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Back in 2020, the European Commission regulated the public sale of orally administered, legal cannabidiol (CBD) products by classifying them as novel foods (NFs). Today, there are still no CBD products that have received NF authorisation in the UK or Europe. Here Libby Clarke, managing consultant for toxicology at specialist CBD contract research organisation Broughton, explores how companies seeking NF regulatory approval can plan their testing strategies to minimise setbacks and maximise their chance of success. Under UK and European law, an NF is defined as a food, drink or ingredient that has not been consumed to a significant degree by people in the European Union before May 1997. This includes food products that have been traditionally consumed in other countries but are new to the EU market, as well as foods produced using new technologies or from newly discovered sources. In the UK, NFs are subject to a specific regulatory framework laid out by the Food Standards Agency (FSA). After the announcement made by the European Commission that oral CBD products would be regulated under NF status, the FSA faced an interesting dilemma: since these products were already on sale, how should it go about ensuring CBD products are safe without crashing an already established market? The FSA decided to allow the continued sale of any products that were on the market at the time of the announcement (13 February 2020), subject to receiving an authorisation application before 31 March 2021. The FSA reviewed the applications and validated those that it deemed could plausibly be approved. Only manufacturers with validated NF applications were permitted to remain on the market. New products or variations seeking to hit the market after this all-important date would require NF authorisation before going on sale. So, how can businesses design a testing strategy for success?

The trouble with the tiers For more common commodities – ones not containing CBD – a tiered framework has been published as a guide for the scientific tests to support market approval. The tiers, proposed by the European Food Safety Authority (EFSA) but adopted more widely, are a way of organising toxicology assessments to maximise efficiency and minimise the use of animals. The approach involves a hierarchy of tests, beginning with simple absorption, in vitro genotoxicity and extended in vivo 90-day toxicity tests. If it’s then deemed necessary, more in-depth studies will need to be carried out. If tier two studies – which may include prenatal developmental toxicity and single-dose absorption, distribution, metabolism and excretion analyses – raise further concerns, then it’s time to move on to the third and final tier. At this point, specialised toxicity studies (immuno-, neuro-, etc.) are carried out, potentially alongside repeated dose volunteer studies. But the tiered system runs aground when applied to CBD products, as was highlighted by the EFSA in June 2022, when the regulatory authority concluded significant data gaps needed to be addressed before CBD product safety could be established. Take dosage, for example. As things stand, a dose level that causes “no adverse effect” for CBD products is still yet to be properly established. Much of the data on dosage comes from clinical trials, such as for GW Pharmaceuticals’ Epidolex, used in the treatment of seizures, and Savitex, used to treat symptoms of multiple sclerosis. Adverse side effects at clinical doses might be acceptable when weighing up benefits to patients, whereas side effects at lower doses in NFs for the general population would not be. Specific studies will therefore need to be carried out to establish liver toxicity, drug interactions, accumulation and a dose at which no effect is registered. A three-month rat study might be appropriate to determine the general toxicity of a CBD product, but it’s likely that human studies will also be required, especially when considering the potential psychological effects of taking CBD at a low dose for extended periods of time. So, if a tiered approach to testing isn’t appropriate for CBD-containing NFs, what is?

Designing a strategy Instead of following the generic tiered framework, a more targeted testing strategy is required. Such a strategy should be designed to answer the specific concerns flagged by EFSA and FSA, to efficiently fill the gaps in data that currently exist. While there may be some tests that can cover multiple bases, others will be highly specific to individual products. For example, solid food products, like a gummy, will take much longer to be absorbed by the body than a drink. CBD is soluble in fats, so an oil-based product may be absorbed even faster. As a result, any absorption data submitted as part of one application will most likely only be relevant to the named product. Depending on the testing strategy, the data-gathering stage could take a year or longer, with additional time for initial study planning, data processing and inclusion of findings in an application. The cost of gathering the required data is likely to be significant and possibly prohibitive, especially for smaller manufacturers, so joining a consortium to collaborate and share the cost of more general studies could be an effective way to mitigate this impact. In the longer term, it could be that EFSA and FSA collate the submitted data from businesses and use it to set generic ranges. It's also important to leverage expertise where you can. Working with contract research organisations who understand the regulatory environment, can support full applications and gap-filling in existing applications. This could be a great way to expedite the process and avoid mistakes along the way.