National nutrivigilance scheme Review of nutrivigilance in 2016 March 2017 French Agency for Food, Environmental and Occupational Health & Safety, 14 rue Pierre et Marie Curie, 94701 Maisons-Alfort Cedex Telephone: + 33 (0)1 49 77 13 50 - Fax: + 33 (0)1 49 77 26 26 - www.anses.fr ANSES/PR1/9/01-04 [version d]
Key words Nutrivigilance, food supplement, novel food, food intended for specific diets, fortified food page 2 / 19 March 2017
CONTENTS Introduction... 4 Acronyms and abbreviations... 5 List of tables... 5 List of figures... 5 1 Review of nutrivigilance reports received by ANSES in 2016... 6 1.1 Number of reports received... 6 1.2 Admissibility of cases... 7 1.3 Identity of the reporters... 8 1.4 Products reported... 10 1.5 Types of food supplements reported... 11 1.6 Types of adverse effects... 12 1.7 Intrinsic causality... 13 1.8 Severity of the cases... 15 2 Review of opinions published by ANSES... 16 2.1 Opinion published in 2016... 16 2.1.1 Food supplements for athletes... 16 2.2 Internal requests in progress... 16 2.2.1 Food supplements for pregnant women... 16 2.2.2 Food supplements containing spirulina... 16 2.2.3 Food supplements containing melatonin... 17 2.2.4 Food supplements containing glucosamine and/or chondroitin... 17 3 Review of information and communication actions... 18 3.1 International exchanges... 18 3.2 Training activities organised... 18 3.3 Other actions... 18 4 Conclusions... 19 page 3 / 19 March 2017
Introduction Implementation of the national nutrivigilance scheme was entrusted to ANSES in July 2009 under the French Act on Regional Health Governance (HPST). The purpose of this scheme is to improve consumer safety by rapidly identifying any possible adverse effects related to the consumption of: - food supplements; - foods or beverages fortified with substances for nutritional or physiological purposes (vitamins, minerals, amino acids, plant extracts, etc.) such as energy drinks; - novel foods and novel ingredients such as phytosterols, guar gum, noni juice; - products intended as food for specific categories of the population (infants, athletes, patients suffering from food allergies, etc.). Healthcare professionals (doctors, pharmacists, dieticians, etc.) are invited to report these specific foods when they identify adverse effects in their patients that they suspect of being related to consumption of these foods. Individuals who wish to submit a report on their own behalf should preferably contact a healthcare professional. The reports are recorded by ANSES while concealing the identity of the consumer, and are then analysed, initially by the Agency (to determine the severity of the incident, the product's composition, the concordance with previous notifications, etc.). For each report, ANSES may contact the reporter again to obtain any missing information if necessary. Reports containing sufficient information are then submitted to medical experts, who analyse the likelihood of a link between consumption of a product and an adverse effect (causality). The Agency informs the authorities of the cases received and may be required to initiate an alert procedure (life-threatening case in which causality is strong). Cases are examined by a group of specialised experts. Depending on the effects observed, the number of cases received and the likelihood of them being associated with consumption of the product in question, the Agency, with the help of the experts, establishes its priorities in terms of risk assessment work to be undertaken. This work leads to the publication of scientific opinions and recommendations intended for healthcare professionals and consumers. These opinions are submitted to the ministries concerned to enable them to implement appropriate management measures. Between the launch of ANSES's nutrivigilance scheme and 31 December 2016, the Agency received 2649 reports of adverse effects. The purpose of this report is to review the activity of the nutrivigilance scheme for 2016. page 4 / 19 March 2017
Acronyms and abbreviations FISD: Food intended for specific diets ANSM: French Health Products Safety Agency FSNP: Food to which substances are added for nutritional or physiological purposes ("fortified food") FS: Food supplement CAP: French Poison Control Centre CRPV: Regional Pharmacovigilance Centre NF: Novel food List of tables Table 1: Rate of admissibility of cases per reporter type... 10 List of figures Figure 1: Change in number of reports between 2009 and 2016... 6 Figure 2: Change in the admissibility of cases received since 2009... 7 Figure 3: Breakdown of spontaneously reported cases according to their admissibility and reason for nonadmissibility in 2016... 8 Figure 4: Identity of reporters (all reports combined)... 9 Figure 5: Identity of the reporters (admissible cases)... 9 Figure 6: Number of admissible cases per reporter type... 10 Figure 7: Types of products reported in nutrivigilance (admissible cases)... 11 Figure 8: Breakdown of the types of food supplements implicated in the nutrivigilance reports in 2015 and 2016... 12 Figure 9: Breakdown of adverse effects reported in 2015 and 2016 (admissible cases)... 13 Figure 10: Causality of cases received in 2015 and 2016 (admissible cases)... 14 Figure 11: Causality according to the type of effect (admissible cases)... 14 Figure 12: Severity of adverse effects reported (admissible cases)... 15 Figure 13: Severity according to causality (admissible cases)... 15 page 5 / 19 March 2017
