- Email: [email protected]
Foods with function claims emerging from the framework of so-called health foods
CHAPTER
Foods with function claims emerging from the framework of so-called health foods
24
Hiroyoshi Moriyama1, Hideko Ikeda2, Debasis Bagchi3 1The
Japanese Institute for Health Food Standards, Bunkyo-ku, Tokyo, Japan; 2Biohealth Research Ltd., Tokyo, Japan; 3University of Houston College of Pharmacy, Houston, TX, VNI, Inc. Lederach, PA, United States
24.1 Introduction We previously provided a wide variety of laws (acts) that regulate foods or health foods (HF), foods and foods with health claims (FHC) such as Food With Specified Health Uses (FOSHU) and Food With Nutrient Function Claims (FNFC) [1]. Foods not permitted to claim functions are called so-called health foods (SCHF), which represents a considerable percentage of the health foods market. The equation HF = FHC + SCHF, where FHC = FOSHU + FNFC, implies that the presence of SCHF is becoming more ambiguously positioned, whereas FHC is clearly being defined. Introduction of the FOSHU system stimulated the HF market in Japan, which was significantly bolstered with the generation of consumer awareness for maintaining good health and well-being. The HF market was also supported by the mass media’s use of the magical “lifestyle-related diseases” around 2000 [1]. Most FOSHU products are designed to be consumed orally as drinks or beverages in polyethylene terephthalate (PET) or aluminum cans or bottles, which are accessible to consumers at nearby stores such as convenience stores (CV), drugstores (DS), and supermarkets. Evidently, the price points of such FOSHU products are higher than those of regular beverages and drinks available on shelves of CV and DS. For example, PET bottles of coffee beverages containing chlorogenic acids or green tea extract with catechin as the relative ingredient have labels with health claims such as “For those concerned with high blood glucose levels” or “Helps keep off body fat,” respectively, although their price point is approximately 1.5 times higher than for regular nonalcohol beverages and drinks. However, FOSHU has gradually lost its impact on the HF industry because of FOSHU’s limitations in health claims and benefits despite the time and cost to develop and obtain approval. Moreover, FOSHU products with similar health claims formulated with less expensive relative ingredients such as indigestible dextrin (“suppresses fat absorption“/“lowers blood triglyceride levels”) have become available at CV, DS, and other easily accessible places with less promotion. The foods with function claims (FFC) system thus emerged from SCHF within the framework of FHC in 2015 in an attempt to provide products with function claims different from those found in the FOSHU system. The website of the Consumer Affairs Agency (CAA) provides the basic concepts and guidelines of the FFC [2]. This chapter describes the requirements, information, and data for registering FFC products. We briefly discuss some of the challenges encountered by applicants or sellers. Although fresh agricultural products such as vegetables and fruits are part of the FFC system, here we deal with products that are not agricultural, because few agricultural products have been registered thus far. Nutraceutical and Functional Food Regulations in the United States and around the World. https://doi.org/10.1016/B978-0-12-816467-9.00024-1 Copyright © 2019 Elsevier Inc. All rights reserved.
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Chapter 24 Foods with function claims emerging from the framework
Table 24.1 Required foods with function claims (FFC) product registration items to be submitted to the Consumer Affairs Agency. Form no.
Description
Form (I) (II)/(II)–1 (III)–1 (III)–2 (III)–3 (IV) (V)–1 (V)–2 (V)–3 (V)–4 (V)–5 (VI)–1 (VI)–2 (VII)–1 (VII)–2 (VII)–3 Others required
Basic information/data associated with scientific evidence on FFC product intended to register for consumers Safety assessment sheet of intended FFC product Information related to manufacture and quality management Information related to fresh agricultural products (not discussed in this chapter) Information related to raw materials and analyses (qualitative and quantitative) Organization related to collecting information about health harms (hazards) Scientific evidence of function claim–related checklist Rationale not following RCT requirement Supplementary information related to scientific evidence supporting function claim for labeling Description related to function claim labeling Search results of databases Checklist of items related to package label Labeling contents/statements related to intended FFC product Basic information related to sellers or applicants Basic information related to FFC intended to register Description related to mechanism of action of intended FFC product Refer to Table 24.2
RCT, randomized controlled trial.
24.2 Foods with function claims system The FFC system was intended and introduced to benefit all stakeholders, particularly consumers, who could select function claim(s) products according to their needs. The FFC system was implemented on Apr. 1, 2015, according the Food Labeling Standards pursuant to the Food Labeling Act [2], with forms provided for fulfilling all documentation, as outlined in Table 24.1. The government thought that the system would potentially activate the HF market, ultimately leading to an expansion of the Japanese foods industry. The system to facilitate applicants (sellers or enterprises of any size) to switch SCHF to FFC by adopting the FFC product registration system, unlike the approval system of FOSHU, thus offered ample opportunities to register any FFC product that fulfilled what the CAA required within 60 days before the intended launch date, as a basic rule. There is a series of basic forms (attachments), from Form I to Form VII [3]. As of May 18, 2018, the total number of registered (notified) dossiers, set of the FFC documents, or FFC products, was 1308 (up to file no. C444), excluding withdrawn notifications [4].
24.3 So-called health foods to foods with function claims Basically, any edible foods, including agricultural products (e.g., soy bean sprout and citrus), are considered FFC products based on scientific evidence, with the focus on safety and efficacy substantiating function claims. Similar to FOSHU, relative ingredients should be qualitatively identifiable and
24.3 So-called health foods to foods with function claims
379
Table 24.2 Other forms required to be submitted to the Consumer Affairs Agency, if necessary. Form no.
