SCIENTIFIC OPINION. Efalex and concentration

Transcription

1 The EFSA Journal (2008) 897, 1-10 SCIENTIFIC OPINION Efalex and concentration Scientific substantiation of a health claim related to Efalex and concentration pursuant to Article14 of Regulation (EC) No 1924/ Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies (Question No EFSA-Q ) Adopted on 4 December 2008 PANEL MEMBERS Jean-Louis Bresson, Albert Flynn, Marina Heinonen, Karin Hulshof, Hannu Korhonen, Pagona Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Andreu Palou, Hildegard Przyrembel, Seppo Salminen, Sean (J.J.) Strain, Stephan Strobel, Inge Tetens, Henk van den Berg, Hendrik van Loveren and Hans Verhagen. SUMMARY Following an application from Efamol Ltd. submitted pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of the United Kingdom, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver an opinion on the scientific substantiation of a health claim related to Efalex and concentration. The scope of the application was proposed to fall under a health claim referring to children s development and health. The food for which the claim made is Efalex products, which contain a combination of the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the n-6 PUFAs gamma-linolenic acid (GLA) and arachidonic acid (ARA). The Panel notes that the complete fatty acid spectra of these products are not reported. The Panel considers that the food for which the claim is made (i.e., Efalex products) is sufficiently characterised regarding the content of DHA, EPA, GLA and ARA. The claimed effect is helps maintain concentration. The target population is children between 2 and 18 years of age. The Panel considers that promoting concentration (interpreted as attention) is beneficial to children s development and health. The applicant identified a total of 56 publications as being pertinent to the health claim. These publications included 33 studies in humans (7 randomised controlled trials (RCTs), 5 quasi 1 For citation purposes: Scientific Opinion of the Panel on Dietetic Products, Nutrition and Allergies on a request from Efamol Ltd. on the scientific substantiation of a health claim related to Efalex and concentration. The EFSA Journal (2008) 897, 1-10 European Food Safety Authority, 2008

2 experimental studies, 14 observational studies), 6 review publications, and 23 non-human studies (21 animal studies, two in vitro studies). Five of the RCTs and two of the one-arm (quasi experimental) studies presented were conducted with intervention foods that differed from the PUFA combination present in Efalex products. The Panel considers that these studies are not suitable sources of data to substantiate the claimed effect. Two RCTs on the effects of Efalex products have been presented. In the first placebocontrolled double-blind study, a range of behavioural and learning problems associated with attention deficit hyperactivity disorder (ADHD) was assessed in children who received capsules to reach a daily dosage of g EPA, g DHA, g GLA, g linoleic acid (LA) and g ARA or in children who received control capsules containing olive oil for 12 weeks. The children, aged 8-12 years, who had learning difficulties, coordination disorder and also exhibited ADHD-like features, were assessed using the Conners Parents Rating Scale (CPRS). The endpoints which showed significant improvement in the active treatment group compared with placebo were 2 out of 7 CPRS subscales (cognitive problems, anxious/shy) and 1 out of 7 CPRS global scales (Conners Index). In the second placebocontrolled double-blind study, a range of behavioural and learning problems associated with ADHD was assessed in children who received eight capsules per day corresponding to daily dosages of g DHA, g EPA, g ARA and g GLA, or in children who received control capsules containing olive oil for 4 months. The children were accepted into the study after parents confirmation of a clinical diagnosis of ADHD. Several tests and subscales were administered at baseline and after 4 months. PUFA supplementation led to a significant improvement in behaviour over placebo of only 2 out of 16 outcome measures that were used. The Panel notes that the small sample size, the relatively low number of significant endpoints compared to the total tested, the small size of the effects, the uncertain relevance of these tests to the claimed effect, and the recruitment of a clinical sample of children with learning difficulties who exhibited ADHD-like features limit the conclusions that can be drawn from these studies in relation to the health claim under evaluation. Two one arm open studies on the effects of Efalex products have been presented. The Panel notes that the lack of appropriate controls and the small sample sizes limit the conclusions that can be drawn from these one-arm studies in relation to the health claim under evaluation. One study conducted with Efalex was only presented in summary form. Owing to the limited information available, the Panel cannot draw a conclusion on that study. On the basis of the data presented, the Panel concludes that a cause and effect relationship has not been established between the consumption of Efalex products, a combination of the n-3 PUFAs EPA and DHA and the n-6 PUFAs GLA and ARA, and the maintenance of concentration (interpreted as attention) in healthy children between 2 and 18 years of age. Key words: Efalex, polyunsaturated fatty acids, eicosapentaenoic acid, docosahexaenoic acid, gamma-linolenic acid, arachidonic acid, concentration, children. The EFSA Journal (2008) 897, 2-10

