European Journal of Pharmacology 668 (2011) S2S9

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European Journal of Pharmacology

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Review

Functional foods and dietary supplements: Products at the interface between pharma and nutrition
Simone R.B.M. Eussen a, b,, Hans Verhagen a, c, d, Olaf H. Klungel b, Johan Garssen b, Henk van Loveren a, c, Henk J. van Kranen a, Cathy J.M. Rompelberg a, 1
a

National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands d University of Ulster, Northern Ireland Centre for Food and Health (NICHE), Cromore Road, Coleraine, BT52 1SA, Northern Ireland, United Kingdom
b c

a r t i c l e

i n f o

a b s t r a c t
It is increasingly recognized that most chronic diseases of concern today are multifactorial in origin. To combat such diseases and adverse health conditions, a treatment approach where medicines and nutrition complement each other may prove to be the most successful. Within nutrition, apart from (disease-related) dietetic regimes, an increasing number of functional foods and dietary supplements, each with their own health claim, are marketed. These food items are considered to be positioned between traditional foods and medicines at the so-called Pharma-Nutrition Interface. This paper encompasses aspects related to the regulatory framework and health claims of functional foods and dietary supplements. The use of functional foods or dietary supplements may offer opportunities to reduce health risk factors and risk of diseases, both as monotherapy and in combination with prescription drugs. Nevertheless, the potential caveats of these products should not be overlooked. These caveats include the increased risk for food-drug interactions due to the elevated amounts of specic functional ingredients in the diet, and the stimulation of self-medication potentially resulting in lower adherence to drug therapy. Health technology assessments should be used more to compare the cost-effectiveness and benetrisk ratios of drugs, functional foods and dietary supplements, and to evaluate the added value of functional foods or dietary supplements to drug therapy. 2011 Elsevier B.V. All rights reserved.

Article history: Accepted 13 July 2011 Available online 27 July 2011 Keywords: Pharma-nutrition Food-pharma Functional food Dietary supplement EU regulation Claim

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Regulatory framework . . . . . . . . . . . . . . . . . . . . . 2.1. Safety and efcacy of drugs. . . . . . . . . . . . . . . . 2.2. Safety of food . . . . . . . . . . . . . . . . . . . . . . 2.3. Efcacy of food: nutrition and health claims . . . . . . . . 2.4. Dietary supplements: regulated as food or drug? . . . . . 3. Opportunities and caveats. . . . . . . . . . . . . . . . . . . . 3.1. Opportunities of functional foods and dietary supplements . 3.2. Caveats of functional foods and dietary supplements . . . . 4. Health technology assessments of food and drugs . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2 S3 S3 S3 S4 S5 S5 S5 S6 S6 S7 S7

Corresponding author at: P.O. Box 80082, 3508 TB Utrecht, The Netherlands. Tel.: + 31 30 253 6966; fax: + 31 30 253 9166. E-mail addresses: S.Eussen@uu.nl (S.R.B.M. Eussen), Cathy.Rompelberg@rivm.nl (C.J.M. Rompelberg). 1 P.O. Box 1, 3720 BA Bilthoven, The Netherlands. Tel.: + 31 30 274 2387; fax: + 31 30 274 4466. 0014-2999/$ see front matter 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.07.008

1. Introduction Since ancient times plants, herbs and other natural products have been used as healing agents. Advances in organic chemistry from the early 19th century have enabled the preparation of numerous synthetic

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Fig. 1. Pharma-Nutrition Interface.

