. According to Salminen, although two “quite nice” clinical studies were conducted (both randomized, placebo-controlled, double-blind intervention studies), they were conducted using two different strains of Bifidobacterium (EFSA,

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136 THE HUMAN MICROBIOME, DIET, AND HEALTH difficult for FDA to be clearer on how to demonstrate strain specificity. As an illustration, he described the difficulty microbiologists have in clearly differentiating pathogenic versus nonpathogenic strains of the same species, such as Escherichia coli. Just as there is no scientific consensus on how to distinguish among strains, there is no scientific consensus on how best to evaluate the safety of a microbial culture. This is unlike nonmicrobial ingredients, for which the guidance provides references to standard toxicology assays. “There are protocols out there that tell one exactly how to do each of those studies,” Levy said. Not so for live microbes. As with identity, the guidance provides only general advice about what information should be submitted to dem- onstrate safety, since this is a rapidly changing area of science. Research on the microbiome is such a rapidly advancing field that it is premature for FDA to develop specific recommendations at this time, Levy remarked. He referred to the same Agency for Healthcare Research and Quality (AHRQ) study on probiotic safety that Mary Ellen Sanders had mentioned previously (Hempel et al., 2011). The authors of that study concluded that while there is no evidence that probiotics are unsafe, they did not have a great deal of confidence in their conclusion. The review found that most trials reported in the scientific literature are either poorly designed or poorly reported, making it difficult to evaluate safety. Many do not mention which strain was used or how the strain was prepared. Others do not explain how adverse events were monitored. The review also found that there has been no real effort to examine long-term safety risks (either safety of long-term exposure or long-term effects that show up after the conclusion of a trial). “Nobody is studying long-term safety in a systematic way,” Levy said. Because the guidance document cannot be specific about areas in which science is rapidly developing, Levy encouraged companies to engage in dialogue with FDA before submitting NDI notifications. “We are using these organisms in new way,” he said. “[The] organisms … sound familiar because they have been present in fermented foods for a long time, but we are selecting them to have properties that were not really selected for pre- viously. That is an intended use that is new and requires a dramatic new efficacy and safety evaluation paradigm.” Questions Levy’s presentation prompted several questions on evaluating probiotic safety. A workshop audience member asked if FDA’s “typical approach” of using an existing benchmark and examining marginal changes from that benchmark could be applicable in the case of live organisms. For example, if an organism already exists in a yogurt product, would it be acceptable

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SOCIETAL AND POLICY IMPLICATIONS 137 to FDA to examine the differences between the organism as it appears in that yogurt product and the organism as it appears in a supplement? Levy responded that the answer lies in intended use or effect. If the intended ef- fect of the organism in the original product was the same, then yes, that is a valid approach. There was a question about a hypothetical probiotic product designed to be administered to cesarean section (C-section) babies in an effort to establish a microbiota that is similar to that developed by a vaginally delivered baby. Would such a product be considered by FDA to be a food or a drug? Levy replied that it is unclear what that type of product would be considered. He would encourage discussion with “representatives from both sides of the agency.” Another participant asked under what circumstances a probiotic is considered a new dietary ingredient as opposed to a food additive. Levy described that type of categorization as “a gray area” because it often depends on how the food is intended to be marketed. He also pointed out that each category has its own safety evaluation paradigm. “However it is represented,” he said, “you have to meet the requirements of that particular paradigm.” Finally, when asked whether any probiotics or prebiotics are being self-determined as generally recognized as safe (GRAS) food ingredients, Levy replied, “It would not surprise me if a lot of people are doing GRAS self-­ eterminations.” However, because GRAS self-determination does not d require FDA notification, FDA does not have a complete list of such de- terminations although there are procedures that allow voluntary notifica- tion of FDA. GRAS determinations, however, are limited to ingredients in conventional foods, not dietary supplements. Mary Ellen Sanders added that she knew of about six GRAS notices for probiotics posted on the FDA website. HEALTH CLAIMS AND FALSE ADVERTISING12 The U.S. regulatory landscape for foods is governed not just by FDA, but also by the Federal Trade Commission (FTC). Michelle Rusk explained how the two agencies share authority on marketing claims not just for foods, but also for supplements, drugs, and other health and medical products. Specifically, through a long-standing liaison agreement, FDA has primary authority for claims appearing on labeling or product packaging, while FTC has primary authority for claims appearing in advertising (with the exception of prescription drugs, over which FDA has authority on both labeling or packaging and advertising). By “advertising,” Rusk was refer- 12  This section summarizes the presentation of Michelle Rusk.

