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SUPPLEMENT ARTICLE Current Marketplace for Probiotics: A Japanese Perspective Harunobu Amagase FreeLife International, Phoenix, Arizona In Japan, probiotics are available as both foods and drugs. Unlike in the United States, probiotics have a long history of cultural acceptance and safe use in Japan. Sales are booming, which may reflect the inception of the regulatory category “foods for specialized health use” (FOSHU), which permits labeling with claims that describe health benefits. A total of 65 probiotic products, containing 16 different strains, are listed among the 579 FOSHU products. Since the US market for probiotics is still small, it has substantial room to grow. In Japan, fermentation using various microorganisms is a traditional method to produce sake (wine made from rice), miso (soybean paste), natto (fermented soybean), pickles, and many other products. Fermented dairy products, which were reintroduced to Japan ∼300 years ago after an extended absence, are also quite popular [1]. In the early 1990s, Japan established the regulatory category “foods for specialized health use” (FOSHU), which permits labeling with health claims on foods that meet specific requirements for safety and efficacy [2]. As of 1 September 1991, to be called “FOSHU,” products must be approved by the Japanese Minister of Health, Welfare, and Labor. Products containing ingredients identical to those in approved products must still undergo this process. The categories of claims include blood pressure, cholesterol, triglycerides, blood sugar, bone minerals (especially calcium), and dental health. Recently, Japan has witnessed a significant increase in the market for health foods, including FOSHU products, which has outpaced sales of over-the-counter (OTC) drugs. In 2005, the Japan Health Food and Nutrition Food Association estimated the Japanese market for probiotics at US$5.3 billion, up from $1.12 billion Reprints or correspondence: Dr. Harunobu Amagase, FreeLife International, 3925 E. Broadway Rd., Ste. 201, Phoenix, AZ 85040 ([email protected]). Clinical Infectious Diseases 2008; 46:S73–5 2008 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2008/4603S2-0005$15.00 DOI: 10.1086/523338 in 1997. As of 27 February 2006, a total of 579 FOSHU products have been approved, including 65 probiotic products containing ⭓1 of the 16 approved bacterial strains: Lactobacillus rhamnosus GG, Bifidobacterium longum BB536, Lactobacillus delbrueckii subsp. bulgaricus 2038, Streptococcus salivarius subsp. thermophilus 1131, Lactobacillus casei Shirota, Bifidobacterium breve Yakult, Bifidobacterium lactis FK120, B. lactis LKM512, Lactobacillus acidophilus CK92, Lactobacillus herbeticus CK60, L. casei SBR1202, Lactobacillus gaseeri SP, Bifidobacterium SP, L. casei NY1301, Lactobacillus LC1, and B. lactis Bb-12 [2, 3]. In recent years, Japan has undergone regulatory reform. One of the driving forces behind these changes has been the country’s rising costs of health care [4]. Ward and Piccolo summarized the current situation by noting that, “[l]ike most industrialized countries, Japan is faced with a rapidly aging population and a declining birthrate” [5]. In 2005, people aged ⭓65 years represented 19.9% of Japan’s population; however, this segment is predicted to increase to 26.0% by 2015 [6]. The increase in elderly persons combined with Japan’s stagnant and slow economic growth are creating a financial crisis for the country’s health care system [5]. Government deregulation of some OTC drugs has been used as a means to reduce health care costs. Some of the OTC drugs with well-established safety records have been reclassified as the category of “quasi-drugs” or as functional foods. These products are no longer limited to being sold at drug stores and pharmacies but can be sold anywhere, including convenience stores, Probiotics in Japan • CID 2008:46 (Suppl 2) • S73 grocery stores, and kiosks at train stations, without a pharmacist’s supervision. The category of drugs for gastrointestinal health is one that was deregulated [7]. Biofermin S (Biofermin Pharmaceutical), which contains live Bifidobacterium bifidum, Streptococcus faecalis, and L. acidophilus, is one popular product for treatment of diarrhea. It was transferred to the quasi-drug (lyaku-bugaihin) category, which represents products with mild effects on the body. Japan is also encouraging the public to adopt healthier lifestyles as another means to reduce spending for health care [8]. Measures include the implementation of antismoking campaigns, the promotion of self-medication, and the use of health