Description
Form 1–1 1–2: list of attachments 2 3 (V)–6 (V)–7 (V)–8 (V)–9 (V)–10 (V)–11 (V)–12 (V)–13 (V)–14 (V)–15 (V)–16 Product sample
Submission form for registering FFC product List of attachments Submission form for change(s) in registered FFC product Submission form for retracting FFC product submitted or registered Literature search flowchart List of selected literature List of excluded literature List of nonreported literature List of reference literature Quality assessment of each paper (clinical trial) Quality assessment of each paper (observational study) Quality assessment of body of evidence Summary sheet (coherent SR) Summary sheet (metaanalysis) Assessment sheet related to results of SR and intended function claim(s) Package and label copy
FFC, foods with function claims; SR, systematic review.
quantifiable to ensure that the evidenced-based efficacious amount of the relative ingredient is formulated in any FFC finished product. A wide range of FFC products are available in the form of tablets, capsules, processed foods and beverages, and many other forms except for those only allowed in drugs. In accordance with the labeling system of FFC, it is required to provide consumers with appropriate information associated with launching FFC products, which should be a good source of the products so as not to mislead consumers, but to help them properly choose FFC products [3]. A noticeable advantage of FFC despite the non-approval system compared with FOSHU is that FFC permit sellers to make function claims that do not belong to any of the FOSHU categories, such as knee joint and cognitive health claims. The claims potentially create health benefits targeting the ever- growing elderly population.
24.3.1 Documentation Preparation of a set of documents (dossier) required by the CAA begins with collecting a significant volume of information, scientific data, and evidence [3,5–9]. The FFC registration system is open to all who are willing to sell FFC products on the HF market, taking advantage of function claims to direct the attention of potential consumers to purchase them, and to minimize misleading labeling and promotional statements. The FFC system differs from the FOSHU system in that those who have registered FFC products should take responsibility for the contents of the submitted documents. The other unique thing about the FFC system is that agricultural products such fruits and vegetables can be considered FFC products. Registration is made via a website using a series of attachments. For example, the required attachments (here called forms) consist of Forms numbered (I)–(VII), and other supplementary forms and documents, listed in Tables 24.1 and 24.2.
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Chapter 24 Foods with function claims emerging from the framework
24.3.1.1 Form (I) through (IV) It is mandatory to exhibit (1) the product’s name, (2) food classification, (3) relative (active) ingredient, (4) intended function claim(s), (5) applicant (e.g., seller, dealer, or manufacturer), (6) date of the documents prepared, and (7) target subjects (healthy, nonpregnant and nonlactating subjects). Checklist items regarding safety or key information related to safety measure should be reviewed carefully before submitting all required forms. Form (I) is an informative sheet designed for consumers that discloses available safety information and data and other required items about an FFC product intended for registration. Precautions (warnings) about ingestion and also manufacturing aspects need to be conveyed to consumers. Form (II) is primarily employed for a safety assessment. The safety of relative ingredient(s) has a pivotal role in the filing of FFC forms, whereas Form (II) includes a thorough evaluation of safety regarding the history of the use in the diet, a safety assessment using a literature search, and any appropriate unpublished data. Furthermore, in vitro and in vivo studies are required for relative ingredients to ensure that they are safe in the foods. The mechanism of action of the relative ingredient also needs to be elaborated, which can be estimated on the basis of in vitro and in vivo studies. The documentation should also discuss whether relative ingredients cause drug interactions and also between or among relative ingredients in the presence of more than two relative ingredients. In addition, the safety of an overdose clinical trial of Japanese healthy subjects is justified using the fivefold daily recommended dose of the relative ingredient(s) in a test product if the intake forms is tablets, capsules, etc, whereas for general or conventional processed foods, threefold is required. Such clinical trials follow overdose requirements for FOSHU products [3]. The production of FFC products is also under the control of various certified facilities, as mentioned subsequently. A safety profile sheet should be available for consumers to read and understand; therefore, the basic safety of the relative ingredient(s) should be written clearly and comprehensibly. Form (III) is associated with production and its quality management. Both concepts of Good Manufacturing Practice (GMP) and Hazard Analysis and Critical Control Point (HACCP) are considered in production. GMP involves manufacturers of dietary supplements in the form of tablets, capsules, sachets, mini drinks/beverages, etc., whereas HCAAP is more related to the production of general or processed food products such as sausages and packed boiled beans. In addition, International Organization for Standardization 22000 and Food Safety System Certification 22000 are applicable to production. In the form regarding raw material(s) and its relative ingredient(s), product specifications including the effective amount of relative ingredient(s) should be mentioned with a system to reject FFC products that are out of specification before distribution in the HF market. Form (III)–3 provides information related to raw material(s) and its analysis. The authorized analytical center name and assay method used to determine the relative ingredient(s) need to be declared, including descriptions of the qualitative and quantitative analyses. All required analyses of relative ingredients are performed in accordance with a recognized procedure manual, which is basic because any authorized third parties should be able to duplicate the analytical procedure. In case any health hazards (harms) occurs from ingesting FFC products that are on the market, prompt action should be taken against such health hazards in accordance with the customer risk management system, which applicants submitted when notified to sell the FFC products. In the FFC documentation, Form (IV) is an attachment that describes such a system. It also delivers detailed information regarding reported health harms. As a consequence, the compiled results should be provided to the CAA, following CAA guidelines.