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138 THE HUMAN MICROBIOME, DIET, AND HEALTH ring to broad-sense marketing, not just television and print advertising but anything intended to promote a product. Despite their coordination and shared authority, the legal frameworks of FDA and FTC differ in significant ways. FTC is primarily a law enforce- ment agency. It does not engage in pre-market approval of claims, nor does it make regulatory distinctions between product categories (e.g., drugs versus supplements versus foods) or between types of claims (e.g., disease risk claim versus structure-function claim versus drug claim), although those distinc- tions probably impact which claims FTC chooses to investigate or challenge. FTC authority stems from two provisions of the FTC Act13: sections 5 and 12. Section 5 prohibits deceptive and unfair acts or practices in commerce, including deceptive advertising. Section 12 prohibits misleading advertising of foods and other products. Together, these two provisions are the basis for the FTC standard that advertising must be truthful and not misleading and that objective claims must be substantiated before they are made. FTC Advertising Investigations When FTC investigates a claim, it asks two basic questions. First, what claim is being conveyed? FTC examines the net impression of an ad and what the consumer takes away, not the intention; it also examines omissions of important information. Rusk remarked that many claims are problematic because they tell only “half the truth.” Information that needs to be disclosed must be clear and prominent and not buried in a “fine print footnote.” Second, are the claims substantiated? FTC typically requires claims about the efficacy or safety of dietary supplements to be supported with “competent and reliable scientific evidence,” defined as “tests, analyses, research, studies or other evidence based on the expertise of professionals in the relevant area, conducted and evaluated in an objec- tive manner by persons qualified to do so, using procedures generally ac- cepted in the profession to yield accurate and reliable results” (FTC, 2001). Rusk explained that while FTC applies a rigorous scientific standard, it is also flexible in its approach. There is no specific number or size of study required, rather the focus is on the quality of the evidence. FTC seeks guid- ance from experts and generally expects double-blind, placebo-controlled human clinical trials. Rusk noted that the substantiation standard in the FDA draft guidance for dietary supplement claims closely mirrors the FTC substantiation standard (FDA, 2011a). FTC claims investigations usually involve three steps. First, FTC ex- amines the internal validity of the studies, often with the help of a con- 13  For more information on the FTC Act, visit the FTC website: http://www.ftc.gov/ogc/ stat1.shtm.

