Safe and correct use of food in interventional human studies

Regulatory framework for food in the EU

The EU knows a comprehensive legal framework for food. “Food” under the General Food Law Regulation[1] in short includes drinks, chewing gum and any substance, including water, intentionally incorporated into the food during its manufacture, preparation or treatment.[2] The EU framework regulates aspects such as food safety, labelling and promotional claims.[3]

Only safe foods may be placed on the market.[4] Food safety must be guaranteed in all stages of the food chain: the production, processing and distribution.[5] In this context, food business operators[6] are obliged to put in place, implement and maintain permanent procedures based on the seven Hazard Analysis and Critical Control Points (HACCP) principles.[7] In short, these principles involve the identification, prevention, elimination and reduction of hazards.[8] Critical Control Points (CCPs), are points in the process of production, processing and distribution at which the risk of hazards can be prevented, eliminated, or reduced to an acceptable level.[9] In case the investigated product is commercially available on the market (and authorized, if applicable) and is used in the usual quantities and manner, in a non-vulnerable population, it is assumed that separate HACCP procedures do not need to be implemented for the interventional human study.[10] 

Medicinal products generally require the submission of clinical trial data to obtain a marketing authorization, the objective of which is to ascertain the safety and/or efficacy of the investigational medicinal product.[11] Most foods, contrary to medicinal products, can be placed on the market without prior authorization or notification. Another difference is that food, instead of medicinal products, may in principle be placed on the market without having conducted an interventional study in humans. This does however not mean that interventional studies in humans related to food are non-existent.

Why interventional studies in humans in the context of food?

Interventional studies in humans may, among others, be especially relevant in support of the authorization application of novel foods or health claims for foods.[12]   

For example, novel foods - foods that were not used for human consumption to a significant degree within the EU before 15 May 1997, falling within one of the categories listed in the Novel Food Regulation[13] – may be placed on the market after having obtained an authorization.[14] The application for a novel food authorization needs to include a scientific risk assessment.[15] The applicant could support the application for an authorization of a novel food by submitting human interventional study data.[16] By way of illustration, the applications for approval as a novel food of LPC-rich oil extract of Antarctic krill[17] and synthetic paraxanthine[18] refer to in human studies.

Further, some foods, including food supplements, may have a positive effect on human health. Such foods are therefore sometimes accompanied by health claims. Health claims need to comply with the requirements as laid down in the Nutrition and Health Claims Regulation and may only be used if authorized, if not already included in the list of authorized health claims and meeting the requirements to use such claims.[19] Health claims should be based on, and substantiated by, generally accepted scientific evidence and food business operators making health claims should justify the use of health claims.[20] As such, it may be possible that a health claim application is evidenced by a human interventional study. For example, according to guidance of the European Food Safety Authority (EFSA) for claims other than those based on the essentiality of nutrients, data from studies in humans addressing the relationship between the consumption of the food/constituent and the claimed effect are required for substantiation. Data from studies in animals or other model systems alone cannot substitute for human data, but may be included only as supporting evidence.[21]

Requirements of the CCMO regarding the safe and correct use of food in interventional studies with humans

Below we lift a tip of the veil of the requirements addressed by the CCMO in relation to the safe and correct use of foods in human interventional studies:

• HACCP analysis
  The manufacturer is required to have implemented food safety procedures based on the HACCP principles. The factual use of the product is relevant here, meaning that the HACCP analysis must be based on the risks of the study. When a study involves a food that is commercially available in the EU (and has the required authorization, if applicable), and is provided in the usual amount and manner to a non-vulnerable research population, it is assumed that the food has entered the market conform HACCP principles. In that case no separate HACCP analyses is needed as part of the study. A product having the ‘Generally Recognized as Safe (GRAS) status – a status used in the US for substances intentionally added to food as a food additive and deemed to be safe for the intended use – is not by definition acceptable in a human interventional study in the Netherlands. This means that even though a substance (or a food containing that substance) has a GRAS status the information as laid down in the CCMO guideline must be submitted to the respective ethics committee.[22]

• Information in the protocol
  The protocol needs to reflect a number of topics. A description of the product to be investigated and an explanation why the specific product is subject of the study should be included (e.g., in case of proteins, this should also include why that specific type of protein is chosen). An overview must be included of previously conducted human, animal or laboratory studies. Further, the research population must be substantiated: does the research population represent the current or future users of the investigated product? Exclusion criteria should refer to possible existing allergies or intolerances. The same applies to products of animal origin, in which case the exclusion criteria should refer to vegans and vegetarians. In principle a risk analysis and risk assessment would be needed in addition to the HACCP analysis. However, insofar they overlap reference to the HACCP analysis would be sufficient. The risk analysis/assessment should also discuss possible interactions between the product and medicinal products. Instructions for subjects and (research)personnel, and information on control on correct use of the product should be mentioned in the protocol as well.[23] For example food for special medical purposes – food  specially processed or formulated and intended for the dietary management of patients -,  must be used under medical supervision, which should be reflected in the protocol.[24] The other subjects to be discussed in the protocol are the: suitability of the product for human consumption, concentration/quantity of the product to be taken by the subjects, duration of the intervention and manner of consumption, storage conditions and management, randomization and blinding, and potential risks for offspring.[25]

• Product information
  The product information contains information related to (i) the product, (ii) preparation/production, (iii) origin/supplier, (iv) composition, (v) microbiological and toxicological safety, (vi) date of minimum durability and stability, and (vii) packaging and labelling.[26]

• Information to subjects
  The subjects of the study should be provided with information regarding the interventional human study. The information and informed consent form model, available on the website of the CCMO for clinical trials, could also be used for interventional human studies with food to provide the respective information. For studies involving food special attention must be paid to informing subjects on a description of the product (e.g. ingredients of animal origin), how the product is consumed, storage and preparation instructions in case the product is (also) used at the subject’s home, and possible risks such as allergies, intolerances, interaction with medicinal products, and risks for offspring.[27]

Next steps

Our teams regularly provide updates on food developments in the EU. Please contact the authors or the Hogan Lovells attorneys with whom you regularly work for additional information or guidance on your human interventional food study.

Authored by Hein van den Bos and Samantha van Dijk