Claims: The US vs. the European Perspective (Part 4). Will the FDA permit the same claim?
This article, which focuses on a health claim approved by the European Food Safety Agency (EFSA) on cocoa flavanols, is the fourth in a series of articles describing similarities and differences between claims for food ingredients in the U.S. and in Europe. In June, 2012, The EFSA Panel on Dietetic Products, Nutrition and Allergies approved an Article 13, general health claim for cocoa flavanols and maintenance of normal endothelium-dependent vasodilation in the general population. EFSA has stated that the following wording is consistent with scientific evidence: “Cocoa flavanols help maintain endothelium-dependent vasodilation, which contributes to normal blood flow. In order to obtain the claimed effect, 200 mg of cocoa flavanols should be consumed daily.” The target amount of cocoa flavanols could be provided by 2.5 g of high-flavanol cocoa powder or 10 g of high-flavanol dark chocolate.1
The Scientific Opinion published by EFSA1 mentioned that five published and one unpublished randomized, controlled intervention studies were identified by the applicant as being especially pertinent to the claim. The studies examined whether regular consumption of cocoa flavanols could increase fasting endothelium-dependent flow-mediated dilation (ED-FMD) in “non-diseased” populations. The EFSA Panel concluded that four out of the six studies could be considered for evaluation of the claim (two were eliminated from consideration due to “important methodological limitations”). One randomized, double-blind, parallel, controlled study in 65 overweight or obese subjects showed that consumption of 900 mg/day cocoa flavanols for 12 weeks caused a statistically significant increase in fasting ED-FMD (p < 0.05). The effect of cocoa flavanols on fasting ED-FMD occurred within 2 hours of ingestion. In an unpublished randomized, double-blind, controlled cross-over study in 20 subjects (weight was not mentioned), a dose-dependent, statistically significant increase in fasting ED-FMD (p < 0.05) occurred after consumption of = 200 mg/day cocoa flavanols for one week. Results of two studies (both randomized, crossover and controlled; one single-blind) in hypertensive subjects with impaired glucose tolerance showed that consumption of 100 g dark chocolate for 15 days (providing 300 or 500 mg/day cocoa flavanols depending on the study) increased ED-FMD.
The applicant also provided results from three additional human intervention studies which investigated the effects of repeated consumption of cocoa flavanols on fasting ED-FMD in subjects with coronary artery disease (CAD) under pharmacological treatment for this condition. Two of the three studies (both randomized, one controlled and double-blind) showed that consumption of cocoa flavanols produced a statistically significant increase in fasting ED-FMD (p < 0.05). The doses of cocoa flavanols provided in the two studies were 750 mg/day or 966 mg/day over a time course of 30 days. In both studies, the effect was observed within seven days and sustained until study termination.
Results of several acute studies that supported the claim were also submitted by the applicant. A randomized, double-blind, controlled crossover study in ten patients with CAD showed that acute (single dose) administration of a cocoa drink containing 371 or 963 mg of flavanols induced a dose-dependent increase in ED-FMD which was maximal two hours after ingestion, paralleled blood concentrations of flavanol metabolites and returned to baseline six hours after ingestion. Information from controlled human intervention studies involving small numbers of subjects (n = 6-21) with at least once risk factor for cardiovascular disease (e.g. smoking, obesity, type 2 diabetes) showed that an acute dose of = 176 mg cocoa flavanols caused an increase in ED-FMD, which peaked two hours after consumption.
Data on the proposed mechanism of action also was included in the submission. With regard to the longer-term effects of cocoa flavanols on fasting ED-FMD, the applicant proposed “an increased expression/activity of endothelial nitric oxide synthase (eNOS), changes in nitric oxide (NO) bioavailability, changes in expression/activity of eNOS-related proteins that may influence cellular localization of eNOS, co-factor availability, or substrate accessibility, or eNOS-independent mechanisms” as biologically plausible mechanisms. The applicant also proposed an enhancement of NO production by eNOS as the most likely and best documented mechanism by which cocoa flavanols could induce (at least in part) an acute effect on endothelium-dependent vasodilation.
In weighing the evidence, the EFSA Panel took into account that one intervention study showed that consumption of cocoa flavanols for 12 weeks increased fasting ED-FMD in the target population and another showed that the effect on ED-FMD was dose-dependent and occurred after one week of ingestion “under the conditions of use proposed by the applicant” (i.e. 200 mg of cocoa flavanols/day). The Panel stated that the effects were supported by two additional repeated dose intervention studies performed with dark chocolate in hypertensive subjects with impaired glucose tolerance and two repeated dose intervention studies in patients with CAD. The Panel also considered results of the acute studies, which showed that consumption of cocoa flavanols on a single occasion induced an acute and dose-dependent increase in ED-FMD that was sustained with regular consumption of cocoa flavanols. Regarding the mechanism of action, EFSA concluded that the evidence provided in support of the long-term effect cocoa flavanols on ED-FMD was weak, but the acute effect of flavanols on ED-FMD may be mediated by the enhancement of NO production in the endothelium each time cocoa flavanols are consumed.
Based on the information provided in the EFSA article and the wording of the claim (Cocoa flavanols help maintain endothelium-dependent vasodilation, which contributes to normal blood flow), it is unlikely that the claim would be permitted as a health claim in the United States. As mentioned in our second newsletter article in the series (2), the FDA evaluates health claims based on reduction of risk of disease. In the U.S., according to 21 USC 343(R)(6), a “disease” is damage to an organ, part, structure, or system of the body such that it does not function properly (e.g. cardiovascular disease), or state of health leading to such dysfunctioning (e.g. high blood pressure). The EFSA-evaluated claim for cocoa flavanols does not mention a disease or a state of health leading to abnormal function. Therefore, based on wording alone, the claim would not be permitted as a health claim by FDA. Further, it is unclear whether FDA would consider the results of the studies that have been evaluated by EFSA to be supportive of a beneficial effect on health at the recommended dose (200 mg cocoa flavanols/day). Of the six repeated dose studies that were considered by EFSA to provide either substantiation or corroborate evidence for the claim, five were performed with cocoa flavanol concentrations greater than 200 mg /day (300-966 mg/day). Further, the study that was performed with 200 mg/day cocoa flavanols was unpublished at the time EFSA evaluated the claim. Based on the history of health claim litigation in the U.S., the body of evidence that was considered by EFSA to substantiate a health claim on cocoa flavanols may not suffice for a health claim in the United States.
It is possible that the EFSA-evaluated claim on cocoa flavanols (or a closely related facsimile) may be permitted for use in the United States as a structure/function claim. However, the FDA may not consider the evidence provided in the EFSA-evaluated claim to be valid for the normal population, based on the preponderance of data from studies involving diseased subjects. If you are interested in making a structure function or health claim for cocoa flavanols, Burdock Group will be delighted to assist you with claim wording or substantiation.
References
EFSA Panel on Dietetic Products, Nutrition and Allergies (2012). Scientific Opinion on the substantiation of a health claim related to cocoa flavanols and maintenance of normal endothelium-dependent vasodilation pursuant to Article 13(5) of Regulation (EC) No 1924/2006. EFSA Journal 10(7):2809-2829.
Dolan, L.C. and Chaumont, V. C. (2011). Claims: The United States and European Perspective. The Burdock Advisor, 12(2)1-2.