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SOCIETAL AND POLICY IMPLICATIONS 139 sultant. It considers control and blinding; duration (i.e., Does the effect persist?); dose-response relationship (i.e., Is there one?); recognized bio- logical mechanisms (i.e., Is there a biological mechanism that is recognized and understood?); peer review or publication in a reputable journal (not a requirement, but it is a “plus”); and statistical significance and clinical meaning. Second, FTC examines the context of the studies that the com- pany is relying on for substantiation. That is, how do the studies fit into the surrounding literature? If there are any inconsistencies, how are those inconsistencies reconciled? Some claims may need to be qualified in such a way that consumers understand the claim is based on emerging science. Claims should not be made if the weight of the evidence contradicts the claim. Rusk noted that this last point may appear self-evident, but FTC does sometimes encounter situations where a marketer makes a claim based on a single preliminary study. Third, FTC examines the relevance of the science to the claim being made. This is where many companies “slip up,” Rusk noted. For example, many weight-loss product claims fail by claim- ing a much greater weekly weight loss than studies actually show. FTC considers both the amount and the form of an ingredient (e.g., effective dose, strain specificity), the population studied, the degree and nature of the effect, and the strength of the science. Examples of Recent Actions Rusk highlighted two recent actions taken by FTC, both consent agree- ments (i.e., the companies did not admit to any law violations). The first was against advertisements for two Dannon yogurt products, DanActive and Activia. FTC challenged claims that DanActive, with its L. casei immunitatas probiotic, helps to prevent colds and flu. It also challenged the claims made during the Jamie Lee Curtis campaign that Activia yogurt, with its Bifidus regularis probiotic, relieves irregularity. One of the issues with the Activia campaign was that 8 of 10 studies showed no significant effect at the adver- tised dose. Rusk noted that FTC was one of many entities investigating the Activia ads and that Dannon settled with both FTC and 39 state attorneys general for a total of $21 million. Increasingly, FTC orders are not purely “cease and desist” orders but also seek monetary relief for the disgorgement of profits from deceptive claims. Where possible, the money is refunded to customers. Otherwise it goes to the U.S. Treasury. The second action was in response to the Nestlé product Kid Essentials Boost, where the probiotic was embedded in the lining of the straw that comes with the drink. The commission challenged claims that the product prevents upper respiratory infections, helps protect against cold and flu, reduces absences from school, and reduces duration of acute diarrhea in children up to age 13. Nestlé submitted some good evidence to support

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140 THE HUMAN MICROBIOME, DIET, AND HEALTH its claims, Rusk said, but FTC concluded that the claims went beyond the evidence. Rusk mentioned recent concern that FTC is raising its substantiation standard. She assured the workshop audience that this is not the case. Rather, the commission is trying to be more specific when it enters into an order with a company it has investigated. In some cases, FTC requires that future claims about specific products go through the FDA approval process. In other cases, it says that claims should be supported by two additional studies conducted by independent researchers. However, these requirements do not reflect a changing standard. Rather, the intention is to be concrete and transparent so that a company under order knows exactly what to expect in terms of compliance. REGULATORY FRAMEWORKS: THE INDUSTRY EXPERIENCE14 Looking through the lens of DuPont, Stuart Craig explored how the changing regulatory landscape is affecting the food industry. DuPont has been a key player in the lactic acid bacteria industry for more than 100 years and works with regulatory agencies worldwide on new legislation and emerging guidelines and requirements related to probiotic safety and efficacy. Indeed, collaborating with regulators to find better ways to ensure food safety and security is a key component of DuPont’s focus on food. As an example of the “paradigm we are in,” Craig mentioned the Cheerios labeling controversy. Even though data showed cholesterol reduc- tion, the claim “cholesterol reduction” is a health claim that falls outside the purview of food. In addition to FDA warning letters stating that studies with disease end points support drug claims, not nutrition claims, FDA has made other recent moves that represent significant change for the food in- dustry. Recent FDA actions include the agency’s new strategic plan for regu- latory science (FDA, 2011a), the Food Safety Modernization Act of 2011,15 and draft guidance on NDI notifications (FDA, 2011b). FDA’s new strategic plan for regulatory science reflects the agency’s overall changing priori- ties: an emphasis on toxicology, personalized medicine, manufacturing and quality, emerging technologies, information sciences, prevention-focused food safety, medical countermeasures, and social and behavioral science. The FSMA legislation is focused on improving the capacity to prevent food safety problems and to detect and respond to food safety problems and on improving the safety of imported food. For a large company such as 14  This section summarizes the presentation of Stuart Craig. 15  FDA Food Safety Modernization Act of 2011, Public Law 111-353, 111th Cong. (Jan. 4, 2011).

