18 Oct 2022

Data Gaps and How to Fill Them

The European Commission (EC) has received over 150 cannabidiol (CBD) applications (ranging from chemically synthesised CBD, purified CBD extracts, and full spectrum CBD products) over the past few years. Of these, only 19 were validated and are currently under risk assessment by the European Food Safety Authority (EFSA). On 07 June 2022, shockwaves were sent across the industry when EFSA published their long-awaited "statement on the safety of cannabidiol as a novel food: data gaps and uncertainties,"1 which outlined several major limitations of the public literature on CBD. Their statement effectively put all current applications on hold until data gaps are filled.

Data gaps

The data gaps and/or concerns mentioned by EFSA are outlined below.

  • Bioavailability of CBD in matrices (as applicable to the novel food) should be considered, as different matrices can have a significant impact;
  • Long-term kinetic behaviour of CBD in humans needs to be clarified (i.e., does it accumulate in the body);
  • Toxicology and clinical studies are needed such that a no-observed-adverse-effect level (NOAEL) can be derived for CBD;
  • Interactions between low-dose CBD, other drugs, and the liver need to be considered;
  • Diarrhoea-triggering effects caused by acute and long-term exposure to CBD in healthy humans should be investigated;
  • Long-term effects of CBD in healthy individuals should be considered, so a dose-response relationship can be determined;
  • Effects of CBD on the endocrine system, immune function, and reproductive system should be investigated, in particular in females consuming low doses of CBD;
  • Genotoxicity with regards to CBD needs to be investigated; and
  • If relevant, the presence of small and/or nanoparticles needs to be considered in accordance with EFSA guidelines.

The EFSA Panel on Nutrition, Novel Foods and Food Allergens concluded that "the data gaps and uncertainties identified in this statementneed to be addressed by the applicants to provide the basis for the safety assessment of CBD as a novel food. The Panel concludes that the safety of CBD as a novel food cannot currently be established." EFSA subsequently held a useful information session for applicants2 on 28 June 2022, to explain their statement in more depth and answer questions from current and potential applicants.

This statement was purely based on published data; it does not consider the multitude of unpublished confidential data that EFSA will have seen in applications they have received so far. For many applicants, some of these gaps may have already been filled, but it seems unlikely that any single applicant will already have the extremely robust dataset required to placate all of the concerns raised by EFSA in the statement.

What will it take to fill these gaps?

It will take a long time and a huge financial investment to conduct the studies required to fill the data gaps identified by EFSA. Companies may find it helpful to form consortia (as some already have) to share this financial burden. However, it remains to be seen how the EC would grant 5 years' exclusivity to individual companies in such cases, as one of the criteria for receiving exclusivity is that applicants must normally have "exclusive right of reference" to the pivotal data.

The first step, and possibly the most important one, is to address the potential presence of small particles or nanoparticles in the ingredient. It is highly recommended to do this work before conducting any new toxicity studies. The type and design of such studies may need to be altered if it is found that the ingredient contains a fraction of (i) small particles (in which case the EFSA Guidance on technical requirements for regulated food and feed product applications to establish the presence of small particles including nanoparticles3 would apply), or (ii) nanoparticles (in which case the EFSA Guidance on risk assessment of nanomaterials to be applied in the food and feed chain: human and animal health would apply4). For example, one of the default Tier 1 genotoxicity studies, the bacterial reverse mutation test (Ames test), is not suitable for an ingredient that contains nanoparticles or a fraction of small particles; in such a case, a mammalian cell mutagenicity test OECD Test Guideline [TG] 476 or 490) would be needed.