24.3 So-called health foods to foods with function claims
381
24.3.1.2 Form (V): evidence check There are two distinct approaches to substantiate the function claim(s) of an FFC product. One is to perform a randomized controlled trial (RCT), preferably with Japanese subjects, or to conduct a systematic review (SR) of finished products with relative ingredients or the relative ingredient itself. If an RCT is used to support function claims based on significant study outcomes, a well-designed protocol is helpful; it fulfils requirements outlined in the guideline given subsequently. It is expected to be registered before the trial at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) to support scientific evidence for outcomes or claims, or at the International Clinical Trial Registry Platform (ICTRP) when the trial is conducted outside Japan. It should follow Consolidated Standards of Reporting Standards (CONSORT) 2010 [6] for guidelines directing the RCT for the FFC to show strong evidence. In brief, CONSORT 2010 items include: 1. title and abstract 2. introduction (background and objective) 3. methods that include trial design, participant, intervention, outcome, sample size, randomization, sequence generation, allocation concealment, implementation, blinding, and statistical method 4. results including participant flow, recruitment, baseline data, number analyzed, outcome and estimation, ancillary analysis, harm, discussion including limitations, generalizability, and interpretation 5. other information include registration, protocol, and funding There is a total of 29 items in the checklist.
24.3.1.3 Form (V) and randomized controlled trials If an RCT is adopted for FFC registration, results of the trial should be significant in supporting function claim(s) of the FFC product, and it follows as a FOSHU requirement (for example, a trial period of 12 weeks). If it deviates or differs from the requirement which the FOSHU or FFC establishes in designing an RCT protocol, an eligible rationale should be proposed using Form (V)–2 to explain why such a deviation or difference took place. Form (V)–3 is used as supplementary information related to scientific evidence to substantiate a function claim. Form (V)–4 is a crucial form that serves as explanatory information (scientific review) about the mechanism of a relative ingredient in the FFC product, proving the function claim statement on the label. The other requirements for a well-designed RCT are that: 1. The trial results should be published in a peer-reviewed journal, and the author(s) conflict of interest should be stated. It is highly recommended that review process be clear. Other associated matters to be clarified are sponsorship, funding, and organizational. 2. It is highly recommended to follow the checklist items in Format (V)–1. 3. A summary related to the RCT should be written simply so that consumers are able to understand it, minimizing technical jargon. The summary should include a title, an objective as explained in PICO (P = participant, I = intervention, C = comparison, and O = outcome), background, the method (experimental design, statistical methodology, etc.), primary results, and the quality of scientific evidence considering different sources of bias.
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Chapter 24 Foods with function claims emerging from the framework
24.3.1.4 Form (V) and systematic review The essence of FFC system is SR, which is not familiar to all stakeholders of the HF industry, except for a limited number of experts in statistics and related areas who practice it extensively in their studies. In addition, an SR differentiates FFC from FOSHU in terms of variation in claims. Basically, an SR of the literature is performed to rate the quality of evidence for use of a relative ingredient, in supporting function claims in an FFC system. Furthermore, an SR for FFC registration should be considered from the viewpoint of the totality of evidence. Implementation of SRs should preferable involve three reviewers with experience in assessing literature in both Japanese and English. In this section, we do not include an observational study such as a cohort study, because most previously registered FFC products are based on RCT studies. To prepare an SR report, Form (V)–4, which is about the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) checklist, composed of 27 items, is essential for evaluating the searched literature rigorously. In case any items cannot be included in the PRISMA checklist, Form (V)–3 is used as supplementary explanation/information related to scientific evidence to support the intended function, as previously remarked. To initiate and complete Form (V)–4, appropriate databases are selected, as well as keywords related to studies that result in outcomes to substantiate intended function claims. Such databases include Embase, MEDLINE, PubMed, Web of Science, Google Scholar, Nutrition and Food Sciences, the Cochrane Library, Clinical Trials.gov, the World Health Organization, Global Health Library, Western Pacific Region Index Medicus, JDreamII, the International Prospective Register of Systematic Review (PROSPERO), UMIN, and ICTRP. For the current system, CiNii, J-stage, and the Japan Medical Abstract Society should be included in the databases, because the literature might be published in Japanese journals. Also, hand searching might be required in case any databases are not feasible. Form (V)–5 (database search results sheet) is used to present the search formula, screening a number of literature citations referring to the relative ingredient coupled with search questions according to PICO. The form includes the date the search was conducted and those who participated in the search. Required items in the form are arranged in accordance with the databases and search formula. Form (V)–6 (document retrieval flowchart) is prepared using public databases that searched clinical trials and keywords for the relative ingredient. Document retrieval is performed in accordance with inclusion and exclusion criteria. A table with a list of studies excluded from the analysis is prepared, including the author, journal, title, and reasons for exclusion, along with a table listing studies included in the analysis. As a result of screening, if the number of acceptable literature citations is more than two, the eligible literature enables a metaanalysis to be conducted. If not, the quality evaluation of the primary and secondary outcomes measures should be performed against the remaining literature after the retrieval. Form (V)–7 summarizes the remaining literature, describing each selected literature citation with the authors, journal, title, study design, PICO, setting, characteristics of participants, placebo, analytical methodologies (ITT [intent to treat], full analysis set, etc.), primary outcome, secondary outcome, harm, and presence of peer-reviewed procedures. Format (V)–8 presents a list of the excluded literature with reason(s) for exclusion, in which each literature citation is identified by author(s), journal, and title. Form (V)–9 shows a list of the unpublished literature using a research registry database such as UMIN-CTR, ICTRP, PROSPERO, and Clinical Trials.gov. Format (V)–10 shows a list of references with the author(s), title, and journals/magazines, etc. Form (V)–11 is used to quality an evaluation of each literature citation (clinical trials). Each item is analyzed with three grades of risk: high (–2); medium/uncertain (–1); and low (0). Bias risk consists of a
24.4 Impacts on stakeholders
383
series of biases such as (1) selection bias (randomization and allocation concealment), (2) blinding bias (participant and clinical staff and data analysts), (3) attrition bias (incomplete outcome data, ITT analysis), (4) selective reporting, and (5) other. In the evaluation table, indirectness (differences in population, differences in intervention, indirect comparison, surrogate outcome, and summary), value before and after each group (control in average of before, control in average of after, P value, test group in average of before, test group in average of after, P value, test versus control in average, P value as in order of tabulation) are indicated. Form (V)–12 is related to observational studies, which are not discussed in this chapter. Form (V)–13 summarizes the body of evidence, including (1) the end point, (2) the study design (RCT), (3) bias risk, (4) indirectness, (5) imprecision, (6) inconsistency, (7) others (publication bias), (8) test versus control (average), and (9) the strength of evidence. Bias, indirectness, imprecision, inconsistency, and others are evaluated with three grades: high (–2), middle/double (–1), and low (0)”, except the body of evidence is evaluated from strong (A) regarding the strength of the evidence. Furthermore, the strength of the evidence is evaluated with four grades: high (A), moderate (B), low (C), and very low (D). Form (V)–14 is a summary sheet of a qualitative SR. Form (V)–15 is a summary sheet for a metaanalysis, which is not discussed here. Form (V)–16 is an assessment sheet related to the results of the SR; they determine the text of the product claim statement(s) to justify the FFC product label.