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SOCIETAL AND POLICY IMPLICATIONS 141 D ­ uPont, these new challenge are “really not an issue,” Craig said, “but for the industry in general, this is going to be quite a change.” With respect to the draft guidance on NDI notifications, Craig expects there to be consid- erable dialogue between the food industry and FDA in the coming years. The global trend in health claims around food is toward higher safety and efficacy standards. As Craig put it, there is a “higher bar.” At the same time, there is also uncertainty around how to scientifically substan- tiate claims. Craig emphasized the significance of having clear rules and guidance. Gray areas of regulation that are open to interpretation are challenging for everyone involved. Typical questions of regulatory affairs staff include the following: What claims can I make based on this study? Can you make a list of suggested claims we can send to customers? Is this one study enough? If not, why not? If I do another study, will that be enough? Can I study the reduction of XXX and claim the maintenance of YYY or ZZZ? Is this GRAS? Should we notify? Do I need to file an NDI notification? The EFSA health claim evaluations have drawn on many of DuPont’s resources over the past couple of years. Craig noted the high level of EFSA rejections industry-wide, a lack of dialogue, and misunderstanding about what is required of health claims for food products. The challenge has been especially difficult for probiotic and prebiotic claims. While some products have seen success, the overall effect on industry investment has been “chill- ing.” Moreover, the effect is spilling over into other countries. The “higher bar” for safety and efficacy is difficult for the food in- dustry for two main reasons. First is return on investment. Human clini- cal studies are expensive, sometimes costing more than $1 million. The food industry model does not compare to the pharmaceutical industry model; with shorter time lines and lower profit margins, protection of research investment in the food industry is lacking. Second, it is more difficult to demonstrate health maintenance than disease intervention. Using the “cholesterol reduction” claim as an example, Craig wondered how a study on cholesterol maintenance would even be designed. Normal subjects should not have elevated cholesterol; they should have normal cholesterol levels, he observed. How does one design a study aimed at evaluating whether a product helps to maintain those normal levels over time? Health maintenance studies need to be longer and involve larger numbers. Inside DuPont Regulatory and Scientific Affairs When conducting its own internal scientific substantiation of claims, DuPont tries to use existing tools, such as the Health Canada Claims Sub- stantiation Template, which includes a list of eight items that are scored; the

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142 THE HUMAN MICROBIOME, DIET, AND HEALTH final score is used to characterize the quality of the study (the eight items are inclusion or exclusion criteria, group allocation, blinding, attrition, exposure or intervention, health effect, statistical analysis, and potential confounders). DuPont also has its own internal tools for rating evidence, including one developed by Craig that rates each study as A (excellent), B (good), C (weak), or F (does not support) and then rates the overall body of evidence based on the cumulative study ratings. For example, a high-quality study that reported a significant effect but only in the elderly and at a high dose might be rated B because it provides only limited support for a claim that a lower dose is effective in the general adult population. Craig noted that opinions sometimes differ on whether a study should be rated an A, B, or C or even on the overall assessment of the evidence, but at least the tool provides a framework for having a discussion. Craig remarked that while DuPont is conscientious about scientific substantiation of claims and will provide its clients with analyses of their claims, final responsibility for scientific substantiation lies with the food manufacturer. Because there is no global system for scientific substantiation, with every region operating according to its own rules, what is needed in one country may differ from what is needed in another country. Navigating these complex regulatory differences across the globe is challenging, espe- cially as the global regulatory environment moves toward a higher scientific standard for safety and efficacy, but “we have to rise to that challenge,” Craig said. He encouraged more discussion among government, industry, and academia. THE REGULATORY ENVIRONMENT: A SYNTHESIS16 Some of the regulatory challenges addressed by previous workshop speakers stem from the fact that “we are struggling to fit” an emerging science into “an outdated paradigm” for conceptualizing the relationship between food and health, Sarah Roller said. The paradigm recognizes that by virtue of essential nutrients it contributes to the body, food is capable of supporting nutritional needs, promoting normal growth and development, and otherwise affecting the structures and functions of the body. However, the paradigm fails to adequately account for contributions food makes to health through components that are not currently classified as essential nu- trients, such as probiotics. The outdated scientific paradigm was codified in the “drug” definition that is part of the FD&C Act adopted in 1938. The drug definition in the FD&C Act continues to play a key role in the regula- tory and enforcement policies of FDA and functions to limit the opportuni- 16  This section summarizes the presentation of Sarah Roller.