The bulk of EFSA's concerns relate to toxicity. The standard Tier 1 battery of studies (in vitro genotoxicity studies and a 90-day toxicity study) is a start, but Tier 1 tests alone are clearly not sufficient to address all of the concerns raised by EFSA. These tests do not address the data gaps on the endocrine, immune, or reproductive systems, nor the specified need for human studies. While a 90-day study does cover Tier 1 for reproductive and developmental toxicity, and additional "optional" parameters can be included in that study to provide as much information as possible on potential endocrine effects, a separate Tier 2 reproduction and developmental toxicity study is almost certainly required in this case. The food additive guidance (which the novel food guidance refers to for toxicity testing) mentions 2 reproductive and developmental toxicity studies: a prenatal developmental toxicity study (OECD TG 414) and an Extended One-Generation Reproduction Toxicity Study (EOGRTS) (OECD TG 443). It is likely that that a clean EOGRTS study would be sufficient for EFSA; however, this study is not straightforward, takes an extremely long time to conduct (about 15 to 18 months) and, depending on the number of cohorts to be included, will cost upwards of €1 million. Factoring approximately €300k+ to conduct the Tier 1 studies, this illustrates a huge financial investment.

At least one human study will also be required, which also won't be cheap. Human studies would need to address EFSA's concerns regarding bodily accumulation, and toxicity to the liver and gastrointestinal tract, following long-term consumption. EFSA's information session for applicants appeared to indicate that a 6-month study would be required—no small undertaking. Including all of the aforementioned parameters in a single long-term study represents a major organisational challenge.

Conclusion

The regulatory pathway for CBD has already been long and challenging to navigate. Those who are considering submitting a novel food application for CBD to European authorities need to understand the large financial investment required to address data gaps, before embarking on what looks to remain a long and expensive journey ahead. As for those already on this journey, it remains to be seen whether EFSA's statement will dissuade them from continuing.

Whether you're a potential applicant, or already have submitted and application, our experts are here to support you every step of the way. EFSA's data gaps are heavily based on toxicity, and they emphasise the need for well-conducted toxicology and human studies to address their concerns. Our highly experienced Registered Toxicologists can represent you as an independent study monitor and provide a full toxicology study management service, which includes selection of Clinical Research Organisations (CROs), assistance with study design, review of protocols, supervision of testing phases, and critical review and interpretation of data, to ensure that your studies are designed appropriately and your reports are presented in the best possible manner.

Intertek can also provide full support for your clinical trials from start to finish, including study design, placement, and manuscript writing. For companies forming consortia, we can act as a non-biased and experienced liaison for all companies involved.

Additional information on EFSA's recent statement on CBD data gaps and uncertainties can be found here: https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2022.7322.

Intertek has extensive experience with overcoming regulatory hurdles and developing unique strategic pathways. If you have any questions feel free to contact us at food.sci-reg@intertek.com

Disclaimer: The foregoing does not constitute legal or regulatory advice and the reader should seek professional guidance for their specific requirements and conditions. Please contact our expert compliance team for further assistance in this regard. Intertek has extensive experience with overcoming regulatory hurdles and developing unique strategic pathways.

To learn more about how we can support your business, visit: https://www.intertek.com/food/consulting/

References

1. https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2022.7322
2. https://www.efsa.europa.eu/en/events/information-session-applicants-safety-cannabidiol-novel-food-data-gaps-and-uncertainties
3. https://www.efsa.europa.eu/en/efsajournal/pub/6769
4. https://www.efsa.europa.eu/en/efsajournal/pub/6768

 

Dayna Lozon Intertek headshot

Dayna Lozon, 
Senior Associate, Food & Nutrition Group, 
Intertek Assuris

Dayna Lozon has been with Intertek for over 4 years and provides expertise in the areas of EU/UK novel foods, food additives, and cannabis regulations. She is a graduate of the University of Guelph with a Bachelor of Science in Toxicology.

 

Kirt Phipps Intertek headshot

Kirt Phipps,
Senior Manager, Toxicology and Regulatory Affairs, Food & Nutrition Group,
Intertek Assuris

Kirt Phipps is involved in the preparation and stewardship of applications for regulated products (novel foods, food additives and food enzymes) in the EU and UK. He is responsible for resolving complex regulatory and toxicological queries raised by the EC and EFSA, which has led to the approval of numerous applications. He is also responsible for the placement and monitoring of toxicology studies at Intertek Assuris, including selection of an appropriate CRO, study design, and dose level selection, overseeing in-life phases, and providing critical reviews of draft reports. These are essential components of the risk assessment for substances to be added to foods.