24.3.1.5 Other forms Other attachment requirements are: Form (VI)–1 is items required for function claims substantiated by scientific evidence. Form(VI)–2 is proposed function claims, daily dose, content of the relative ingredient per day, storage, administration, and precautions. Form (VII)–1 provides basic information related to the seller or applicants, including the company name, office address, name(s) of contract manufacturer(s), customer service telephone, and website for inquiries. Form (VII)–2 includes the product name, product classification (processed or capsule/tablet), and the statement about the consumer being a healthy adult except if pregnant or nursing or with a medical condition. Form (VII)–3 describes the mechanistic action of the relative ingredient. Data derived in vitro and in vivo are referenced to elaborate the mechanism.
24.4 Impacts on stakeholders Stakeholders who might have found value (benefit) in the new system might be those in primary food, beverage, and other industries such as toiletry and cosmetics enterprises, and potentially pharmaceuticals. FFC product sellers questioned whether consumers could acquire benefits from FFC products, while the CAA basically established the system for consumers to be able to make a proper choice of products for their health benefits. However, it is also important to be aware of the availability of FFC products in various distribution channels because of the efforts of sellers who should attempt their best to promote them and the government who should support FFC sellers by effectively controlling acts (regulations) regarding HF. The fate of the system in general depends on sellers to promote FFC properly and sincerely in the marketplace, because all responsibility after FFC products are launched belong to the sellers.
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Chapter 24 Foods with function claims emerging from the framework
In the system, dosage forms benefit GMP-certified contract manufacturers because hard and soft capsules, tablets, and other forms are strongly recommended for such FFC products under GMP. On the other hand, small to medium-size manufacturers may be challenged to maintain consistent FFC product quality because their analytical, essential equipment and well-experienced human resources are inadequate for fulfilling FFC despite being GMP certified. Obviously, the CAA inspects whether FFC products are manufactured properly as formulated with efficacious amounts of specified relative ingredients that should substantiate function claim(s). Concurrently, the CAA monitors violations of food associated with multiple regulations, primarily acts against unjustifiable premiums and misleading representation, and the health promotion and food sanitation acts, directing attention to labeling and promotional statements.
24.5 Potential challenges The FFC system became effective on Apr. 1, 2015 as part of Prime Minister Abe’s economic strategies to stimulate the Japanese economy, especially the health food industry at the beginning. Several years have passed since the system was implemented. During those years, many FFC products were registered, and a limited number of registered FFC were actually introduced into the HF marketplace. Small and medium-size HF enterprises (sellers) seemed to be perplexed by the system and found the FFC documentation difficult, because all data provided in the submitted forms are substantiated by applicants. In addition, some of the FFC requirements are similar to those of FOSHU; for example, overdose clinical trials are essential to ensuring safety of finished FFC products, as mentioned earlier. Conducting such trials often causes financial burden onto small to medium enterprises. It is expected that some alternative measures will be introduced in future so that such trials against healthy subjects may be exempted. Many HF companies are thus obliged to sell SCHF products, which according to the CAA should be strictly regulated so as not to mislead consumers. Consumers perceive the current economic situation to be less optimistic than what the government’s statistical data report, and to some extent the gap affects the nutritional sufficiency of Japanese people, particularly children and elderly people. Moreover, the Japanese medical reimbursement system has gradually stopped benefiting some of population groups in Japan. Under such circumstances, it should be questioned whether FFC are indeed safe and effective as FFC sellers state for benefits of consumers who pay extra money for FFC products.
24.6 Conclusion This chapter described a health claim system that was developed from SCHF on Apr. 1, 2015. FHC now consists of FOSHU, FNFC, and FFC; however, SCHF continues to be undefined. Whether or not the new category has brought respective health and revenue benefits to consumers and enterprises, the system has been continuously reassessed by the government. Therefore, it is hoped that the system will provide health and profits to both stakeholders. Nevertheless, the CAA should demonstrate more support and opportunities for any FFC applicants, facilitating them to capitalize on the system and reducing the number of SCHF products for the betterment of consumers. Furthermore, the CAA should periodically monitor whether FFC would be appropriate to deliver health and function benefits to users.
