Health Claims Substantiation for Probiotic and Prebiotic Products

Health claims substantiation for probiotic and prebiotic products

Mary Ellen Sanders,1,* James T. Heimbach,2 Bruno Pot,3 Daniel Tancredi,4 Irene Lenoir-Wijnkoop,5 Anu Lähteenmäki-Uutela,6 Miguel Gueimonde7 and Silvia Bañares8 1Dairy and Food Culture Technologies; Centennial, CO USA; 2JHeimbach LLC; Port Royal, VA USA; 3Institut Pasteur-Lille; France; 4University of California; Davis, CA USA; 5Danone Research; Palaiseau, France; 6University of Turku; Turku, Finland; 7Instituto de Productos Lácteos de Asturias; 8University Abat Oliva; Barcelona, Spain

he topic of “Health Claims Introduction TSubstantiation for Probiotic and Prebiotic Products” was discussed at In August, 2010, a discussion group on the the 8th annual International Scientific topic of “Health Claims Substantiation Association for Probiotics and for Probiotic and Prebiotic Products” was Prebiotics (ISAPP) meeting. The topic convened at the 8th annual International is especially timely considering that the Scientific Association for Probiotics and regulatory review process for health Prebiotics (ISAPP) meeting held just out- benefit claims on probiotic and prebi- side of Barcelona, Spain. The scope of otic products in Europe has not resulted this discussion was on regulatory issues ©2011 Landes Bioscience. Landes in a single©2011 claim being approved (120 with regard to substantiation of health Do not distribute. not negative opinionsDo on probiotic claims claims on foods and food supplements and 19 negative opinions on prebiotic (not drugs). The group was composed of claims through February 2011). This academic and industry scientists, as well situation in Europe and elsewhere has as lawyers specializing in food labeling driven companies to seek clarity on a (Table 1). Although the discussion outline research path that would stand up to was comprehensive (Table 2), this report scientific scrutiny as well as satisfy focuses on the most important themes regulatory demands for health claim that emerged during the discussion. All substantiation. It can be challenging to these would be worthy of further consid- negotiate rigid regulatory distinctions, eration and consensus development. such as between health and disease, when these states are more realisti- Regulatory Boxes vs. Continua cally represented by continua. One research approach focused on improved Key differences between the current regu- Key words: probiotic, prebiotic, regu- homeostasis is explored as a statisti- latory situations in Europe, the United latory, health claims, substantiation, cally robust approach to measuring States, Canada, Japan, China and India This manuscript has been published online, prior to printing. Once the issue is complete and page numbers have been assigned, the citation will change accordingly. the issue is complete and page numbers have Once to printing. has been published online, prior This manuscript homeostasis, ISAPP physiological parameters in healthy were discussed. An overriding challenge populations, which are the required is managing the different ways that con- Abbreviations: ISAPP, International target for food and supplement claims. sumers, healthcare professionals, regula- Scientific Association for Probiotics Diverse global regulatory frameworks tors, legislators and scientists see the health and Prebiotics; FDA, Food and Drug complicate this issue, and harmoni- benefit claims on probiotic and prebiotic Administration zation of different approaches glob- products. A lack of unified perspective Submitted: 03/02/11 ally would simplify requirements for exists: while most consumers, healthcare Revised: 04/25/11 industry, decrease consumer confusion professionals and scientists perceive a con- and improve the scientific framework tinuum between the extremes of “health Accepted: 04/27/11 for the research community to set up and disease”, “food and drugs”, “emerging DOI: XXXXXXX appropriate research pathways. This evidence and supported with significant Correspondence to: Mary Ellen Sanders; report highlights key points from this scientific agreement”, generally legisla- Email: [email protected] discussion. tion—and the subsequent enforcement of