3 TABLE OF CONTENTS Panel Members...1 Summary...1 Table of Contents...3 Background...4 Terms of reference...4 EFSA Disclaimer...4 Acknowledgements Information provided by the applicant Food/constituent as stated by the applicant Health relationship as claimed by the applicant Wording of the health claim as proposed by the applicant Specific conditions of use as proposed by the applicant Assessment Characterisation of the food/constituent Relevance of the claimed effect to human health Scientific substantiation of the claimed effect...7 Conclusions...8 Documentation provided to EFSA...9 References...9 Glossary / Abbreviations...10 The EFSA Journal (2008) 897, 3-10

4 BACKGROUND Regulation (EC) No 1924/ harmonises the provisions that relate to nutrition and health claims and establishes rules governing the Community authorisation of health claims made on foods. As a rule, health claims are prohibited unless they comply with the general and specific requirements of that Regulation and are authorised in accordance with this Regulation and included in the lists of authorised claims provided for in Articles 13 and 14 thereof. In particular, Articles 14 to 17 of that Regulation lay down provisions for the authorisation and subsequent inclusion of reduction of disease risk claims and claims referring to children s development and health in a Community list of permitted claims. According to Article 15 of that Regulation, an application for authorisation shall be submitted by the applicant to the national competent authority of a Member State, who will make the application and any supplementary information supplied by the applicant available to European Food Safety Authority (EFSA). Steps taken by EFSA: The application was received on 11/02/2008. The scope of the application was proposed to fall under a health claim referring to children s development and health. During the check for completeness 3 of the application, the applicant was requested to provide missing information on 03/03/2008 and on 15/05/2008. The applicant provided the missing information on 05/05/2008 and on 23/08/2008. The scientific evaluation procedure started on 15/09/2008. During the meeting on 04/12/2008, the NDA Panel, after having evaluated the overall data submitted, adopted an opinion on the scientific substantiation of a health claim related to Efalex and concentration. TERMS OF REFERENCE EFSA is requested to evaluate the scientific data submitted by the applicant in accordance with Article 16 of Regulation (EC) No 1924/2006. On the basis of that evaluation, EFSA will issue an opinion on the scientific substantiation of a health claim related to: Efalex and concentration. EFSA DISCLAIMER The present opinion does not constitute, and cannot be construed as, an authorisation to the marketing of Efalex, a positive assessment of its safety, nor a decision on whether Efalex is, or is not, classified as a foodstuff. It should be noted that such an assessment is not foreseen in the framework of Regulation (EC) No 1924/2006. It should also be highlighted that the scope, the proposed wording of the claim and the conditions of use as proposed by the applicant may be subject to changes, pending the outcome of the authorisation procedure foreseen in Article 17 of Regulation (EC) No 1924/ European Parliament and Council (2006). Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Official Journal of the European Union OJ L 404, Corrigendum OJ L 12, , p In accordance with EFSA Scientific and Technical guidance for the Preparation and Presentation of the Application for Authorisation of a Health Claim The EFSA Journal (2008) 897, 4-10

5 ACKNOWLEDGEMENTS The European Food Safety Authority wishes to thank Carlo Agostoni and the members of the Working Group for the preparation of this opinion: Jean-Louis Bresson, Albert Flynn, Marina Heinonen, Hannu Korhonen, Ambroise Martin, Andreu Palou, Hildegard Przyrembel, Seppo Salminen, Sean (J.J.) Strain, Inge Tetens, Henk van den Berg, Hendrik van Loveren and Hans Verhagen. The EFSA Journal (2008) 897, 5-10

