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The Human Microbiome, Diet, and Health: Workshop Summary (2013)

Chapter: 6 Societal and Policy Implications

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Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 (including 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 percent 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 demographics; 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.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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 something 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 calories (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 percent). 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 growing 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 changing demographics and greater concern about sodium among older adults. Again, as with calories, even though people are expressing more interest

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 sodium 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, cholesterol, 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-

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 experience 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 functional food market, according to Peggy Steele. In 2001, probiotics accounted 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,

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2 This section summarizes the presentation of Peggy Steele.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 consolidation 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 include 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 applications). 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] acidophilus 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 digestive and immune function,” and “helps naturally regulate your digestive system.” Structure-function claims require more documentation than content 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-

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 substantiated 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 Nutrition 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 communities 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 Bifidobacterium 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 randomized across three treatments (the two probiotic treatments and one placebo

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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.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 antibiotic 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 digestive health, including its use of a celebrity (Jamie Lee Curtis) to promote 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 probiotic 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 (Ibrahim et al., 2010; Makelainen et al., 2009).

Finally, DuPont scientists are investigating new health end points. For example, Amar and colleagues (2011) reported that B. lactis 420 can reverse 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.

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5 The HOWARU product line was launched by Danisco.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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 population 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 previous speakers and workshop participants on the issue of causality (i.e., that most of the evidence on diet-microbiome-health relationships is associational, 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 scientific requirements for claims on gut health and immunity (EFSA, 2011b). The document summarizes experience from earlier assessments, gives guidance on factors associated with gut health and immunity, summarizes beneficial 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-

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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).

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 assessment of a benefit, (2) function claims about the maintenance or improvement 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 demonstrated 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 questionnaires 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 Organization (FAO-WHO, 2002) definition, probiotics are defined as “live microorganisms 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 modulation of the microbiota” (Pineiro et al., 2008). On the basis of these definitions and other parameters laid out by FAO and WHO, Salminen explained

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

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 association 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 identifying 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 characterization 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,

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

2008). One mixture had B. animalis ssp. lactis Bb12 (DSM 15954), the other B. breve 99 (DSM 13692). Because the two studies used the same product but in two different probiotic combinations, the combined evidence was insufficient to establish a causal relationship between the product and a reduction in abdominal discomfort. Salminen noted that it is not clear whether the difference between each strain would have an impact on effect, but noted the fact that there are biological differences among different strain combinations.

The health effect of xylitol, a prebiotic, on caries risk is an example of a well-supported health claim. Dental caries is very common among Europeans, and a review article estimated the prevalence of caries to be up to 100 percent, depending on the country (Bagramian et al., 2009). A well-recognized risk factor for dental caries is thickness of dental plaque at specific sites in the mouth. Several intervention studies have demonstrated a reduction in dental caries risk as a result of chewing xylitol-sweetened gum, as reviewed in Deshpande and Jadad (2008).

In conclusion, Salminen remarked that most researchers do not usually think about health claims when designing their studies, but in many cases, redirecting studies to address health claims requires making only small changes to the study design.

EVALUATION OF VIABLE MICROBES USING REGULATORY REQUIREMENTS DEVELOPED FOR NONVIABLE INGREDIENTS8

FDA is, as Dan Levy expressed, “a creature of the statutes.” FDA must operate within parameters laid out in the law, which, in the case of foods, is primarily the Federal Food, Drug, and Cosmetic Act (FD&C Act) initially passed in 19389 and amended many times thereafter. Of particular relevance to probiotic-containing food products is the 1994 Dietary Supplement Health and Education Act (DSHEA).10 The DSHEA defined a dietary supplement as “a product (other than tobacco) intended to supplement the diet that bears or contains one or more … dietary ingredients.” The statute includes a list of substances that can be dietary ingredients. Substances not on the list cannot be dietary ingredients. The list consists of vitamins, minerals, amino acids; herbs or other botanicals; dietary substances for use by man to supplement the diet by increasing total dietary intake; and concentrates, metabolites, constituents, extracts, or combinations of any of the

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8 This section summarizes the presentation of Dan Levy.

9 For more detailed information on the FD&C Act, visit the FDA website: http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/default.htm.

10 Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 103rd Cong. (Oct. 25, 1994).

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
×

above ingredients. The only appropriate category for probiotics is “dietary substance for use by man to supplement the diet by increasing the total dietary intake.” The draft guidance suggests that this definition is limited to substances previously in the diet, suggesting that an entirely new bacterium must enter the food supply as a food other than a dietary supplement.