In the following sections we will rst address the regulatory framework for drug and food safety and efcacy. In particular, we will focus on functional foods and dietary supplements, and the health claims related to these food products (Section 2.1 to 2.3). Within the extensive regulatory framework, some (herbal) dietary supplements fall in between food and drug regulations, though (Section 2.4). Subsequently we describe the opportunities for functional foods and dietary supplements to reduce health risk factors and risk of diseases (Section 3.1), and discuss potential caveats of these food products (Section 3.2). Section 4 explains how health technology assessments, i.e. cost-effectiveness and risk-benet analyses, can be used to make evidence-based decisions about which therapy, or combination of therapies, will result in the most successful and cost-effective management of health risk factors and chronic diseases. Finally, conclusions are drawn at the end of this paper (Section 5). 2. Regulatory framework 2.1. Safety and efcacy of drugs An extensive legal regulatory system is in place for pharmaceutical products. Already shortly after the thalidomide affair in the 1960s, national and international regulatory authorities were established to monitor drug safety (Lisman and Lekkerkerker, 2005). Since 1995, the European Medicines Agency (EMA) is responsible for the scientic evaluation and monitoring of the safety and efcacy of pharmaceuticals in Europe (http://www.ema.europa.eu/ema/index.jsp?curl=/pages/ home/Home_Page.jsp). The agency was set up to reduce disparities in drug regulation across the different European Member States. Yet, the majority of the existing pharmaceuticals throughout the European Member States remain authorized nationally, whereas the majority of novel medicines are authorized through the European Medicines Agency. Directive 2001/83/EC requires that all medicinal products are registered before they are placed on the European market (European Commission, 2001a). Registration involves standard procedures to examine the efcacy, safety and quality of the product. In exceptional circumstances, individual Member States may grant permission for the availability of pharmaceuticals without market authorization under the compassionate use program (European Commission, 2001b). This program makes promising therapies available to select patients with a seriously debilitating or life-threatening disease when no alternative authorized treatment exists (European Commission, 2001b). A different, simplied registration procedure (traditional-use registration) is in place regarding the efcacy of traditional herbal medicinal products. For these medicinal products the provision of data from pre-clinical tests and clinical trials is not required, as long as their efcacy is plausible on the basis of longstanding use and experience (European Commission, 2004b). 2.2. Safety of food Food safety has long been a matter of national policy (Szawlowska, 2001). Following the bovine spongiform encephalopathy (BSE) crisis and other food scares in the 1990s, in January 2000 the European Commission published a White Paper on Food Safety (European Commission, 2000a). The Paper outlines a comprehensive range of actions needed to complement and modernise existing European food legislation, and led to the introduction of the General Food Law (Regulation (EC) 178/2002) (European Commission, 2002). This regulation formed the basis for the establishment of the independent European Food Safety Authority (EFSA) in 2002. This Authority is responsible for providing the European Commission with independent scientic advice on all matters with a direct or indirect impact on food safety (http://ec.europa.eu/food/efsa_en.htm). Nowadays, the European Commission has established a legal framework regulating the food supplements market, the fortied food market and the

medicines. Yet, the majority of the medicinal substances available today have their origin in natural compounds. The best known example is aspirin (acetylsalicylic acid), originally derived from the bark of the white willow tree (Leroux, 1830; Mahdi et al., 2006). Other examples include the immunosuppressive cyclosporines (Borel et al., 1990), the anthracycline antibiotics (Nadas and Sun, 2006) and the HMG-CoA reductase inhibitors, commonly known as statins (Endo, 2004). Traditionally, pharmaceuticals have been used to cure diseases or to alleviate the symptoms of disease. Nutrition, on the other hand, is primarily aimed to prevent diseases by providing the body with the optimal balance of macro- and micronutrients needed for good health. Due to the emerging knowledge of disease, medicines are now increasingly being used to lower risk factors, and thereby to prevent chronic diseases. Prime examples are blood pressure lowering and blood lipid-lowering agents which reduce the risk of cardiovascular disease. The appearance of functional foods and dietary supplements on the market has further blurred the distinction between pharma and nutrition (Fig. 1). Functional foods are foods that are claimed to improve health, quality of life or well-being beyond basic nutritional functions (Henry, 2010; Howlett, 2008; ILSI Europe, 1999; van Kreijl et al., 2006). Examples of functional foods are margarines enriched with cholesterol-lowering phytosterols, cereals fortied with soluble bres and yoghurts with specic bacterial cultures added. Thus, functional foods resemble conventional food products in appearance and are consumed as part of the usual diet. In contrast, dietary supplements are typically marketed in the form of a capsule, pill, powder or gel and are not presented for use as a conventional food, meal or diet. Dietary supplements contain one or more dietary ingredients (e.g., vitamins, minerals, amino acids, herbs or other botanicals) and are intended to supplement the diet (http://ods.od. nih.gov/) (U.S. Food and Drug Administration, 1994; van Kreijl et al., 2006). Today's functional foods and dietary supplements are typically marketed to large (sub)groups of the total population. For example, phytosterol-enriched functional foods are targeted to all adults with (moderately) elevated cholesterol levels and products with claimed pre- and probiotic activity are aimed at general healthy populations. The recent advances in pharmaco- and nutrigenomics have formed the basis for developing the concepts of personalized medicine (Personalized Medicine Coalition, 2009) and personalized nutrition (Kaput, 2008; Kussmann and Fay, 2008). These emerging elds rely on targeted therapies based on a person's genetic risk prole. Pharmaceuticals (Caskey, 2010; Pravenec and Kurtz, 2007), as well as several dietary components (Afman and Mller, 2006), have been recognized to modulate gene and protein expression and thereby metabolic pathways, homeostatic regulation, and presumably health and disease. In addition, genes also contribute largely to different responses to diet or drug exposure, including interindividual variations in the occurrence of adverse drug reactions (Friso and Choi, 2002; Lee et al., 2010).