1 Review of nutrivigilance reports received by ANSES in 2016 Due to the limited number of cases, the quantified data presented below have not undergone comparisons based on statistical tests. 1.1 Number of reports received Figure 1 illustrates the change in the annual number of reports since the creation of the nutrivigilance scheme. 648 474 498 432 340 Figure 1: Change in number of reports between 2009 and 2016 Until 2011, cases of nutrivigilance were spontaneously reported by healthcare professionals. In 2012, ANSES initiated a process of proactively seeking out cases from manufacturers and other vigilance schemes (pharmacovigilance, toxicovigilance). The spontaneous reports were therefore joined by solicited cases. The sharp increase in the number of spontaneous cases in 2013 can be explained by the choice of certain manufacturers, after having been solicited the first time, to spontaneously report other cases brought to their attention. The total number of reports received in 2014 was slightly higher (498 cases) compared to the previous year (474 cases). The number of spontaneously reported cases (183 cases) fell compared to 2013 (343 cases), but was however still in line with the continuous growth observed since 2009, regardless of the 2013 artefact. In addition, until 2014, the ANSM only systematically informed ANSES of serious cases involving a product concerned by nutrivigilance. In 2014, following a request by ANSES to also be notified of non-serious cases, the ANSM transmitted a further 135 cases. In 2015, there was an increase in spontaneous reports but a fall in the number of cases transmitted following solicitation by ANSES, leading to a total number of 432 cases. In 2016 the growth of spontaneous reports was confirmed with an increase of 26 cases over the previous year. However, the decrease in the number of cases transmitted by manufacturers and other vigilance schemes following solicitation by ANSES continued, leading to a total of 340 cases. page 6 / 19 March 2017
1.2 Admissibility of cases Analysing admissibility involves verifying that the report received relates to a case that falls within the scope of nutrivigilance, and that it is sufficiently documented to be exploited. This phase may lead ANSES to request additional information from the reporter. From 2009, only sufficiently documented adverse effects occurring under the normal conditions of use of a foodstuff were declared admissible. With effect from 2016, and in accordance with the provisions of the Public Health Code (Art. R1323-3), the adverse effects resulting from a use that is not compliant with normal use (overdoses or suicide attempts) have also been deemed admissible, if they are sufficiently documented. For 2016, one case of overdose and two cases of attempted suicide were thus deemed admissible. Figure 2 illustrates the proportion of admissible cases received since 2009. 84% 73% 16% 27% Figure 2: Change in the admissibility of cases received since 2009 Although the total number of cases decreased between 2015 and 2016, the rate of admissibility increased sharply from 16% to 27%. The proportions of admissible cases and the different reasons for non-admissibility are illustrated by Figure 3. More than half the reported cases (59%) were not admissible because of the absence of sufficient information (product not identified or dates of consumption unknown, for example). page 7 / 19 March 2017
Figure 3: Breakdown of spontaneously reported cases according to their admissibility or reason for non-admissibility in 2016 In 2016 there was a decrease in the number of cases compared to the previous year, but an increase in the rate of admissibility. 1.3 Identity of the reporters Accounting for more than 35% of the reports transmitted in 2016, the regional pharmacovigilance centres (CRPV) were the main reporters in nutrivigilance, followed by manufacturers (32.6%). Hospitals accounted for around 10% of reporters, pharmacies 7% and doctors 5%. Individuals, who are not meant to participate directly in the nutrivigilance scheme, reported 4% of cases. Lastly, the Poison Control Centres (CAPs) and the other reporters (nurses, medical testing laboratories, the AGEPS, etc.) each submitted less than 3% of reports (Figure 4). page 8 / 19 March 2017