References
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References [1] Ohama H, Ikeda H, Moriyama H. Health foods and foods with health claims in Japan. In: Bagchi D, editor. Nutraceutical and functional regulations in the United States and around the World. USA: Elsevier; 2014. p. 257–99. [Chapter 16]. [2] Guidelines on notifications of foods with function claims consumer affairs agency. 2018. [in Japanese]. http:// www.caa.go.jp/foods/pdf/150330_guideline.pdf. [3] Revised FFC guideline for the CAA. 2018. [in Japanese]. http://www.caa.go.jp/policies/policy/food_labeling/ foods_with_function_claims/pdf/food_with_function_clains_180328_0001.pdf. [4] Register FFC search. 2018. [in Japanese]. https://www.fld.caa.go.jp/caaks/cssc01/. [5] CONSORT2010 statement. 2018. http://www.consort-statement.org/. [6] PRISMA checklist. 2018. http://www.caa.go.jp/policies/policy/food_labeling/about_foods_with_function_ claims/pdf/about_food_with_function_report_180416_0002.pdf. [7] Kojimahara N, Nakayama T, Morizane T, Yamaguchi N, Yoshida M, editors. Minds manual for guideline development 2017. Tokyo: Japan Council for Quality Health Care; 2017. [in Japanese]. [8] Taku K, Yoshida Y, Omori T. Practice guideline of evidence-based medicine: preprreded Reporting Items for systematic reviews and meta-analyses (the PRIMSA statement). Hoho Kanri J Inf Proc Manag 2011;54:254– 66. [abstract in English]. [9] GRDE. 2018. http://www.gradeworkinggroup.org/.
Foods with function claims emerging from the framework of so-called health foods
24
Hiroyoshi Moriyama1, Hideko Ikeda2, Debasis Bagchi3 1The
Japanese Institute for Health Food Standards, Bunkyo-ku, Tokyo, Japan; 2Biohealth Research Ltd., Tokyo, Japan; 3University of Houston College of Pharmacy, Houston, TX, VNI, Inc. Lederach, PA, United States
24.1 Introduction We previously provided a wide variety of laws (acts) that regulate foods or health foods (HF), foods and foods with health claims (FHC) such as Food With Specified Health Uses (FOSHU) and Food With Nutrient Function Claims (FNFC) [1]. Foods not permitted to claim functions are called so-called health foods (SCHF), which represents a considerable percentage of the health foods market. The equation HF = FHC + SCHF, where FHC = FOSHU + FNFC, implies that the presence of SCHF is becoming more ambiguously positioned, whereas FHC is clearly being defined. Introduction of the FOSHU system stimulated the HF market in Japan, which was significantly bolstered with the generation of consumer awareness for maintaining good health and well-being. The HF market was also supported by the mass media’s use of the magical “lifestyle-related diseases” around 2000 [1]. Most FOSHU products are designed to be consumed orally as drinks or beverages in polyethylene terephthalate (PET) or aluminum cans or bottles, which are accessible to consumers at nearby stores such as convenience stores (CV), drugstores (DS), and supermarkets. Evidently, the price points of such FOSHU products are higher than those of regular beverages and drinks available on shelves of CV and DS. For example, PET bottles of coffee beverages containing chlorogenic acids or green tea extract with catechin as the relative ingredient have labels with health claims such as “For those concerned with high blood glucose levels” or “Helps keep off body fat,” respectively, although their price point is approximately 1.5 times higher than for regular nonalcohol beverages and drinks. However, FOSHU has gradually lost its impact on the HF industry because of FOSHU’s limitations in health claims and benefits despite the time and cost to develop and obtain approval. Moreover, FOSHU products with similar health claims formulated with less expensive relative ingredients such as indigestible dextrin (“suppresses fat absorption“/“lowers blood triglyceride levels”) have become available at CV, DS, and other easily accessible places with less promotion. The foods with function claims (FFC) system thus emerged from SCHF within the framework of FHC in 2015 in an attempt to provide products with function claims different from those found in the FOSHU system. The website of the Consumer Affairs Agency (CAA) provides the basic concepts and guidelines of the FFC [2]. This chapter describes the requirements, information, and data for registering FFC products. We briefly discuss some of the challenges encountered by applicants or sellers. Although fresh agricultural products such as vegetables and fruits are part of the FFC system, here we deal with products that are not agricultural, because few agricultural products have been registered thus far. Nutraceutical and Functional Food Regulations in the United States and around the World. https://doi.org/10.1016/B978-0-12-816467-9.00024-1 Copyright © 2019 Elsevier Inc. All rights reserved.
377
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Chapter 24 Foods with function claims emerging from the framework
Table 24.1 Required foods with function claims (FFC) product registration items to be submitted to the Consumer Affairs Agency. Form no.
Description
Form (I) (II)/(II)–1 (III)–1 (III)–2 (III)–3 (IV) (V)–1 (V)–2 (V)–3 (V)–4 (V)–5 (VI)–1 (VI)–2 (VII)–1 (VII)–2 (VII)–3 Others required
Basic information/data associated with scientific evidence on FFC product intended to register for consumers Safety assessment sheet of intended FFC product Information related to manufacture and quality management Information related to fresh agricultural products (not discussed in this chapter) Information related to raw materials and analyses (qualitative and quantitative) Organization related to collecting information about health harms (hazards) Scientific evidence of function claim–related checklist Rationale not following RCT requirement Supplementary information related to scientific evidence supporting function claim for labeling Description related to function claim labeling Search results of databases Checklist of items related to package label Labeling contents/statements related to intended FFC product Basic information related to sellers or applicants Basic information related to FFC intended to register Description related to mechanism of action of intended FFC product Refer to Table 24.2
RCT, randomized controlled trial.
24.2 Foods with function claims system The FFC system was intended and introduced to benefit all stakeholders, particularly consumers, who could select function claim(s) products according to their needs. The FFC system was implemented on Apr. 1, 2015, according the Food Labeling Standards pursuant to the Food Labeling Act [2], with forms provided for fulfilling all documentation, as outlined in Table 24.1. The government thought that the system would potentially activate the HF market, ultimately leading to an expansion of the Japanese foods industry. The system to facilitate applicants (sellers or enterprises of any size) to switch SCHF to FFC by adopting the FFC product registration system, unlike the approval system of FOSHU, thus offered ample opportunities to register any FFC product that fulfilled what the CAA required within 60 days before the intended launch date, as a basic rule. There is a series of basic forms (attachments), from Form I to Form VII [3]. As of May 18, 2018, the total number of registered (notified) dossiers, set of the FFC documents, or FFC products, was 1308 (up to file no. C444), excluding withdrawn notifications [4].