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SOCIETAL AND POLICY IMPLICATIONS 143 ties to convey the health benefits of food products, particularly when the benefits are attributable to components that are not currently recognized to be essential nutrients and/or when the component plays a role in prevent- ing, mitigating, or treating disease. Under the FD&C Act legal framework, marketing claims that represent a product to have disease prevention, mitigation, or treatment-related benefits are prohibited unless the product is an FDA-approved drug and is marketed in compliance with the terms of the FDA approval. Roller pointed out, however, that the regulatory framework FDA has developed for conventional pharmaceutical products is not designed to accommodate foods that can play a useful role in disease prevention, mitigation, or treatment. The obstacles associated with the outdated paradigm are not limited to the FD&C Act framework. The old paradigm has been influential in shaping the legal standards that govern the regulation of food marketing claims under the FTC Act, the federal Lanham Act, other federal statutes administered by the U.S. Department of Agriculture’s Food Safety and Inspection Service, and food and drug laws and consumer protection statutes that have been adopted by the 50 states. Roller called attention to the fact that many state laws allow consumers to sue companies for money damages and injunctive relief when consumers have been misled by the marketing claims companies use to promote their products. In the current legal environment, Roller noted that health benefit claims for food and dietary supplement products are commonly targeted in consumer class action lawsuits filed under state laws. Roller explained that consumer class action lawsuits of this kind are commonly filed in the wake of FDA warning letters and FTC consent orders challenging food marketing claims based on the outdated paradigm. As a result, inadequate federal policies can have a cascading effect under state law, which has costly liability implications for and may deter companies from communicating ac- curate scientific information about the health benefits of food and dietary supplements, including prebiotics and probiotics. Roller observed that these trends also have the potential to deter industry investment in products that she believes could hold “huge promise for public health.” Roller suggested that it will be necessary to confront the limitations of the FD&C Act “drug” definition as it is applied to food and dietary supplement products to provide sufficient flexibility to allow accurate, substantiated information to be conveyed about the health benefits of these products in commercial contexts, consistent with First Amendment requirements and sound science. Back in 1938, Roller said, the old para- digm probably made sense from a scientific standpoint. At that time, there was little scientific evidence to establish that disease prevention, mitiga- tion, and treatment claims could rightly characterize the benefits of food products. Since that time, science has marched on, and the old “drug” definition and the scientific paradigm upon which it is based no longer

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144 THE HUMAN MICROBIOME, DIET, AND HEALTH support an adequate regulatory framework for food and dietary supple- ments, according to Roller. Under FDA regulations implementing the food provisions of the FD&C Act, FDA has recognized that there are different categories of “food”: conventional foods and beverages, chewing gum, food ingredients and components, dietary supplements, food for special dietary use (FSDU), and medical food. Roller referred to Levy’s discussion of the challenges that the dietary supplement category creates for probiotic-containing food. She emphasized that further development of FDA policies concerning foods for special dietary use and medical foods is needed and could represent an important but yet “untapped opportunity” for probiotics, in her opinion. FSDU is an old category that was used more often in the past, before the Nutritional Labeling and Education Act of 1990. This category includes foods used for disease-related purposes, specifically for “supplying dietary needs which exist by reason of a physical, physiological, pathological or other condition, including … the conditions of diseases, convalescence, pregnancy, lactation, allergic hypersensitivity to food, underweight, and overweight.” Roller suggested that probiotics used to equilibrate the mi- crobiome after antibiotic therapy might be considered FSDU. Medical foods are foods that are to be consumed under a physician’s supervision. Lofenalac, an infant formula made for infants with phenylketonuria (PKU), is a classic example of a medical food. In Roller’s opinion, between these two food categories, FDA has a “huge amount of discretion.” Changing the Legal Framework To strengthen the legal framework in the ways that are necessary, Roller urged that the outdated and dualistic “food versus drug” con- ceptual framework be reconsidered, in view of the distinctions between the cause-and-effect relationships that explain the mechanisms by which pharmaceuticals commonly deliver benefits and those that characterize the mechanisms by which food and dietary patterns deliver benefits. She urged that environmental health and ecological models of causation be given care- ful consideration in the development of regulatory policies governing food marketing claims for food and dietary supplement products. In the specific context of claims characterizing the benefits of prebiotic and probiotic components of food and dietary supplement products, Roller outlined several types of claims that she believes would hold promise for product marketing purposes. These include (1) content claims that com- municate information about how much of a given prebiotic or probiotic is present in a food, (2) dietary contribution claims that communicate in- formation about the contribution that is made to overall dietary intake of certain prebiotics or probiotics from consumption of particular products