www.landesbioscience.com Gut Microbes 1 Table 1. Composition of discussion group convened on the topic of “Health claims substantiation for probiotic and prebiotic products” at the 8th annual ISAPP meeting Name Affiliation Country Mary Ellen Sanders (chair) Dairy & Food Culture Technologies (consultant), Executive Director, ISAPP USA Seppo Salminen (co-chair) University of Turku FINLAND Lara Ambrosetti Ginsana SA/subsidiary of Boehringer Ingelheim GmbH SWITZERLAND Silvia Bañares Professor of Commercial Law, University Abat Oliva, Barcelona SPAIN Linda Duffy NIH, National Center for Complementary and Alternative Medicine USA Frederic Durmont Institut Rosell/Lallemand SWITZERLAND Reg Fletcher Kellogg Europe Trading Ltd IRELAND Miguel Gueimonde IPLA (Spanish Government Research Institute) SPAIN Raj Gupta Biocodex USA James Heimbach JHEIMBACH LLC USA Ulrika Hinkel Boehringer Ingelheim GmbH GERMANY Ivana Jankovic Nestle SWITZERLAND Gunhild Kozianowski Beneo Institute GERMANY Jha Ashok Kumar Sathguru Management Consultants INDIA Anu Lähteenmäki-Uutela University of Turku FINLAND Niklas Larsson Probi SWEDEN Irene Lenoir-Wijnkoop Danone Research FRANCE Greg Leyer Danisco USA USA Sandra Macfarlane Microbiology and Gut Biology Group, University of Dundee SCOTLAND Tami Mackle Pfizer Nutrition USA Lorenzo Morelli Microbiology Institute, Catholic University, Piacenza ITALY ©2011 Landes Bioscience. Landes ©2011 Do not distribute. Raymond O’Rourke not Do Food Lawyer IRELAND Andreu Palou Spanish Food Agency Authority SPAIN Kayla Polzin Cargill USA Bruno Pot Institut Pasteur de Lille FRANCE Department of Medical Microbiology and Immunology, St. Antonius Hospital, Ger Rijkers NETHERLANDS Nieuwegein Institute of Agrochemistry and Food Technology, Spanish National Research Yolanda Sanz SPAIN Council Margriet Schoterman FrieslandCampina Domo NETHERLANDS Assistant Professor of Pediatrics, UC Davis School of Medicine and Center for Dan Tancredi USA Healthcare Policy and Research Henk van Loveren Professor of Immunotoxicology, Maastricht University NETHERLANDS Carey Walker Mead Johnson Nutrition USA Rob Welch University of Ulster Coleraine NORTHERN IRELAND Jia Zhao Yakult Europe NETHERLANDS this legislation—partitions these entities (accompanied, perhaps, by an indication responsiveness to drug therapy. This con- into distinct compartments (Fig. 1). The of the strength of the support). However, version of foods into drugs occurs despite regulatory box paradigm adopted by many in some regulatory frameworks, substances the fact that healthcare providers on a countries imposes substantial hurdles for recognized in general as foods, which are daily basis counsel their patients in how to research, consumer understanding and safely consumed by consumers with sub- incorporate foods into their diet for many marketing of functional foods. A scien- optimal health status, are lumped together of these supposed “treatment” purposes. tific argument can be made that in the with drugs if they are labeled (or in some In many countries, the distinction cases where a product meets the safety cases, even studied) to provide dietary between drugs and foods relies on how standard for a food, it would be sensible management of health conditions, reduce the product is labelled and used. A prod- that labels on foods should be able to com- the risk of developing an acute condition, uct labelled to treat or prevent disease is municate whatever use is substantiated ameliorate symptoms or improve a patient’s considered a drug by many regulatory

2 Gut Microbes Volume 2 Issue 3 Table 2. Outline for discussion on the topic of “Health claims substantiation for probiotic and prebiotic products” at the 8th annual ISAPP meeting Brief update on current situation with claims on probiotic/prebiotic products Standards of evidence required for claims: • How much is enough • What types are enough • Is scientific rigor and magnitude of effects required for foods/supplements the same as for drugs? • What is a “gold standard” of evidence for probiotic foods/supplements? Overview of the challenges of nutrition research: establishing causality between foods and health benefits Perspectives of a biostatistician on: • Negative studies or conflicting results • Statistical significance compared to biological meaningfulness • The lack of the ideal human trial What study populations are appropriate for food claims? • Extrapolation from study populations to general population • Population subgroups: elderly, infants, children, etc., • How might approaches need to adapt with new information from human microbiome project, individualized