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market for so-called novel foods (Schwitters et al., 2007; Verhagen et al., 2009). The Food Supplements Directive 2002/46/EC species permitted vitamin and mineral substances, and provides maximum and minimum levels of vitamins and minerals in food supplements. Regulation (EC) 1925/2006 (Food Fortication Regulation) provides a positive list of vitamins, minerals and specic other substances (e.g. herbal extracts) that may be added to foods. When a functional food contains novel ingredients or is produced by a novel process it may fall under Regulation (EC) 258/97 (currently under revision (European Commission, 2008)). This regulation requires that all novel foods or novel food ingredients, i.e. food (ingredients) without a history of signicant consumption in the European Union prior to 15 May 1997 (European Commission, 1997), undergo a science-based safety assessment before being placed on the European market. In the USA, functional foods are regulated as a category of foods and must meet all provisions for conventional foods as specied in the Federal Food Drug and Cosmetic Act. Dietary supplement ingredients sold in the USA before implementation of the Dietary Supplement Health and Education Act (DSHEA) on October 15, 1994 are considered old dietary ingredients and are presumed to be safe, whereas dietary ingredients marketed after October 15, 1994 are new ingredients requiring pre-market review of safety by the Food and Drug Administration (Taylor, 2004; U.S. Food and Drug Administration, 2009). Unlike the European situation where food and drug safety are regulated by distinct agencies, in the USA the U.S. Food and Drug Administration is responsible for both drug regulation and food safety. 2.3. Efcacy of food: nutrition and health claims Dietary supplements and functional foods are meant to benet health. Consequently, such food products typically contain claims on

their label stating their benets. In order to harmonize those claims at the European level, in December 2006 the European Union published Regulation No 1924/2006 on nutrition and health claims made on foods (European Commission, 2006). This regulation distinguishes two categories of claims: nutrition claims and health claims. Nutrition claims are claims that state, suggest or imply that a food has particular nutritional properties. Such claims may, e.g. state that a product contains calcium, or is low in salt or sugar. Health claims are statements that imply that a relationship exists between a food product and a health condition. Examples are general function claims (Article 13(5) claims), reduction of disease risk claims (Article 14(1) (a) claims) and claims referring to the growth and development of children (Article 14(1)(b) claims) (Verhagen et al., 2010). The European Food Safety Authority evaluates the scientic data related to food and food ingredients that contain a nutrition or health claim into an opinion which is put forward to the European Commission for approval and authorization (see Table 1 for an overview of authorized health claims). In the European Union medical claims, i.e. claims for the prevention, treatment or cure of human disease, are reserved for medical products (European Commission, 2000b). For example, an authorized health claim states that Phytostanol/-sterol esters have been shown to lower/reduce blood cholesterol. High cholesterol is a risk factor in the development of coronary heart disease (EFSA, 2009a; European Commission, 2009a, 2010a). This does not explicitly claim that phytostanol and phytosterol esters reduce the risk of coronary heart disease, although this assumption may easily be made by most consumers (Katan and de Roos, 2003). Thus, the European Union differentiates between reduction of disease risk factor and prevention to acknowledge that diet and certain foods can make important contributions to maintain health and manage disease risk factors, but they may not bear a claim that they can prevent disease (European