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SOCIETAL AND POLICY IMPLICATIONS 145 under specified conditions (frequency and quantity), and (3) “ecological” balance and support claims that communicate information about how con- sumption of a given prebiotic or probiotic affects the microbiome. Ultimately, Roller expressed hope that the health benefits that are being linked to prebiotics and probiotics with respect to supporting and maintain- ing a healthy microbiome will help inspire the kinds of policy reforms that are needed to allow food and dietary supplement manufacturers to convey accurate and substantiated information about the benefits of prebiotics and probiotics and the products that contain them, consistent with sound sci- ence and First Amendment standards. In Roller’s opinion, the current legal framework—the existing “food versus drug” construct that is codified in the FD&C Act—is based on outdated science and is too rigid to allow FDA to account for current science or future advances in science. According to Roller, the current legal framework draws an artificial line between the permissible food benefits of “disease risk reduction” or “health promotion” and the benefits of “disease prevention, mitigation, and treatment,” which are categorically reserved for FDA-approved “drugs,” even when the dis- tinction may not align with scientific facts. In Roller’s opinion, the current situation with probiotics is probably a key moment of opportunity that can allow this long-standing problem to be addressed. Failing to do so could have huge opportunity costs for public health, she added. Roller speculated on whether it might be possible to adopt an ecologi- cal approach to regulating health claims for food products intended to have a beneficial impact on the microbiome, in the same way that environmental law has adopted an ecological approach. For example, fisheries law is based not on individual fish or fish populations, but rather on the environmental conditions required for fish to thrive. She asked, “Does it work for us to think about the microbiome that way?” REFERENCES Amar, J., C. Chabo, A. Waget, P. Klopp, C. Vachoux, L. G. Bermudez-Humaran, N. Smirnova, M. Berge, T. Sulpice, S. Lahtinen, A. Ouwehand, P. Langella, N. Rautonen, P. J. Sansonetti, and R. Burcelin. 2011. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: Molecular mechanisms and probiotic treatment. EMBO Molecular Medicine 3(9):559-572. Bagramian, R. A., F. Garcia-Godoy, and A. R. Volpe. 2009. The global increase in dental c ­ aries. A pending public health crisis. American Journal of Dentistry 22(1):3-8. Deshpande, A., and A. R. Jadad. 2008. The impact of polyol-containing chewing gums on den- tal caries: A systematic review of original randomized controlled trials and observational studies. Journal of the American Dental Association 139(12):1602-1614. EFSA (European Food Safety Authority). 2008. LGG MAX and gastro-intestinal discomfort— scientific substantiation of a health claim related to LGG MAX and reduction of gastro- intestinal discomfort pursuant to Article 13(5) of Regulation (EC) No. 1924/2006[1]. European Food Safety Authority Journal 853:1-15. http://www.efsa.europa.eu/de/scdocs/ doc/853.pdf.

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