6 1. Information provided by the applicant Applicant s name and address: Efamol Ltd., 14 The Moles Business Park, Leatherhead, Surrey, KT22 7BA, UK. The application includes proprietary data Food/constituent as stated by the applicant Efalex. Efalex provides the n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and the n-6 PUFAs gamma-linolenic acid (GLA) and arachidonic acid (ARA). The source of these fatty acids in Efalex is from high DHA fish oil and Efamol evening primrose oil Health relationship as claimed by the applicant The applicant states that Efalex provides a dietary supply of fatty acids and their precursors that are important for brain and eye development and function, that DHA and ARA are two of the main PUFAs within the brain, and that deficiencies of these nutrients have been associated with learning problems that effect concentration Wording of the health claim as proposed by the applicant Efalex may help maintain concentration Specific conditions of use as proposed by the applicant Efalex Capsules: Adults and children aged 5 years and over: 4 capsules per day with food or drink. Children 2-5 years: 2-3 or 4 capsules per day with food or drink. Efalex Liquid: Adults and children aged 5 years and over: 2 teaspoons (10 ml) per day with food or drink. Children 2-5 years: 1 teaspoon (5 ml) per day with food or drink. Efalex Chewies: Capsules can be chewed or swallowed with food. Children aged 5 years and over: 1-2 capsules per day. Children 3-5 years: 1 capsule per day. 2. Assessment 2.1. Characterisation of the food/constituent The food for which the claim made is Efalex products (capsules, liquid, chewies) made from fish oil and from evening primose oil, which contain polyunsaturated fatty acids (PUFA) of both the n-3 and the n-6 series. The main PUFAs included in the fat blend used to manufacture Efalex products are the n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and the n-6 PUFAs gamma-linolenic acid (GLA) and arachidonic acid (ARA), which are well characterised and can be measured in foods by established analytical methods. Absorption of these PUFAs has been demonstrated in humans. Efalex products also contain 5 mg per serving of vitamin E, which is used as antioxidant to stabilise the PUFA. Efalex capsules and liquid also contain small amounts of thyme oil. The specific contents of DHA, EPA, GLA and ARA in the different Efalex formulations are as follows: Efalex capsules, version 1: 65 mg DHA, 17.5 mg EPA, 5 mg ARA, and 12.5 mg GLA per capsule. The EFSA Journal (2008) 897, 6-10