24.3 So-called health foods to foods with function claims Basically, any edible foods, including agricultural products (e.g., soy bean sprout and citrus), are considered FFC products based on scientific evidence, with the focus on safety and efficacy substantiating function claims. Similar to FOSHU, relative ingredients should be qualitatively identifiable and
24.3 So-called health foods to foods with function claims
379
Table 24.2 Other forms required to be submitted to the Consumer Affairs Agency, if necessary. Form no.
Description
Form 1–1 1–2: list of attachments 2 3 (V)–6 (V)–7 (V)–8 (V)–9 (V)–10 (V)–11 (V)–12 (V)–13 (V)–14 (V)–15 (V)–16 Product sample
Submission form for registering FFC product List of attachments Submission form for change(s) in registered FFC product Submission form for retracting FFC product submitted or registered Literature search flowchart List of selected literature List of excluded literature List of nonreported literature List of reference literature Quality assessment of each paper (clinical trial) Quality assessment of each paper (observational study) Quality assessment of body of evidence Summary sheet (coherent SR) Summary sheet (metaanalysis) Assessment sheet related to results of SR and intended function claim(s) Package and label copy
FFC, foods with function claims; SR, systematic review.
quantifiable to ensure that the evidenced-based efficacious amount of the relative ingredient is formulated in any FFC finished product. A wide range of FFC products are available in the form of tablets, capsules, processed foods and beverages, and many other forms except for those only allowed in drugs. In accordance with the labeling system of FFC, it is required to provide consumers with appropriate information associated with launching FFC products, which should be a good source of the products so as not to mislead consumers, but to help them properly choose FFC products [3]. A noticeable advantage of FFC despite the non-approval system compared with FOSHU is that FFC permit sellers to make function claims that do not belong to any of the FOSHU categories, such as knee joint and cognitive health claims. The claims potentially create health benefits targeting the ever- growing elderly population.
24.3.1 Documentation Preparation of a set of documents (dossier) required by the CAA begins with collecting a significant volume of information, scientific data, and evidence [3,5–9]. The FFC registration system is open to all who are willing to sell FFC products on the HF market, taking advantage of function claims to direct the attention of potential consumers to purchase them, and to minimize misleading labeling and promotional statements. The FFC system differs from the FOSHU system in that those who have registered FFC products should take responsibility for the contents of the submitted documents. The other unique thing about the FFC system is that agricultural products such fruits and vegetables can be considered FFC products. Registration is made via a website using a series of attachments. For example, the required attachments (here called forms) consist of Forms numbered (I)–(VII), and other supplementary forms and documents, listed in Tables 24.1 and 24.2.
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24.3.1.1 Form (I) through (IV) It is mandatory to exhibit (1) the product’s name, (2) food classification, (3) relative (active) ingredient, (4) intended function claim(s), (5) applicant (e.g., seller, dealer, or manufacturer), (6) date of the documents prepared, and (7) target subjects (healthy, nonpregnant and nonlactating subjects). Checklist items regarding safety or key information related to safety measure should be reviewed carefully before submitting all required forms. Form (I) is an informative sheet designed for consumers that discloses available safety information and data and other required items about an FFC product intended for registration. Precautions (warnings) about ingestion and also manufacturing aspects need to be conveyed to consumers. Form (II) is primarily employed for a safety assessment. The safety of relative ingredient(s) has a pivotal role in the filing of FFC forms, whereas Form (II) includes a thorough evaluation of safety regarding the history of the use in the diet, a safety assessment using a literature search, and any appropriate unpublished data. Furthermore, in vitro and in vivo studies are required for relative ingredients to ensure that they are safe in the foods. The mechanism of action of the relative ingredient also needs to be elaborated, which can be estimated on the basis of in vitro and in vivo studies. The documentation should also discuss whether relative ingredients cause drug interactions and also between or among relative ingredients in the presence of more than two relative ingredients. In addition, the safety of an overdose clinical trial of Japanese healthy subjects is justified using the fivefold daily recommended dose of the relative ingredient(s) in a test product if the intake forms is tablets, capsules, etc, whereas for general or conventional processed foods, threefold is required. Such clinical trials follow overdose requirements for FOSHU products [3]. The production of FFC products is also under the control of various certified facilities, as mentioned subsequently. A safety profile sheet should be available for consumers to read and understand; therefore, the basic safety of the relative ingredient(s) should be written clearly and comprehensibly. Form (III) is associated with production and its quality management. Both concepts of Good Manufacturing Practice (GMP) and Hazard Analysis and Critical Control Point (HACCP) are considered in production. GMP involves manufacturers of dietary supplements in the form of tablets, capsules, sachets, mini drinks/beverages, etc., whereas HCAAP is more related to the production of general or processed food products such as sausages and packed boiled beans. In addition, International Organization for Standardization 22000 and Food Safety System Certification 22000 are applicable to production. In the form regarding raw material(s) and its relative ingredient(s), product specifications including the effective amount of relative ingredient(s) should be mentioned with a system to reject FFC products that are out of specification before distribution in the HF market. Form (III)–3 provides information related to raw material(s) and its analysis. The authorized analytical center name and assay method used to determine the relative ingredient(s) need to be declared, including descriptions of the qualitative and quantitative analyses. All required analyses of relative ingredients are performed in accordance with a recognized procedure manual, which is basic because any authorized third parties should be able to duplicate the analytical procedure. In case any health hazards (harms) occurs from ingesting FFC products that are on the market, prompt action should be taken against such health hazards in accordance with the customer risk management system, which applicants submitted when notified to sell the FFC products. In the FFC documentation, Form (IV) is an attachment that describes such a system. It also delivers detailed information regarding reported health harms. As a consequence, the compiled results should be provided to the CAA, following CAA guidelines.