Table 1 Health claims authorized by the European Commission (March 2010) divided into general functional claims (Table 1a), reduction of disease risk claims (Table 1b) and claims referring to the growth and development of children (Table 1c) (European Commission, 2011). Panel a. Function claim (Article 13(5)) Substance, nutrient, food Water-soluble tomato concentrate (WSTC I and II) Claim Water-Soluble Tomato Concentrate (WSTC) I and II helps maintain normal platelet aggregation, which contributes to a healthy blood ow European Commission Decision No 2009/980/EU (European Commission, 2009c) EFSA opinion reference (EFSA, 2009e, 2010b)

Panel b. Reduction of a disease risk claim (Article 14(1)(a)) Substance, nutrient, food Plant sterols/plant stanol esters Chewing gum sweetened with 100% xylitol Claim European Commission Regulation EFSA opinion reference

Plant sterols and plant stanol esters have been shown to lower/ No 384/2010 (European Commission, 2010a) No 983/2009 (EFSA, 2008a,b, 2009a,b) reduce blood cholesterol. High cholesterol is a risk factor in the (European Commission, 2009a) development of coronary heart disease. (EFSA, 2008c) Chewing gum sweetened with 100% xylitol has been shown to No 1024/2009 (European Commission, 2009b) reduce dental plaque. High content/level of dental plaque is a risk factor in the development of caries in children

Panel c. Claims referring to the growth and development of children (Article 14(1)(b)) Substance, nutrient, food Claim European Commission Regulation No 983/2009 (European Commission, 2009a) No 983/2009 (European Commission, 2009a) No 983/2009 (European Commission, 2009a) No 1024/2009 (European Commission, 2009b) No 957/2010 (European Commission, 2010b) No 957/2010 (European Commission, 2010b) No 983/2009 (European Commission, 2009a) EFSA opinion reference (EFSA, 2008d) (EFSA, 2008e,f) (EFSA, 2008e,g) (EFSA, 2008h) (EFSA, 2009c) (EFSA, 2009d) (EFSA, 2008i)

-linolenic acid & linoleic acid, Essential fatty acids are needed for normal growth and essential fatty acids development of children. Calcium Calcium is needed for normal growth and development of bone in children. Vitamin D Vitamin D is needed for normal growth and development of bone in children. Phosphorus Phosphorus is needed for the normal growth and development of bone in children. Iodine Iodine contributes to the normal growth of children Iron Iron contributes to normal cognitive development of children Protein Protein is needed for normal growth and development of bone in children. EFSA; European Food Safety Authority.

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Commission, 2003). Also in the United States, medical claims on foods and dietary supplements with regard to diagnosis, treatment, curing or prevention of specic diseases or classes of diseases are not allowed (U.S. Food and Drug Administration, 2005).

2.4. Dietary supplements: regulated as food or drug? Herbs and botanicals are often proposed as functional ingredients in functional foods and dietary supplements. Also medicines frequently contain ingredients derived from plant material. A product containing herbs or botanicals will be considered a medicinal product when presented as having properties for treating or preventing disease in humans, or when it may be used in or is administered to humans either with a view to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action, or to make a medical diagnosis (European Commission, 2004a). It is the competence and responsibility of the Member States to decide, on a case-by-case basis, whether an herbal or botanical product falls within the denition of a medicinal product. This may lead to a situation in which a product containing exactly the same bioactive ingredients and in the same dosage is considered a dietary supplement in some European Member States, but is registered as a medicine in others. Since the way of presentation of a product and its anticipated pharmacological, immunological or metabolic action determine its classication as food or drug it is also possible that herbs and botanicals are exploited both as a dietary supplement as well as a medicine within a Member State, depending on dosage and form. E.g., in the Netherlands, the herbals Ginkgo biloba, Valerian and St. John's Wort are sold both as food and as drugs. The distinction between a food item and a medicine is of great signicance for legal practice, since medicines are more tightly regulated than foods. The recognized therapeutic active level of substances may be used as a cut-off point to differentiate between a food item and a medicine (Coppens et al., 2006a). Products with a recommended daily intake level that is higher than this cut-off point would be classied as a medicinal product, whereas products with a recommended daily dosage that is lower than this cut-off point would be regarded as a dietary supplement. This is in agreement with the view taken by the European Court of Justice. According to the Court, the medicines legislation only applies to a product if the product at the