nutrition issues? Guidelines for the design, conduct and reporting of human studies to evaluate the health benefits of foods Wording of health claims Probiotic/prebiotic research targets often are on endpoints that are not measurable with validated biomarkers and have no recognized risk factors that are intermediate measures of health responses. What are recommendations for research on probiotics/prebiotics for foods? Clinical endpoints and biomarkers in probiotic research • Present proposal to develop a position paper on biomarkers/risk factors with the following goals: o analyze all the markers used to assess health benefits in human studies with pro and prebiotics (we can start with ILSI guidelines and list all markers and benefits mentioned there) ©2011 Landes Bioscience. o estimateLandes the relevance of using biomarkers compared©2011 to clinical outcomes and propose the best solution for each benefit o adistribute. nalyze each of the proposed biomarkersnot (method of assessment,Do levels in healthy individuals, increased risk levels, validation status…) drawing from available literature o propose what needs to be done to validate each biomarker • Present example biomarkers (validated and non-validated) • Is there consensus of value of proceeding with this? If so, than how to do it (ISAPP, ILSI, both or ?) Perspectives on the problem of bioequivalency among different in vitro factors that might impact probiotic functionality in vivo frameworks, whereas foods may be used information was available about the role or borderline condition.5 Even though the to support or maintain normal body func- of food and food ingredients in maintain- medical community does not uniformly tions or reduce the risk of disease in the ing health and affecting the structure and agree, people who may be experiencing generally healthy population. However, function of the body, and fewer borderline suboptimal health, symptoms, syndromes the distinction between disease prevention products existed. However, both the sci- or illness [defined as the subjective response and risk reduction is not clear scientifi- ence and the markets have progressed. If of the patient to being unwell6,7] are all cally. Furthermore, the growing body of regulations were written de novo today, viewed as having a “disease” by many reg- scientific evidence demonstrates that some functional foods and medicines might be ulatory interpretations. Under this inter- foods may be able to prevent or mitigate regulated under a common framework pretation, use of a “food” to help improve certain disease or illness. Rigorous scien- for various types of health-related claims such health conditions would be viewed tific demonstration of this capability may and their substantiation. A complicating as a drug-use and would not be allowed. be rendered meaningless by regulatory con- situation is that despite the regulatory cat- This is true even though in some cases, straints on communicating these findings. egories, the difference between food and products commonly understood as foods Also, even if the regulatory environment drugs is not always clear to the consumer. may provide a safe and effective approach is restrictive of claims, it is important that There appears to be a similarly non- for the management of so-defined disease it be recognized that there is a difference fluid regulatory view of health and dis- situations. For example, a food or dietary between research and claims, and even if ease in many countries.1-4 A noteworthy supplement shown to ameliorate the allowable claims are limited, the research exception exists in Japan, where Foods for nausea that results from chemotherapy on foods shouldn’t be. The current inter- Specialized Health Use (FOSHU) is tar- and thus help cancer patients reduce the pretations of the border between foods geted not only to healthy people, but also inanition and wasting (but not treat the and drugs perhaps made sense when less to people at the first stage of any illness cancer) that often accompany the disease,

www.landesbioscience.com Gut Microbes 3 Figure 1. Regulatory compared to scientific understanding of terms found in food and drug law. In regulations, discrete distinctions are made between health and disease, food and drugs and acceptable and unacceptable levels of evidence to support claims. In scientific practice and clinical practice, these concepts are understood to span a continuum.