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24.3.1.2 Form (V): evidence check There are two distinct approaches to substantiate the function claim(s) of an FFC product. One is to perform a randomized controlled trial (RCT), preferably with Japanese subjects, or to conduct a systematic review (SR) of finished products with relative ingredients or the relative ingredient itself. If an RCT is used to support function claims based on significant study outcomes, a well-designed protocol is helpful; it fulfils requirements outlined in the guideline given subsequently. It is expected to be registered before the trial at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) to support scientific evidence for outcomes or claims, or at the International Clinical Trial Registry Platform (ICTRP) when the trial is conducted outside Japan. It should follow Consolidated Standards of Reporting Standards (CONSORT) 2010 [6] for guidelines directing the RCT for the FFC to show strong evidence. In brief, CONSORT 2010 items include: 1. title and abstract 2. introduction (background and objective) 3. methods that include trial design, participant, intervention, outcome, sample size, randomization, sequence generation, allocation concealment, implementation, blinding, and statistical method 4. results including participant flow, recruitment, baseline data, number analyzed, outcome and estimation, ancillary analysis, harm, discussion including limitations, generalizability, and interpretation 5. other information include registration, protocol, and funding There is a total of 29 items in the checklist.
24.3.1.3 Form (V) and randomized controlled trials If an RCT is adopted for FFC registration, results of the trial should be significant in supporting function claim(s) of the FFC product, and it follows as a FOSHU requirement (for example, a trial period of 12 weeks). If it deviates or differs from the requirement which the FOSHU or FFC establishes in designing an RCT protocol, an eligible rationale should be proposed using Form (V)–2 to explain why such a deviation or difference took place. Form (V)–3 is used as supplementary information related to scientific evidence to substantiate a function claim. Form (V)–4 is a crucial form that serves as explanatory information (scientific review) about the mechanism of a relative ingredient in the FFC product, proving the function claim statement on the label. The other requirements for a well-designed RCT are that: 1. The trial results should be published in a peer-reviewed journal, and the author(s) conflict of interest should be stated. It is highly recommended that review process be clear. Other associated matters to be clarified are sponsorship, funding, and organizational. 2. It is highly recommended to follow the checklist items in Format (V)–1. 3. A summary related to the RCT should be written simply so that consumers are able to understand it, minimizing technical jargon. The summary should include a title, an objective as explained in PICO (P = participant, I = intervention, C = comparison, and O = outcome), background, the method (experimental design, statistical methodology, etc.), primary results, and the quality of scientific evidence considering different sources of bias.
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24.3.1.4 Form (V) and systematic review The essence of FFC system is SR, which is not familiar to all stakeholders of the HF industry, except for a limited number of experts in statistics and related areas who practice it extensively in their studies. In addition, an SR differentiates FFC from FOSHU in terms of variation in claims. Basically, an SR of the literature is performed to rate the quality of evidence for use of a relative ingredient, in supporting function claims in an FFC system. Furthermore, an SR for FFC registration should be considered from the viewpoint of the totality of evidence. Implementation of SRs should preferable involve three reviewers with experience in assessing literature in both Japanese and English. In this section, we do not include an observational study such as a cohort study, because most previously registered FFC products are based on RCT studies. To prepare an SR report, Form (V)–4, which is about the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) checklist, composed of 27 items, is essential for evaluating the searched literature rigorously. In case any items cannot be included in the PRISMA checklist, Form (V)–3 is used as supplementary explanation/information related to scientific evidence to support the intended function, as previously remarked. To initiate and complete Form (V)–4, appropriate databases are selected, as well as keywords related to studies that result in outcomes to substantiate intended function claims. Such databases include Embase, MEDLINE, PubMed, Web of Science, Google Scholar, Nutrition and Food Sciences, the Cochrane Library, Clinical Trials.gov, the World Health Organization, Global Health Library, Western Pacific Region Index Medicus, JDreamII, the International Prospective Register of Systematic Review (PROSPERO), UMIN, and ICTRP. For the current system, CiNii, J-stage, and the Japan Medical Abstract Society should be included in the databases, because the literature might be published in Japanese journals. Also, hand searching might be required in case any databases are not feasible. Form (V)–5 (database search results sheet) is used to present the search formula, screening a number of literature citations referring to the relative ingredient coupled with search questions according to PICO. The form includes the date the search was conducted and those who participated in the search. Required items in the form are arranged in accordance with the databases and search formula. Form (V)–6 (document retrieval flowchart) is prepared using public databases that searched clinical trials and keywords for the relative ingredient. Document retrieval is performed in accordance with inclusion and exclusion criteria. A table with a list of studies excluded from the analysis is prepared, including the author, journal, title, and reasons for exclusion, along with a table listing studies included in the analysis. As a result of screening, if the number of acceptable literature citations is more than two, the eligible literature enables a metaanalysis to be conducted. If not, the quality evaluation of the primary and secondary outcomes measures should be performed against the remaining literature after the retrieval. Form (V)–7 summarizes the remaining literature, describing each selected literature citation with the authors, journal, title, study design, PICO, setting, characteristics of participants, placebo, analytical methodologies (ITT [intent to treat], full analysis set, etc.), primary outcome, secondary outcome, harm, and presence of peer-reviewed procedures. Format (V)–8 presents a list of the excluded literature with reason(s) for exclusion, in which each literature citation is identified by author(s), journal, and title. Form (V)–9 shows a list of the unpublished literature using a research registry database such as UMIN-CTR, ICTRP, PROSPERO, and Clinical Trials.gov. Format (V)–10 shows a list of references with the author(s), title, and journals/magazines, etc. Form (V)–11 is used to quality an evaluation of each literature citation (clinical trials). Each item is analyzed with three grades of risk: high (–2); medium/uncertain (–1); and low (0). Bias risk consists of a
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series of biases such as (1) selection bias (randomization and allocation concealment), (2) blinding bias (participant and clinical staff and data analysts), (3) attrition bias (incomplete outcome data, ITT analysis), (4) selective reporting, and (5) other. In the evaluation table, indirectness (differences in population, differences in intervention, indirect comparison, surrogate outcome, and summary), value before and after each group (control in average of before, control in average of after, P value, test group in average of before, test group in average of after, P value, test versus control in average, P value as in order of tabulation) are indicated. Form (V)–12 is related to observational studies, which are not discussed in this chapter. Form (V)–13 summarizes the body of evidence, including (1) the end point, (2) the study design (RCT), (3) bias risk, (4) indirectness, (5) imprecision, (6) inconsistency, (7) others (publication bias), (8) test versus control (average), and (9) the strength of evidence. Bias, indirectness, imprecision, inconsistency, and others are evaluated with three grades: high (–2), middle/double (–1), and low (0)”, except the body of evidence is evaluated from strong (A) regarding the strength of the evidence. Furthermore, the strength of the evidence is evaluated with four grades: high (A), moderate (B), low (C), and very low (D). Form (V)–14 is a summary sheet of a qualitative SR. Form (V)–15 is a summary sheet for a metaanalysis, which is not discussed here. Form (V)–16 is an assessment sheet related to the results of the SR; they determine the text of the product claim statement(s) to justify the FFC product label.