recommended dosage is capable of modifying human physiological functions by exerting a pharmacological, immunological or metabolic action (Baeyens and Gofn, 2009). In the case of Hecht-Pharma, red rice capsules were judged to be classied as a food agent. Although the capsules contained monacolin K, which is identical to the prescription drug lovastatin, the recommended daily dosage (1.33-4 mg/day) was lower than what is considered effective for lovastatin (2080 mg/day) (Bradford et al., 1994). Nevertheless, differences in the production process, auxiliary agents and ratio of active and auxiliary ingredients between food products and medicines may contribute to differences in effectiveness.

3. Opportunities and caveats 3.1. Opportunities of functional foods and dietary supplements Functional foods or dietary supplements, i.e. those that carry substantiated health claims, can be helpful in reducing health risk factors and may thereby contribute to prevent chronic diseases. They are generally intended to be used by two categories of consumers. The rst category comprises persons with modestly elevated risk factors who can take functional foods or dietary supplements as part of a healthy lifestyle, or to compensate for an unhealthy one. However, persons in this rst category will often be unaware of their increased risk (de Jong et al., 2007). The second category comprises persons that are eligible for drug therapy in order to reduce a particular risk factor. They can take functional foods or dietary supplements as add-on to their therapy. This might be especially benecial for patients who do not achieve optimal treatment goals with drug monotherapy. Examples are phytosterol/-stanol-enriched products in addition to statin therapy for the prevention of cardiovascular disease (EFSA, 2008a,b), calcium-fortied foods or drinks in addition to hormone replacement therapy for the prevention/minimization of osteoporosis (EFSA, 2010c) and products containing the long-chain -3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in addition to antihypertensive agents to reduce blood pressure (EFSA, 2009f). Thus, functional foods and dietary supplements are not meant to replace drug therapy, since they cannot equal the health effects of pharmaceuticals. However, persons who consistently use the food products may be able to lower the dose of

Table 2 Clinically important food-drug interactions. Substance, nutrient, food Grapefruit (Dahan and Altman, 2004; Ulbricht et al., 2008) St. John's wort (Borrelli and Izzo, 2009; Ulbricht et al., 2008) Vitamin K (Rohde et al., 2007) Drug(s) CYP3A4 substrates, e.g. some benzodiazepines, calcium channel antagonists, statins, and cyclosporine CYP3A4 and/or P-glycoprotein substrates, e.g. some anticancer drugs, antiretroviral drugs, oral contraceptives, and cyclosporine Anticoagulant drugs, e.g. warfarin, and antiplatelet drugs, e.g. aspirin Digoxin, some statins Possible mechanism Inhibition of intestinal CYP3A4 by grapefruit Result of interaction Increased bioavailability and peak levels of CYP3A4 substrates Decreased activity of CYP3A4 substrates Decreased drug effectiveness, decreased International Normalised Ratio (INR) Decreased drug effectiveness

Induction of CYP3A4 and P-glycoprotein by St. John's wort Direct antagonism by vitamin K content in food

Soluble dietary bre, e.g. guar gum and -glucan (Brown et al., 1978; Huupponen et al., 1984; Richter et al., 1991)

Interfering with drug absorption due to binding of the drug to bre or forming an unstirred water layer in intestinal lumen Calcium (Maton and Burton, 1999; Neuhofel et al., Antibiotics, e.g. quinolones and tetracyclines, Interfering with drug absorption due to the 2002; Schneyer, 1998; Wallace et al., 2003) and levothyroxine formation of insoluble complexes between the drug and calcium Ginkgo (Abad et al., 2010; Ulbricht et al., 2008) Anticoagulant drugs, e.g. warfarin, and Decreased platelet aggregation due to antiplatelet drugs, e.g. aspirin interactions with platelet-activating factor and collagen Allicin-containing garlic (Colalto, 2010) CYP3A4, CYP2E1 and P-glycoprotein substrates, Induction of P-glycoprotein and CYP3A4 by allicin-containing garlic e.g. some anaesthetics, calcium channel blockers, antiretroviral drugs