should not be treated as a drug. Children the review process is required to provide that requires a reasonable level of evidence of with ear infections (but with healthy guts) “scientific assessment of the highest possi- substantiation of a health benefit may serve prescribed antibiotics should be able to eat ble standard,” health claims are “based on all stakeholders better than a standard of ©2011 Landes Bioscience. a probiotic-Landes or prebiotic-containing food and substantiated©2011 by generally accepted the highest possible evidence. Finally, when 17 demonstrateddistribute. by rigorous research tonot help scientific Do evidence.” However, it seems considering the different standards of evi- keep their guts healthy during therapy. that in practice, the reviewers expect the dence required in different geographical Certain probiotics have been shown to evidence must meet the highest possible regions, it becomes apparent that a har- reduce the infection rate with Clostridium standard. In the United States the stan- monized approach to health benefit claims difficile,8 reduce the risk, severity or dura- dard was “significant scientific agreement” could provide clear benefits. Compliance tion of rotavirus-induced gastroenteri- until the Food and Drug Administration with all regulations on substantiation and tis,9 reduce the risk of developing atopic (FDA) was successfully sued on the basis wording of health benefit claims in differ- dermatitis,10,11 or reduce the incidence of that this standard unduly restricted com- ent regions of the world is a sizable chal- common infectious diseases.12,13 Certain mercial free speech.18 This ruling created lenge, and efforts to seek harmonization prebiotics have been shown to reduce the “qualified health claims” in the US, a perhaps through Codex or other interna- incidence of conditions such as travelers’ standard which acknowledges the con- tional collaborations could be worthwhile. diarrhea,14 antibiotic-associated diarrhea15 tinuum between emerging evidence and and infant diarrhea.16 Examples of such significant scientific agreement. Although Foods vs. Drugs uses for foods are numerous. Although claims now can be based on evidence that the number of studies required to consti- falls short of significant scientific agree- Certain current regulatory frameworks tute convincing evidence for these uses is ment, the claim still requires pre-approval require that food-form products that pre- a subject of much discussion, the impor- from the FDA. Such qualified health vent or manage diseases be subjected to tant point is that if validated, such uses for claims pose the challenge of accurately drug oversight. But important differences foods would be useful for consumers but communicating the subtleties of limited exist between scientific substantiation for often precluded by regulatory authorities. scientific evidence to scientifically naïve foods and drugs, and these differences can Another example where continua pose consumers. This is no trivial undertaking, make it difficult (and unnecessary) for foods challenges for regulators lies in consider- and those tasked with approval of claim to meet drug standards.19 Some of these dif- ing levels of evidence supporting health language clearly have an underlying con- ferences that are relevant to food as a subject benefit claims. The strength of evidence cern for protecting the consumer against of interventional human studies are: on health benefits of foods can range misleading marketing messages. Although • Foods and food ingredients meet a from “emerging evidence” to “significant the scientific community would agree that higher standard of safety than do drugs: scientific agreement,” and understand- evidence in support of health claims must risk vs. benefit is generally not part of the ably, regulations favor the latter over the be compelling, it also recognizes that all assessment. History of safe use is often an former. In the European Union, whereas studies have limitations, and a standard important component of safety assessments.

4 Gut Microbes Volume 2 Issue 3 • Foods are readily available to the total population, in non-limited amounts. Zero intake for a control group in a study may not be attainable. • Foods must be considered as part of an overall healthy diet. • Choice of a control product can be difficult when assessing functional ingredients in foods. The food without the functional ingredient is a likely choice for a control, but the control food itself may contribute to a physiological effect (e.g., conventional yogurt compared to a probiotic yogurt). The choice of a control product is driven in part by the research question being asked; however, to achieve blinding in a study on functional food, a control comprised of the food matrix must be used. • Generally the anticipated magnitude Figure 2. Visualization of the concept of improved homeostasis. An intervention able to minimize of effect is smaller than for drugs. the variation around the mean for a specific measure, even in the absence of changing the mean, • Unlike pills, food formulations can would be a demonstration of improved homeostasis. change frequently (new flavors, functional ingredients, levels of macronutrients, tar- required for efficacy may be different. For meaningful studies on probiotics or pre- geted formulations for different geograph- example, Blumberg et al.20 