Probiotic and prebiotic claims in Europe: seeking a clear roadmap.

In 2008, the European Food Safety Authority (EFSA) began reviewing the proposed health benefit claims on all foods. To date, none of the 164 claims of the benefits of probiotic or prebiotic products submitted to EFSA and reviewed by the Panel on Dietetic Products, Nutrition, and Allergies (NDA) have been accepted (see Table 1). Those who are not aware of either the research supporting specific probiotics and prebiotics or the NDA review process may come to the fallacious conclusion that probiotics or prebiotics have not been shown to have health benefits. Without doubt, fraudulent or exaggerated claims are being made for some products. However, the scientists and clinical investigators belonging to the Board of Directors of the International Scientific Association for Probiotics and Prebiotics (ISAPP) are concerned that claims supported by solid scientific evidence are also being rejected. They are further concerned that there is a lack of clarity regarding the criteria – from study design through wording of the claim – for a dossier suitable for a positive regulatory opinion. One unintended consequence of the current review process may well be that the responsible companies studying the physiological effects of their probiotic or prebiotic products will decide that continued investment into this line of research is not cost-effective if, in the end, evidence supporting product benefits deemed valid by the scientific community cannot be communicated to the consumer. Certainly, evaluation of evidence to support claims is not a simple process. The NDA scientists must implement challenging legislation and assess a flood of dossiers providing evidence, which in the nature of all research could always be improved. But the process is difficult for industry scientists, too, who must prepare a dossier in support of a claim with only general guidance from the NDA. A successful dossier requires not only compelling studies on efficacy, but also specification of a physiological effect that will be considered by the NDA as beneficial and a claim that is worded to accurately reflect the science but also be in compliance with regulations. Some recent documents have been drafted by the NDA to provide guidance on their interpretation of what constitutes beneficial effects and acceptable outcome measures (http:// www.efsa.europa.eu/en/consultationsclosed/call/nda100928. pdf), but many questions remain unanswered. This opinion is reflected in a letter (http://www.gut-health.eu) by the European scientists expressing dissatisfaction with the process. As of 23 February 2011, 148 scientists have signed this letter. One overriding concern with the review process is the standard of evidence required by the NDA. The legislation states that ‘Health claims should only be authorised for use in the Community after a scientific assessment of the highest possible standard’. However, this seems to be interpreted by the NDA to mean that the evidence (as opposed to the assessment) must meet the highest possible standard. A more realistic standard is expressed in article 6 of the EC Regulation 1924/2006, which states that health claims shall be based on and substantiated by ‘generally accepted scientific evidence’. Thus, regulators have indicated a definite roadmap: generally accepted scientific evidence is not the same as the notion that evidence must be based on a restrictive number of criteria established by a closed group of individuals. Generally accepted scientific evidence is a well-established concept, and is the basis for the peer review process of scientific journals, evaluation of grant applications or scientific productivity of researchers, and grading recommendations in evidencebased medicine. In the latter case, this means that findings of a single randomised control study with narrow CI can constitute level 1b of evidence and invoke a recommendation of top, Grade A, intervention. In practice, this means that the recommendation should be applied unless there is a specific reason for not doing it. An example of implementing the ‘highest possible standard’ is apparent when the NDA rejected the validity of an independently conducted study published in the British Medical Journal (2) to support a claim that a probiotic food could reduce Clostridium difficile toxin in the gut and reduce the risk of acute diarrhoea in patients receiving antibiotics. One concern expressed by the NDA panel judgement of the trial was with study blinding. Although the products were not identified to the patients, the bottle shapes were different for the placebo and the test product, but only for product sent home with a subset of discharged patients. It is unclear how the NDA expected this small imperfection to influence the level of C. difficile toxin in faeces. Importantly, the staff who conducted the toxic analysis on the stool samples from patients who had diarrhoea remained fully blinded to the test group assignment. An additional criticism of the study was that C. difficile toxin was measured only in patients with diarrhoea and not in all study participants. However, it is common practice in a hospital environment to assay toxin only when diarrhoea occurs. The authors of this study concluded ‘Consumption of a probiotic drink. . . can reduce the incidence of antibiotic-associated diarrhoea and C. difficile-associated diarrhoea. This has the potential to decrease morbidity, healthcare costs and mortality if used routinely in patients aged over 50.’ Yet the NDA deemed the evidence in this study as not of sufficiently high quality to support communication of the protective effect of the product against antibiotic-associated diarrhoea and C. difficile toxin production. British Journal of Nutrition (2011), page 1 of 3 q The Authors 2011