Decreased drug effectiveness

Increased risk of bleeding

Decreased activity of CYP3A4 substrates

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medicine needed to control risk factors. Since side effects of drugs are often correlated to higher doses, lowering the dose of the drug may consequently lead to less drug-associated side effects (Eussen et al., 2010a). 3.2. Caveats of functional foods and dietary supplements Persons who use functional foods or dietary supplements may be able to lower the dose of their prescribed drug without decreasing the therapeutic effect. Nonetheless, persons should only lower the drug dose after consulting a doctor or pharmacist. This immediately reveals one of the caveats of functional foods and dietary supplements: the stimulation of self-medication. In a recent study performed by Alevizos et al. (2007), almost 90% of the patients who acknowledged to have heard of phytosterols declared that they were willing to switch statin therapy with phytosterol/-stanol-enriched products. Moreover, in a retrospective study it has been observed that patients who use margarines enriched with phytosterols/-stanols in addition to their prescribed statins were more likely to discontinue drug therapy (Eussen et al., 2010b), thereby increasing rather than decreasing their disease status. This underscores the importance of thorough communication between patients and their health care providers about combination therapies in order to urge the patient not to take functional foods as replacement for their prescribed medication. Even if patients use their medicines and functional foods or dietary supplements as intended, the combined intake may have caveats. Due to the elevated amounts of specic functional ingredients in the diet, there is an increased risk for food-drug interactions (see Table 2 for important interactions). For example, functional foods enriched with water-soluble dietary bres, e.g. guar gum or -glucan, might decrease the intestinal absorption, and thereby the cholesterollowering effects, of statins (Richter et al., 1991; Eussen et al., 2011). St. John's wort might diminish the clinical effectiveness of medicines which are substrates of cytochrome P450 3A4 (Markowitz et al., 2003) and dietary supplements rich in vitamin K might decrease the anticoagulant effects of oral anticoagulants (Booth and Centurelli, 1999; Franco et al., 2004). It should be noted, however, that also nonsupplemented intake levels of certain food products, e.g., grapefruit (juice), can give raise to a food-drug interaction. Additionally, interactions between drugs in multidrug regimens are more common and possibly more serious than food-drug interactions (Cannon, 2008; Scheen, 2007). Nevertheless, whereas in most pharmacies drug prescriptions are computer-checked for drug-drug interactions, most pharmacists do not inquire about patients' use of functional foods or dietary supplements. The European Commission requests that all adverse drug reactions and drug-drug interactions are reported to the Union Pharmacovigilance database (http://eudravigilance.ema.europa.eu/human/ index.asp). Moreover, post-authorization safety studies on medicines are required to ensure adequate ongoing pharmacovigilance monitoring (European Commission, 2001a). In contrast, there is currently no post-market monitoring system for functional foods or dietary supplements that deals with adverse effects after market-launch. Such a monitoring system may provide the means to evaluate the (longterm) exposure and safety under customary conditions of use, such as overconsumption of specic nutrients, adverse effects in potential risk groups, unforeseen long-term health effects and interaction effects with nutrients and/or drugs, and as such has been proposed for novel foods (de Jong et al., 2008; Hepburn et al., 2008). 4. Health technology assessments of food and drugs The aging of the population together with the rising health care costs underline the need to consider the cost-effectiveness of a treatment. It has been suggested that functional foods and dietary