recently ques- biotics in healthy humans. How does one ical regions). An important consideration tioned the appropriateness of randomized show that health is improved—or even ©2011 Landes Bioscience. for researchLandes on foods is determining when controlled©2011 trials for foods. more challenging, maintained—in a a new distribute. food formulation differs substannot - A regulatoryDo framework that recog- healthy person? What does “maintained” tively from the researched food, requiring nized the existence of the above-described mean as a study outcome? One approach confirmatory efficacy studies. continua would provide an environment is demonstration of reduced incidence of • Profit margins are lower for foods where the full role of foods (including disease or illness. Such a study would be than for drugs. This leads to a disparity nutritional supplements) in promoting conducted in healthy people, but it may be with research investment possible by food health, reducing the risk of disease and prohibitively expensive due to low incidence compared to drug companies. managing health conditions could be or long latency, depending on the endpoint • Foods are most often natural rather realized. being examined. Tracking the incidence of than synthetic products, not produced Implementing such a regulatory frame- dental caries is an example of an endpoint under drug manufacturing practices, and work would present numerous challenges, that may be successfully undertaken with are more likely to show batch-to-batch but in the end consumers may benefit a manageable budget and time frame. But variability. from such changes. However, one unin- measuring the impact on immune func- It should be noted that although tended consequence of this regulatory tion with concomitant demonstration of dietary supplements are generally con- approach that would need to be consid- reduced common infectious diseases, for sidered within food regulations, some of ered is the risk of therapy substitution. example, would be a much more expen- the differences highlighted above between Many health conditions require medi- sive and lengthy study. Another approach, foods and drugs do not pertain to dietary cal intervention, for which foods cannot which would not require tracking a disease supplements. For example, formulation substitute. Consumers are attracted to the or illness endpoint, would entail measure- of an inert placebo for a dietary supple- ready availability, economy and lack of ment of homeostasis, as suggested by D. ment is generally a straightforward choice, side effects from foods, but must be ade- Tancredi. From a statistical point of view, supplements do not contribute calorically quately informed by clear labeling when if an intervention were able to minimize to consumers’ diet, matrix effects may not foods cannot substitute for needed medi- the variation around the mean for a specific be as variable for supplement formulations cal intervention. measure (even in the absence of changing and zero-intake may be easy to establish the mean; Fig. 2), it could be a reflection for subjects in studies. Homeostasis and Health: of improved health, assuming a biological Studies on foods should be of high- A Statistical Approach rationale exists that tighter control of the quality and well-controlled. But differ- parameter is physiologically advantageous. ences between foods and drugs compel One sizable challenge due to the current In other words, lessening the fluctuation recognition that the type of evidence regulatory frameworks is how to conduct around an individual’s biomarker could

www.landesbioscience.com Gut Microbes 5 Figure 3. The concept of homeostasis as expressed by reducing the magnitude or duration of fluctuations. Such a study could be conducted in healthy people, by collecting repeated measures of the physiological measure and comparing intervention and control groups on summary measures of the amount of within-person fluctuation. The study design could also include a timed sequence of challenges designed to disturb the measure, allowing between-group comparisons on resistance to perturbation. Modified after Ger Rijkers, personal communication. be interpreted as contributing to improv- able to use information on within-person Economic Impact ing health. This novel idea emphasizes the variations in biomarker levels, even those importance of homeostasis as a focus of who did not become ill. Partly as a result of According to a 2006 World Bank report studies on health, and provides a rationale the more efficient use of study data, such a on health enhancing foods, “cost-effec- based in solid statistical theory as a way to trial would require far fewer subjects than tiveness of functional foods in reducing measure this. an intervention that instead addressed the disease burden and lost productivity is an One challenge to demonstrating the hypothesis that treatment is associated important research gap.”24 While there ©2011 Landes Bioscience. value of thisLandes approach is to identify appro- with fewer©2011 healthy persons becoming ill. is a growing interest in evidence-based priate distribute. biomarkers that could be studied.not A mountingDo understanding of the health care, evidence on cost-effective- The following properties would be impor- value of stability of the colonizing micro- ness is often lacking. The pharmaceutical tant to a biomarker: bial