24.3.1.5 Other forms Other attachment requirements are: Form (VI)–1 is items required for function claims substantiated by scientific evidence. Form(VI)–2 is proposed function claims, daily dose, content of the relative ingredient per day, storage, administration, and precautions. Form (VII)–1 provides basic information related to the seller or applicants, including the company name, office address, name(s) of contract manufacturer(s), customer service telephone, and website for inquiries. Form (VII)–2 includes the product name, product classification (processed or capsule/tablet), and the statement about the consumer being a healthy adult except if pregnant or nursing or with a medical condition. Form (VII)–3 describes the mechanistic action of the relative ingredient. Data derived in vitro and in vivo are referenced to elaborate the mechanism.
24.4 Impacts on stakeholders Stakeholders who might have found value (benefit) in the new system might be those in primary food, beverage, and other industries such as toiletry and cosmetics enterprises, and potentially pharmaceuticals. FFC product sellers questioned whether consumers could acquire benefits from FFC products, while the CAA basically established the system for consumers to be able to make a proper choice of products for their health benefits. However, it is also important to be aware of the availability of FFC products in various distribution channels because of the efforts of sellers who should attempt their best to promote them and the government who should support FFC sellers by effectively controlling acts (regulations) regarding HF. The fate of the system in general depends on sellers to promote FFC properly and sincerely in the marketplace, because all responsibility after FFC products are launched belong to the sellers.
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In the system, dosage forms benefit GMP-certified contract manufacturers because hard and soft capsules, tablets, and other forms are strongly recommended for such FFC products under GMP. On the other hand, small to medium-size manufacturers may be challenged to maintain consistent FFC product quality because their analytical, essential equipment and well-experienced human resources are inadequate for fulfilling FFC despite being GMP certified. Obviously, the CAA inspects whether FFC products are manufactured properly as formulated with efficacious amounts of specified relative ingredients that should substantiate function claim(s). Concurrently, the CAA monitors violations of food associated with multiple regulations, primarily acts against unjustifiable premiums and misleading representation, and the health promotion and food sanitation acts, directing attention to labeling and promotional statements.
24.5 Potential challenges The FFC system became effective on Apr. 1, 2015 as part of Prime Minister Abe’s economic strategies to stimulate the Japanese economy, especially the health food industry at the beginning. Several years have passed since the system was implemented. During those years, many FFC products were registered, and a limited number of registered FFC were actually introduced into the HF marketplace. Small and medium-size HF enterprises (sellers) seemed to be perplexed by the system and found the FFC documentation difficult, because all data provided in the submitted forms are substantiated by applicants. In addition, some of the FFC requirements are similar to those of FOSHU; for example, overdose clinical trials are essential to ensuring safety of finished FFC products, as mentioned earlier. Conducting such trials often causes financial burden onto small to medium enterprises. It is expected that some alternative measures will be introduced in future so that such trials against healthy subjects may be exempted. Many HF companies are thus obliged to sell SCHF products, which according to the CAA should be strictly regulated so as not to mislead consumers. Consumers perceive the current economic situation to be less optimistic than what the government’s statistical data report, and to some extent the gap affects the nutritional sufficiency of Japanese people, particularly children and elderly people. Moreover, the Japanese medical reimbursement system has gradually stopped benefiting some of population groups in Japan. Under such circumstances, it should be questioned whether FFC are indeed safe and effective as FFC sellers state for benefits of consumers who pay extra money for FFC products.
24.6 Conclusion This chapter described a health claim system that was developed from SCHF on Apr. 1, 2015. FHC now consists of FOSHU, FNFC, and FFC; however, SCHF continues to be undefined. Whether or not the new category has brought respective health and revenue benefits to consumers and enterprises, the system has been continuously reassessed by the government. Therefore, it is hoped that the system will provide health and profits to both stakeholders. Nevertheless, the CAA should demonstrate more support and opportunities for any FFC applicants, facilitating them to capitalize on the system and reducing the number of SCHF products for the betterment of consumers. Furthermore, the CAA should periodically monitor whether FFC would be appropriate to deliver health and function benefits to users.
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