supplements, as part of healthy eating habits, can have a substantial effect on health care costs (Milner, 2000). Although cost-effectiveness assessments for pharmaceuticals are being used increasingly (Taylor et al., 2004), the cost-effectiveness of the use of functional foods or dietary supplements remains largely unexamined (Kotilainen et al., 2006). Moreover, to help policy-makers in making reimbursement decisions, comparative cost-effectiveness analyses of drugs v. functional foods/dietary supplements in persons with a modestly elevated risk prole are indicated. Comparing the cost-effectiveness of drugs plus functional foods/dietary supplements v. drug therapy alone can be useful in assessing the additive value of a functional food or dietary supplement in patients with a high risk prole. Besides the importance of considering the cost-effectiveness of health care interventions, regulators also focus on their benetrisk prole. The European Commission requires manufactures of pharmaceuticals to supply the European Medicines Agency with all information relevant for the evaluation of the benets and risks related to a medical product. When therapeutic alternatives are available, one should perform a comparative benetrisk assessment (European Commission, 2001a; Garattini, 2010). So far, no benetrisk assessment is required for the approval and market introduction of (novel) functional foods or dietary supplements (Tijhuis et al., Epub ahead of print). Nonetheless, potential health benets of these products are currently being assessed under Regulation (EC) 1924/2006 (Section 2.3.), and evaluating food safety is an established eld of research (Section 2.2.) (Coppens et al., 2006b; European Commission, 2000a). The concept of integrated benetrisk assessments of food (products) and nutrition is new (Fransen et al., 2010; Hoekstra et al., 2010; Pascal, 2009). It envisages expressing both benets and risks in similar units, e.g., quality- or disability-adjusted-life-years, thereby permitting direct comparisons of adverse and benecial effects. The European Food Safety Authority has recently developed guidance for performing benetrisk assessment of foods (EFSA, 2010a). This guidance is applicable to all foods, but might be especially appropriate for (novel) functional foods or dietary supplements that may be benecial to health, but may also cause health risks due to the over- or underconsumption of specic nutrients, unforeseen adverse health effects or long-term effects, and interactions (Section 3.2.). Due to the absence of a history of safe use, novel functional foods and dietary supplements may be more frequently related to adverse health effects. Phytosterol-enriched products, for example, are effective in reducing total and LDL cholesterol levels, but have been associated with a reduction in -carotene levels (Katan et al., 2003). Moreover, the increased serum phytosterol concentration might contribute to a higher atherosclerotic risk (Patel and Thompson, 2006). The changes in dietary intake level after the introduction of a (novel) functional food or dietary supplement provide for assessing a benet risk balance both before and after market introduction. Several major European initiatives are currently ongoing in the area of benetrisk assessment of foods, including BEPRARIBEAN (http://en.opasnet.org/w/Bepraribean), BRAFO (http://www.ilsi.org/ europe/pages/brafo.aspx) and PLANTLIBRA (http://cordis.europa.eu/ fp7/projects_en.html). The BEPRARIBEAN (Best Practices in Risk Benet Analysis) project aims to push forth the area of benetrisk analysis for foods by approaching benetrisk analysis for food and nutrition from perspectives and experience in other areas, i.e. medicines, food microbiology, environmental health, economic and marketing-nance and consumer perception. In the BRAFO (Benet risk Analysis for Foods) project a tiered (stepwise) approach for performing a benetrisk assessment of foods is established. The approach consists of four tiers, including the individual assessment of benets and risks and a qualitative and quantitative integration of benets and risks (Hoekstra et al., 2010). PLANTLIBRA (PLANT food supplements: Levels of Intake, Benet and Risk Assessment) focuses on the safe use of food supplements containing plants or herbal extracts by collecting food supplement intake data and developing methodologies for benet and risk assessment.

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5. Conclusion Most chronic diseases of concern today are multifactorial in origin. For control, an approach in which medicines and nutrition are considered together and complement each other may result in the most successful and cost-effective management of health risk factors and chronic diseases. Functional foods and dietary supplements may become important players at the interface between pharma and nutrition, and merit attention from both a public health and a marketing perspective. The attention of the European Union and USA regarding functional foods and dietary supplements has been principally directed to food safety and (claims of) efcacy, and most of the research focuses on these two areas. Currently little is known about the opportunities and caveats of functional foods and dietary supplements under customary conditions of use. Relevant issues for further research comprise the benecial and harmful effects of the combined use of functional foods/dietary supplements and medicines, the stimulation of self-medication with the use of functional foods and dietary supplements, and the long-term safety of these products. A post-launch monitoring system assessing the effectiveness and safety of a food product after it has been placed on the market may be valuable in this respect. Health technology assessment is a useful tool to make evidence-based (reimbursement) decisions about which therapy, or combination of therapies, provides the most favourable benetrisk and cost-effectiveness ratio. References
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