communities makes this endpoint an industry and the medical community have • maintaining moderate levels of the attractive one to consider. Perturbation of introduced science-based economic evalu- biomarker is associated with good health; gut microbiota is associated with intestinal ation of health management programs • high or low values are associated with dysfunction, as illustrated during antibi- and care protocols as well as standardized ill health; otic treatment. Specific probiotics have treatment protocols. These studies have • biomarker levels in the same person been shown to promote a quicker rebound established the principles of cost-benefit can fluctuate over time; and from antibiotic-induced microbiota dis- and cost-effectiveness assessments, evalu- • reducing the magnitude or duration ruption, including a study on Lactobacillus ating not only the health spending but of such fluctuations in healthy people is rhamnosus GG (LGG).21 This paper con- also the economic benefits.25,26 Such ben- considered desirable (Fig. 3). cludes “…that a key mechanism for the efits could include, for example, the public Such a biomarker could be an individ- protective effect of LGG supplementation health savings induced by health manage- ual endpoint or be formed as a ratio of two on the subsequent development of aller- ment programs. Approaches that establish other biomarkers, when maintaining the gic disease is through the promotion of a procedures for the assessment of the role of same relative amounts of the two compo- stable, even and functionally redundant food with particular beneficial effects on nent biomarkers would be desirable. infant gastrointestinal community.” health, well-being and quality of life in our Assuming a biomarker with the above However, it would be useful to define society are needed. Such assessment would properties is available, it could be used additional biomarkers that would be appro- provide important perspective on the eco- as the outcome measure in a randomized priate targets for this type of investigation. nomic impact of a regulatory framework controlled trial to provide evidence that In pediatric nutrition, the measurement that encourages research and communica- the experimental food is able to improve of metabolic homeostasis has become a tion on the health benefits of foods, and the maintenance of health in humans. standard approach when developing infant the subsequent broad implementation in Statistically, the trial would be set up to formulas.22 The concept of homeostatis the diet of target populations. address the hypothesis that the experi- as a model to distinguish between foods mental substance is associated with lower (including food supplements) and medici- Conclusions variation in biomarker levels, compared nal products was explored by the Council to the control arm, in subjects who were of Europe,23 and is an interesting correlate A reassessment of the regulatory approach healthy at baseline. Such a trial would be to the above hypothesis. to functional foods in general, and

6 Gut Microbes Volume 2 Issue 3 References 18. Emord JW. Pearson v. Shalala: The beginning of probiotics and prebiotics in particular, the end for FDA speech suppression. J Public Policy is needed. Promulgated in the interest in 1. Hofmann B. Simplified models of the relationship Marketing 2000; 19:139-43. between health and disease. Theor Med Bioeth 2005; 19. de Vos WM, Castenmiller JJM, Hamer RJ, Brummer protecting the consumer from fraudu- 26 :355-77. RJM. Nutridynamics—studying the dynamics of lent claims or from unsafe products, 2. Tengland PA. Health promotion and disease preven- food components in products and in the consumer. in some cases the regulatory standards tion: logically different conceptions? Health Care Curr Opin Biotechnol 2006; 17:217-25. Anal 2010; 18:323-41. 20. Blumberg J, Heaney RP, Huncharek M, Scholl T, being implemented have the unintended 3. Tengland PA. Health promotion or disease preven- Stampfer M, Vieth R, et al. 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Br J Nutr 2010; 27:1-9. among all stakeholders to work toward Rizzardi S, Boehm G. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces regulatory frameworks more consistent the incidence of allergic manifestations and infec- with accepted scientific concepts of “con- tions during the first two years of life. J Nutr 2008; tinuum” and “suboptimal” are needed. 138:1091-5. ©2011 Landes Bioscience. Landes 11. Moro©2011 G, Arslanoglu S, Stahl B, Jelinek J, Wahn U, The “continuum”distribute. approach does notnot seem Boehm G.Do A mixture of prebiotic oligosaccharides fully possible without a change in law, as reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 2006; 91:814-9. the current law clearly separates products, 12. Merenstein D, Murphy M, Fokar A, Hernandez health conditions and evidence into dis- RK, Park H, Nsouli H, et al. Use of a fermented crete entities. 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Regulation (Ec) No 1924/2006 of the European The authors gratefully acknowledge the Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods, Article contributions of each discussion group 6. 2006; (Accessed February 24, 2011, at http://eur- member (Table 1) and the creative assis- lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L: 2006:404:0009:0025:EN:PDF). tance of Alexandra Kamins in preparing graphics.