Figure 4: Identity of reporters (all reports combined) If only admissible cases are considered (Figure 5), the notifications from the CRPVs were still the leading source of reports. In contrast, reports from manufacturers represented a smaller proportion. This can be explained by the low rate of admissibility (18%) among these reporters (Figure 6; Table 1). Figure 5: Identity of the reporters (admissible cases) page 9 / 19 March 2017
Figure 6: Number of admissible cases per reporter type Table 1: Rate of admissibility of cases per reporter type CRPVs Manufacturers Hospitals Pharmacies Doctors Individuals CAPs Other Admissible cases 31% 18% 34% 43% 28% 14% 33% 33% Non-admissible cases 69% 82% 66% 57% 72% 86% 67% 67% In 2016, the CRPVs were the main reporters in the nutrivigilance scheme, with 121 cases reported, of which 31% were admissible. The remainder of the report only concerns admissible cases, i.e. reports that have been sufficiently documented, involving products falling within the scope of nutrivigilance, used under normal conditions or conditions that are not compliant with normal use (overdoses or suicide attempts). In addition, it should be reiterated that no attempt should be made to interpret the variations observed from one year to the next because of the low number of reported cases. 1.4 Products reported Although nutrivigilance concerns four categories of food products: food supplements (FS), food intended for specific diets (FISD), fortified foods (FSNP), and novel foods (NF), the vast majority of the cases it collects involve food supplements, which accounted for 90.2% of the cases deemed admissible. This predominance of food supplements is seen year after year (Figure 7). page 10 / 19 March 2017
Figure 7: Types of products reported in nutrivigilance (admissible cases) 1.5 Types of food supplements reported Among the 92 admissible cases, 83 involved at least one food supplement. The food supplements reported most frequently were those for "Vitality/tone", "Joints" and "Eyesight" (10 cases each). The breakdown, however, shows great variability from one year to the next (Figure 8). page 11 / 19 March 2017
Figure 8: Breakdown of the types of food supplements implicated in the nutrivigilance reports in 2015 and 2016 1.6 Types of adverse effects The main types of adverse effects reported in 2016 involved digestive (25 cases), general (21 cases), liver (15 cases) and dermatological (15 cases) disorders. This breakdown differed from that observed in 2015 (Figure 9), in particular for allergic effects, which decreased sharply. In half of the cases, this decrease was linked to a change in the ranking of allergic effects, which from 2016 were classified with the dermatological effects in the absence of any evidence of an allergic reaction. page 12 / 19 March 2017
Figure 9: Breakdown of adverse effects reported in 2015 and 2016 (admissible cases) 1.7 Intrinsic causality For each sufficiently documented report received by the nutrivigilance scheme, the causality is determined, i.e. the likelihood that the adverse effect reported is related to consumption of the product. The method for assessing causality was defined in ANSES's opinion No. 2010-SA-0195 of 11 May 2011 on the development of a method for determining causality in reports of adverse reactions in nutrivigilance. This opinion is available on the ANSES website. Causality may be: excluded (I0), unlikely (I1), possible (I2), likely (I3) or very likely (I4). Out of the 92 admissible cases whose causality was analysed, causality was excluded in one case (I0), was unlikely (I1) in 18 cases (19.6%), possible (I2) in 38 cases (41.3%), likely (I3) in 31 cases (33.7%) and very likely (I4) in 4 cases (4.3%). This breakdown showed a higher proportion of possible cases than the previous year (Figure 10). page 13 / 19 March 2017
Figure 10: Causality of cases received in 2015 and 2016 (admissible cases) Analysing the causality by type of effect reveals that the very likely cases were associated with digestive, cardiovascular, allergic, rheumatologic and other effects. Caution should however be exercised when interpreting this finding, given the low number of cases studied (Figure 11). The sum of the cases presented in this diagram is greater than the number of admissible cases (92) because a single case can report several types of adverse effects. Figure 11: Causality according to the type of effect (admissible cases) page 14 / 19 March 2017