Pre-Market Notification for New Dietary Ingredients: Implications for Probiotics

The FD&C Act requires pre-market notification to FDA describing the safety of a dietary supplement containing “new dietary ingredients.” New dietary ingredients are defined as dietary ingredients not marketed in the United States prior to October 15, 1994. However, there is an exemption from the notification requirement for a dietary supplement containing only dietary ingredients that have been present in the food supply “as an article used for food in a form in which the food has not been chemically altered.” When it passed the DSHEA, Congress included a “legislative agreement” describing what “chemically altered” does not mean. It does not include minor loss of volatile components, dehydration, lyophilization, milling, tincture or solution in water, slurry, powder, or solid in suspension. Yet even with this list, there are uncertainties. For example, what does “tincture or solution in water” mean? Levy commented that everyone would probably agree that making an extract by soaking leaves in hot water would not be “chemically altered.” More complicated extractions, such as the use of organic solvents and chromatography, make more significant changes in the chemical composition of the extract, changes that may be described as chemically altered.

The issue of whether or not something is chemically altered is especially challenging for live microbial organisms used in food production because chemical characterization is usually not used to describe the difference between microorganisms. For example, when a strain of a Lactobacillus species that has been used to ferment cheese is selected to produce a variant having properties that optimize its use in an industrial fermentation for the production of a dietary supplement, is the selected strain chemically altered relative to the strain that was in the original dairy product?

The FDA Food Safety Modernization Act (FSMA) of 201111 required FDA to publish guidance on new dietary ingredients to help industry and other stakeholders understand when new dietary ingredients (NDIs) require pre-market notifications and what those notifications should include (see Box 6-1). FDA published a draft guidance in July 2011, with a comment

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11 FDA Food Safety Modernization Act of 2011, Public Law 111-353, 111th Cong. (Jan. 4, 2011).

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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BOX 6-1
FDA Draft Guidance on New Dietary
Ingredients: Implications for Probiotics

FDA published draft guidance in July 2011 to help industry and other stakeholders understand when new dietary ingredients require pre-market notification and what those notifications should include. With respect to live microbial ingredients, here is what the guidance recommends for identity and safety. The italicized text is text that Levy highlighted during his presentation.

On identity, the guidance reads: “FDA considers each strain of a bacterial or yeast species to be a separate ingredient. You should explain how your strain was obtained and how it varies from other members of the same species. If your strain was genetically modified using either random mutagenesis or bioengineering, you should describe the process used and how you characterized the properties of the new strain…. You should include a complete description of the organism, including: the strain, methods used to establish the identity of the strain, such as identification by internationally recognized third-party repositories (e.g., the American Type Culture Collection), and the relationship of the strain to the strain(s) of the same species used to establish the history of use or other evidence of safety for the dietary ingredient…. For organisms that come from species or genera with pathogenic strains: Is there a consensus that there are valid scientific ways to distinguish between pathogenic and non-pathogenic members or to prevent horizontal transfer of genes for pathogenic traits?”

On safety, the guidance reads: “You should identify any human pathogens that are phylogenetically related to the microbial NDI at the species or genus level.

deadline of December 2011 (FDA, 2011b). At the time of the Institute of Medicine (IOM) workshop, FDA was still reviewing the more than 100,000 pages of comments received. The need for the guidance was illustrated by FDA’s objections to many NDI notifications, many of which were based on uncertainty about the identity of the ingredient and comparison of that ingredient to the ingredient(s) used in the safety comparison. Levy noted that the challenge is very similar to what EFSA is dealing with in terms of characterization of strains in probiotic products (see the summary of Seppo Salminen’s presentation). Many of the FDA objection letters say something like, “Without such information, it is unclear how the product you intend to market is qualitatively and quantitatively similar to the substances described in the information that you rely on as evidence of safety or how that information forms the basis for a reasonable expectation of safety under the intended conditions of use.” Levy reminded the workshop audience that guidance “does not bind anybody to do anything.” Rather, “it is just our best thinking” at the time it is published.

FDA is addressing the challenge of whether or not a live microbial

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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You should identify any toxins, classes of toxins, or other deleterious substances known to be present in the same species or in a phylogenetically related family or genus. You should also document the absence (or the amount, if present) of such toxins or other deleterious substances in the NDI. You should document resistance to any clinically relevant antibiotics, and if applicable, the genetic nature of the resistance. If the microbial NDI is resistant to any clinically relevant antibiotics, it is also recommended that you perform an assessment of the ability of the antibiotic resistance genes to mobilize and transfer to human pathogens under the conditions of use of the dietary supplement…. If your notification cites the history of use of a live microorganism as evidence of safety, FDA recommends a careful assessment of the relative level of historical exposure compared to the proposed conditions of use of the NDI, including a discussion of how the form of the dietary supplement and any excipients used in it affect delivery of the NDI to various points in the human gastrointestinal tract…. If history of use data are inadequate to support the safety of the microbial NDI, you should include safety studies in humans or appropriate animal models in your notification. FDA considers pigs to be the most appropriate animal model for the human digestive tract. Human or animal safety studies should include measurements of the persistence of the organism in the body after administration, the ability of the organism to translocate outside of the gastrointestinal tract, and tolerance of the ingredient using the proposed serving form. Because this is a rapidly evolving scientific discipline, FDA recommends that notifiers be familiar with the state of the recent scientific literature at the time the notification is submitted.”