7 Efalex capsules, version 2: 80 mg DHA, 18 mg EPA, 6 mg ARA, and 16 mg GLA per capsule. Efalex liquid: 140 mg DHA, 35 mg EPA, 11 mg ARA, and 25 mg GLA per 5 ml. Efalex chewies: 65 mg DHA, 15 mg EPA, 5 mg ARA, and 12.5 mg GLA per capsule. The Panel notes that the complete fatty acid spectra of Efalex products are not reported. The Panel considers that the food for which the claim is made (i.e., Efalex products) is sufficiently characterised regarding the content of DHA, EPA, GLA and ARA Relevance of the claimed effect to human health The claimed effect is helps maintain concentration. The target population is children between 2 and 18 years of age. Even though concentration has not been defined by the applicant, the applicant has referred to studies which have considered a range of psychological constructs some of which can be measured with a questionnaire and could be considered as markers for attention, which is a well defined psychological construct. The Panel considers that promoting concentration (interpreted as attention) is beneficial to children s development and health Scientific substantiation of the claimed effect The applicant performed a literature search in Medline to retrieve studies in English related to the supplementation with Efalex or any combination of DHA, EPA, ARA and GLA in children with learning disorders on either fatty acid status or any measures of brain and eye development using the search terms DHA learning in children and ARA and learning in children. The applicant also searched for population studies on fatty acid status and brain and eye development and for animal studies on the effects of DHA, EPA, ARA and GLA on brain and eye function. In addition to the Medline search, tree searching and hand searching were performed. The Panel notes that a clear decision tree for the selection of the studies pertinent to the application has not been presented by the applicant. The applicant identified a total of 56 publications as being pertinent to the health claim. These publications included 33 studies in humans (7 randomised controlled trials (RCTS), 5 quasi experimental studies, 14 observational studies, 6 review publications), and 23 non-human studies (21 animal studies, two in vitro studies). Five of the RCTs (Aman et al., 1987; Hirayama et al., 2004, Richardson and Montgomery, 2005; Sinn and Bryan, 2007; Voigt et al., 2001) and two of the one-arm (quasi experimental) intervention studies presented (Germano et al., 2007; Sorgi et al.; 2007) were conducted with intervention foods that differed from the PUFA combination present in Efalex products. The Panel considers that these studies are not suitable sources of data to substantiate the claimed effect. Two RCTs on the effects of Efalex products have been presented (Richardson and Puri, 2002; Stevens et al., 2003, proprietary data). In the first placebo-controlled double-blind study (Richardson and Puri, 2002, proprietary data), a range of behavioural and learning problems associated with attention deficit hyperactivity disorder (ADHD) was assessed in children (n=32 on randomisation) who received capsules to reach a daily dosage of g EPA, g DHA together with a mix of other n-6 polyunsaturated fatty acids (0.096 g GLA; g linoleic acid; g ARA) or in The EFSA Journal (2008) 897, 7-10

8 children (n=19 at randomisation) who received control capsules containing olive oil for 12 weeks. The children, aged 8-12 years, who had learning difficulties, coordination disorder and also exhibited ADHD-like features, were assessed using the Conners Parents Rating Scale (CPRS). The endpoints which showed significant improvement in the active treatment group compared with placebo were 2 out of 7 CPRS subscales (cognitive problems, anxious/shy) and 1 out of 7 CPRS global scales (Conners Index). In the second placebo-controlled double-blind study (Stevens et al., 2003, proprietary data), a range of behavioural and learning problems associated with ADHD was assessed in children (10 years mean age, n=25 on randomisation) who received eight capsules per day, each containing 60 mg DHA, 10 mg EPA, 5 mg AA, 12 mg GLA and 3 mg Vitamin E as preservative, (corresponding to daily dosages of g DHA, g EPA, g ARA and g GLA) or in children (n=25 at randomisation) who received control capsules containing olive oil for 4 months. The children, aged 10+2 years, were accepted into the study after parents confirmation of a clinical diagnosis of ADHD, but no professional reconfirmation of the diagnosis had been obtained. Several tests and subscales were administered at baseline and after 4 months. Both per protocol and intention-to-treat (ITT) analyses (only 18 in the supplemented group and 15 in the placebo group completed the protocol) were used. PUFA supplementation led to a significant improvement in behaviour over placebo of only 2 out of 16 outcome measures that were used, and by secondary ITT analysis alone. One of these tests might be expected to be significant by chance alone. The Panel notes that the small sample size, the relatively low number of significant endpoints compared to the total tested, the uncertain relevance of these tests to the claimed effect, and the employment of a clinical sample of children with learning difficulties who exhibited ADHDlike features limit the conclusions that can be drawn from these RCTs in relation to the health claim under evaluation. Two one-arm open studies on the effects of Efalex products have been presented (Lindmark and Clough, 2007; Stordy, 2000, proprietary data). The Swedish study (Lindmark and Clough, 2007, proprietary data) included 24 boys (aged 9 to 17 years with dyslexia on the basis of speed reading scores) who were supplemented with 8 capsules of Efalex per day (daily dosages of g DHA, g EPA, g ARA and g GLA) for 20 weeks. Statistically significant improvements in reading scores were observed at the end of the intervention period. Another one arm study from the UK enrolled 15 children 5 to 12 years old with dyspraxia who were supplemented with 8 capsules of Efalex per day (daily doses of g DHA, g EPA, g ARA and g GLA) for 4 months (Stordy, 2000, proprietary data). The study suggests a change in functional response in some behavioural scores. The Panel notes that the lack of appropriate controls and the small sample sizes limit the conclusions that can be drawn from these one-arm studies in relation to the health claim under evaluation. One study (Stordy et al., in press, proprietary data) conducted with Efalex was only presented in summary form. Owing to the limited information available, the Panel cannot draw a conclusion on that study. The Panel considers that a cause and effect relationship has not been established between the consumption of Efalex products, a combination of the n-3 PUFAs EPA and DHA and the n-6 PUFAs GLA and ARA, and the maintenance of concentration (interpreted as attention) in healthy children between 2 and 18 years of age. CONCLUSIONS The food for which the mail is made (i.e., Efalex products) is not sufficiently characterised. The EFSA Journal (2008) 897, 8-10

