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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?”
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