SOURCE: FDA, 2011b.

ingredient has been chemically altered by applying the logic used for botanical extracts. For botanical extract composition, the draft guidance recommends supplying information on solvent used, extraction ratios, and special cultivars or harvest conditions. The new guidance document contains specific examples of specification sheets for a botanical extract dietary ingredient. The draft also suggests that detailed information on the analytic methods used to characterize the composition of the new dietary ingredient be included.

The guidance document also includes recommendations for describing a live microbial ingredient. Although FDA does not require the use of scientific names for microbes, the guidance encourages it. Because the guidance suggests that each strain of a bacterial or yeast species be a separate ingredient, the guidance encourages applicants to explain how their strain was obtained and how it varies from other members of the same species. Levy recognized that the guidance on identity for live microbial ingredients is not detailed. He explained that the lack of scientific consensus on strain specificity, including how to differentiate between strains, makes it

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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 demonstrate 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 previously. 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

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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 effect 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-determinations.” However, because GRAS self-determination does not require FDA notification, FDA does not have a complete list of such determinations although there are procedures that allow voluntary notification 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-

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12 This section summarizes the presentation of Michelle Rusk.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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 enforcement 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 distinctions 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 objective manner by persons qualified to do so, using procedures generally accepted 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 guidance 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 examines the internal validity of the studies, often with the help of a con-

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13 For more information on the FTC Act, visit the FTC website: http://www.ftc.gov/ogc/stat1.shtm.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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sultant. It considers control and blinding; duration (i.e., Does the effect persist?); dose-response relationship (i.e., Is there one?); recognized biological 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 company 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 claiming 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 agreements (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 advertised 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

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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 reduction, 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 industry. Recent FDA actions include the agency’s new strategic plan for regulatory 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 priorities: 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

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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).

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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DuPont, 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 considerable 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 substantiate 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 “chilling.” Moreover, the effect is spilling over into other countries.

The “higher bar” for safety and efficacy is difficult for the food industry for two main reasons. First is return on investment. Human clinical 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 Substantiation Template, which includes a list of eight items that are scored; the

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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, especially 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 nutrients, 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 regulatory and enforcement policies of FDA and functions to limit the opportuni-

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16 This section summarizes the presentation of Sarah Roller.

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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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 preventing, 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 accurate 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 paradigm probably made sense from a scientific standpoint. At that time, there was little scientific evidence to establish that disease prevention, mitigation, 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

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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support an adequate regulatory framework for food and dietary supplements, 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 microbiome 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” conceptual 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 careful 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 communicate information about how much of a given prebiotic or probiotic is present in a food, (2) dietary contribution claims that communicate information about the contribution that is made to overall dietary intake of certain prebiotics or probiotics from consumption of particular products

Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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under specified conditions (frequency and quantity), and (3) “ecological” balance and support claims that communicate information about how consumption 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 maintaining 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 science 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 distinction 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 ecological 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?”

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Suggested Citation:"6 Societal and Policy Implications." Institute of Medicine. 2013. The Human Microbiome, Diet, and Health: Workshop Summary. Washington, DC: The National Academies Press. doi: 10.17226/13522.
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The Food Forum convened a public workshop on February 22-23, 2012, to explore current and emerging knowledge of the human microbiome, its role in human health, its interaction with the diet, and the translation of new research findings into tools and products that improve the nutritional quality of the food supply. The Human Microbiome, Diet, and Health: Workshop Summary summarizes the presentations and discussions that took place during the workshop. Over the two day workshop, several themes covered included:

  1. The microbiome is integral to human physiology, health, and disease.
  2. The microbiome is arguably the most intimate connection that humans have with their external environment, mostly through diet.
  3. Given the emerging nature of research on the microbiome, some important methodology issues might still have to be resolved with respect to undersampling and a lack of causal and mechanistic studies.
  4. Dietary interventions intended to have an impact on host biology via their impact on the microbiome are being developed, and the market for these products is seeing tremendous success. However, the current regulatory framework poses challenges to industry interest and investment.
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