1.8 Severity of the cases The scale of severity in nutrivigilance goes from Level 1 (low severity) to Level 4 (death). The admissible effects reported in 2016 were predominantly Level 1 (39%) and 2 (35%) (Figure 12). Figure 12: Severity of adverse effects reported (admissible cases) One single admissible case of Level 4 severity was reported in 2016, concerning liver damage that resulted in the death of the patient. However, the interval between consumption of the product and occurrence of the adverse effect was deemed incompatible, which led to the causality being determined as possible (I2). Figure 13 shows that the cases whose causality was very likely (I4) were of Level 2 or 3 severity, while the cases of likely causality (I3) were predominantly Level 1. Figure 13: Severity according to causality (admissible cases) page 15 / 19 March 2017
2 Review of opinions published by ANSES The analysis of reports received by its nutrivigilance scheme enables ANSES, with the help of its experts, to establish its priorities for risk assessment. In this context, since 2009, ANSES has published around a dozen opinions on a wide range of products monitored by nutrivigilance, especially concerning the risks associated with the consumption of certain substances found in food supplements (lutein, zeaxanthin, synephrine, red yeast rice, etc.), so-called energy drinks, and beverages other than breast milk and its substitutes in the diet of infants under one year of age. 2.1 Opinion published in 2016 One opinion was published in 2016 in the framework of an internal request. 2.1.1 Food supplements for athletes On 7 November 2016, ANSES issued an opinion on the risks associated with the consumption of food supplements for athletes seeking to develop muscle or reduce body fat. Effects that are potentially serious, primarily cardiovascular (tachycardia, arrhythmia and stroke) and psychological (anxiety and mood disorders), have been observed. The Agency therefore advises against the use of these food supplements by people with cardiovascular risk factors or suffering from heart disease, impaired kidney or liver function, or neuropsychiatric disorders, or by children, adolescents, and pregnant or breastfeeding women. ANSES also recommends avoiding the consumption of food supplements containing caffeine before and during any sporting activity, as well as the concomitant consumption of several food supplements, or their combined consumption with medicinal products. ANSES reiterates the need to seek advice from a healthcare professional before taking food supplements. ANSES's opinion can be consulted via the following link: https://www.anses.fr/fr/system/files/nut2014sa0008ra.pdf 2.2 Internal requests in progress Four internal requests are currently being examined. Their publication is planned for 2017. 2.2.1 Food supplements for pregnant women Fourteen reports of adverse effects that may be associated with the consumption of food supplements during pregnancy have been brought to ANSES's attention since the establishment of the national nutrivigilance scheme. Ten of these reports were ruled admissible. These adverse effects mainly concerned endocrinological and metabolic disorders (neonatal hypercalcaemia and hypothyroidism). As the severity of the effects concerned a vulnerable population (newborns), and the causality was sometimes high, ANSES decided to issue an internal request to assess the endocrine and metabolic risks related to the intake during pregnancy of vitamin D and iodine through food supplements. The results of this expert appraisal will be published in an opinion in the first quarter of 2017. 2.2.2 Food supplements containing spirulina ANSES issued an internal request to assess the risks associated with the presence of spirulina in food supplements, following the receipt of sixteen reports of adverse effects since the nutrivigilance scheme was set up. Seven of these reports were admissible, and six of these were considered serious according to the definition given by Article R1323-3 of the Public Health Code. The adverse effects described were mainly allergic, dermatological, digestive and rheumatic. The results of this expert appraisal will be published in an opinion at the start of the second half of 2017. page 16 / 19 March 2017
2.2.3 Food supplements containing melatonin Since the establishment of the nutrivigilance scheme in 2009, sixty-nine reports of adverse effects likely to be associated with the consumption of food supplements containing melatonin have been brought to the attention of ANSES. The main adverse effects described are general, psychological and cardiovascular. Seven reports had Level 3 severity. Nine reports were comprehensive enough to establish causality, which in six of these was deemed likely. Given the growing renown of this compound and the adverse effects reported, ANSES issued an internal request for an assessment of the risks associated with the consumption of food supplements containing melatonin. The work will lead to an opinion being published in the second half of 2017. 2.2.4 Food supplements containing glucosamine and/or chondroitin Eighteen reports of adverse effects that may be associated with the consumption of food supplements for joint health containing glucosamine and/or chondroitin have been brought to ANSES's attention since the establishment of the national nutrivigilance scheme. The adverse effects described were mainly dermatological, digestive, haematological and liver effects. Six of these reports were considered admissible, and three of the cases were deemed serious according to the definition given by Article R1323-3 of the Public Health Code. The causality of one of these serious cases was deemed to be very likely. An ANSES opinion will be published at the end of 2017. page 17 / 19 March 2017