foods to prevent or reduce the risk of disease. Japan’s regulatory classification system is shown in figure 1 [2]. Health foods, represented by the category “foods with health claims” (which includes the categories FOSHU and foods with nutrient claims) must undergo approval based on the Nutrition Improvement Act (section 12-1). These products contain ingredients that influence physiological functions of the body and can be used to maintain health and/or to achieve specific health effects. For example, some probiotic foods claim to maintain gastrointestinal health. Probiotics are used today in many major Japanese hospitals to treat gastrointestinal disorders, such as diarrhea and constipation, and symptoms related to antibiotic use. An example of one such product, marketed by Wakanuga, contains 3 strains: L. acidophilus KS-13, B. bifidum G9–1, and B. longum MM-2 [9, 10]. These strains are sold as a prescription drug, an OTC drug, and a quasi-drug. To support the marketing of this product in all these categories, the following information was determined: efficacy [11–14], stability [15] (Food Products Laboratory, Portland, Oregon, personal communication), resistance to stomach acids [12, 16, 17] (Food Products Laboratory, Portland, Oregon, personal communication), implantation (colonization) [18], adherence to the gastrointestinal tract [19], and in vivo distribution and recovery [20]. Health targets for probiotic FOSHU marketed in Japan include gastrointestinal conditions, immunity, allergy, cold and influenza-like symptoms, cholesterol levels, blood pressure levels, and diabetes. Recent correspondence with Japanese authorities highlights the current and future directions for probiotics in Japan (Japanese Regulatory Authority, personal communication): 1. Probiotics (lactic acid–producing bacteria) are used as medicines and can be used as foods without medicinal claims. 2. As foods, probiotics have no specific restrictions. However, fermented milk or lactic acid drinks are required to have a lower limit of lactic acid bacteria. 3. If probiotics are marketed as foods, efficacy claims are prohibited on the labeling. To make claims about efficacy, one must obtain special permission from the Ministry of Health and Welfare for the product to be considered FOSHU, for which substantiation of efficacy and safety is mandatory. 4. Good manufacturing practices are required for drugs but not for foods. On the basis of the Japanese experience, there are issues that the United States will need to address with regard to probiotics. Good manufacturing practices, including regulatory audits, should be required for probiotics. Testing should address stability and cell viability, which are important not only for shelflife determination but also for efficacy. Cell viability is determined during stability testing, and numbers of viable cells should be included on the label, reflecting the numbers at the time of consumption, not at the time of manufacture. Because probiotics exert their effects through the secretion of substances such as vitamins and bateriocins, viable-cell counts reflect this capacity. The source of the cell line is also important. It may affect how the strain implants in the luminal epithelial cells of the human intestinal tract, which can, in turn, influence the probiotic efficacy. Efficacy should be presented in scientific publications. Figure 1. Regulatory positioning and classifications of food and drugs in Japan. Adapted from [2], with permission from Elsevier. S74 • CID 2008:46 (Suppl 2) • Amagase To date, Japan has been the global market leader in probiotics. Although safety considerations remain a concern of the US medical and scientific communities, most probiotics sold today as FOSHU in Japan and as foods or dietary supplements in the United States and Europe have a long history of safe use. With more education about probiotics, in conjunction with new scientific findings and changing consumer demands and social attitudes, the US market, currently estimated at $700 million, is poised to expand [21]. Acknowledgments Supplement sponsorship. This article was published as part of a supplement entitled “Developing Probiotics as Foods and Drugs: Scientific and Regulatory Challenges,” sponsored by the Drug Information Association, the National Institutes of Health National Center for Complementary and Alternative Medicine (1R13AT003805-01 to Patricia L. Hibberd), the California Dairy Research Foundation, Chr. Hansen, the Dannon Company, General Mills, Institut Rosell, and Yakult International. Potential conflicts of interest. 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