9 The claimed effect is to maintain concentration levels. The target population is children between 2 and 18 years of age. Concentration can be interpreted as attention, which is a well defined psychological construct. Promoting concentration (interpreted as attention) is beneficial to children s development and health. A cause and effect relationship has not been established between the consumption of Efalex products, a combination of the n-3 PUFAs EPA and DHA and the n-6 PUFAs GLA and ARA, and the maintenance of concentration (interpreted as attention) in healthy children between 2 and 18 years of age. DOCUMENTATION PROVIDED TO EFSA Health claim application on Efalex and concentration pursuant to Article 14 of Regulation (EC) No 1924/2006. (Claim serial No: 0041b-UK). August Submitted by Efamol Ltd. REFERENCES Aman MG, Mitchell EA, Turbott SH, The effects of essential fatty acid supplementation by Efamol in hyperactive children. Journal of Abnormal Child Psychology 15, Germano M, Meleleo D, Montorfano G, Adorni L, Negroni M, Berra B, Rizzo AM, Plasma red blood cells phospholipids and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD). Nutr. Neurosci. 10, 1-9. Hirayama S, Hamazaki T and Terasawa K, The effect of docosahexaenoic acidcontaining food administration on symptoms of attention-deficit/hyperactivity disorder a placebo controlled double-blind study. Eur. J. Clin. Nutr. 58, 838. Lindmark L and Clough P, 2007 (proprietary data). A 5-month open study with long-chain polyunsaturated fatty acids in dyslexia. J. Med. Food 10, Richardson AJ and Puri BK, 2002 (proprietary data). A randomized double-blind, placebocontrolled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog. Neuropsychopharm Biol. Psychiatry 26, Richardson AJ and Montgomery P, The Oxford-Durham study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics 115, Sinn N and Bryan J, Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J. Dev. Behav. Pediatr. 28, Sorgi PJ, Hallowell EM, Hutchins HL, Sears B, Effects of an open-label study with highdose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder. Nutr. J. 6, 16. Stevens L, Zhang W, Peck L, Kuczek T, Grevstad N, Mahon A, Zentall SS, Arnold LE, Burgess JR, 2003 (proprietary data). EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviour. Lipids 38, Stordy BJ, 2000 (proprietary data). Dark adaptation, motor skills, docoahexaenoic acid, and dyslexia. Am. J. Clin. Nutr. 71(suppl), 323S-6S. The EFSA Journal (2008) 897, 9-10

10 Stordy BJ, Harragan S, Thomas A, Mackay I, Clough P (proprietary data). The effect of a long chain polyunsaturated fatty acid supplement on boys with behaviour and emotional problems. J. Hum. Nutr. Dietet. In press. Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta MC, Heird WC, A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J. Pediatr. 139, GLOSSARY / ABBREVIATIONS ADHD ARA CPRS DHA EPA GLA ITT PUFA RCT Attention deficit hyperactivity disorder Arachidonic acid Conners Parents Rating Scale Docosahexaenoic acid Eicosapentaenoic acid Gamma linolenic acid Intention to treat Polyunsaturated Fatty Acids Randomised controlled trial The EFSA Journal (2008) 897, 10-10