3 Review of information and communication actions 3.1 International exchanges In the context of the free movement of goods, it is essential to pool knowledge of product composition and the cases reported in other European countries. Apart from France's initiative in terms of nutrivigilance, several other countries are investigating or have already established a similar scheme (Italy, Sweden, etc.). In 2014, in order to bring these schemes together and raise awareness among other Member States, ANSES began setting up a European network on this topic. On 12 June 2014, ANSES held a kick-off meeting in Maisons-Alfort for this nutrivigilance information exchange network, which was attended by 13 Member States. Since then, a monthly exchange of information has led to the pooling of cases, literature and concerns. In 2015, this network expanded outside Europe with the inclusion of Brazil. In 2016, 19 countries were involved in the nutrivigilance network: Germany, Belgium, Brazil, Croatia, Cyprus, Denmark, Spain, Finland, France, Ireland, Italy, Latvia, Luxembourg, Norway, Netherlands, Slovenia, Sweden, Czech Republic and the United Kingdom. 3.2 Training activities organised As part of efforts to promote nutrivigilance among healthcare professionals, in 2016 ANSES continued its training actions among students of pharmacy (3 rd and 4 th years, Master and DU degree), medicine (3 rd year and Master) and sport science (Master and DU) at different faculties in France. It also offered training to other students in the framework of Master or specialised DU courses in nutrition. 3.3 Other actions A presentation of the nutrivigilance scheme was given to the members of Synadiet (the French Food Supplements Association). page 18 / 19 March 2017
4 Conclusions Since its creation in 2009, the nutrivigilance scheme has received a growing number of spontaneous reports. Nevertheless, 2016 saw an overall decline in the number of reported cases. These reports help improve consumer safety, because their analysis helps ANSES establish its priorities in terms of expert appraisals, in conjunction with its experts, and generate input for the risk assessments it carries out. In this regard, the Agency wishes to remind healthcare professionals of the importance of their participation as reporters to notify ANSES of cases of adverse effects that they suspect of being associated with the consumption of food supplements. ANSES asks them to continue questioning their patients during medical consultations about their use of food supplements and other special dietary foods such as fortified beverages, and to notify the nutrivigilance scheme of any adverse effects they are made aware of. ANSES reiterates that deficiencies in nutrients are very rare in the general population, and mainly concern a few specific substances (vitamin D, etc.) or particular population groups (pregnant women, the elderly, economically vulnerable populations, etc.). In these specific population groups, additional intakes of vitamins, minerals and other nutrients through food supplements may be of benefit, but on medical advice. For a large majority of the population, a balanced diet provides most of the nutrients required to meet nutritional needs. ANSES wishes to stress that food supplements are not without danger. They should not be used as a substitute for a varied diet, and the advice of a healthcare professional should always be sought when taking them. Pregnant and breastfeeding women, children and people taking medication should seek advice from their general practitioner before consuming food supplements. In general, the Agency advises consumers to: - report to a healthcare professional any adverse effect occurring after consumption of a food supplement; - comply with the conditions of use determined by the manufacturer; - avoid taking food supplements on a prolonged, repeated or multiple basis throughout the year without having sought the advice of a healthcare professional; - exercise extreme caution with products promoted as "miracle" cures and/or those sold through alternative channels, in particular through the Internet. page 19 / 19 March 2017