November 2021
RE: Food Standard Authority (FSA) Novel Food applications for cannabidiol; Implications for replicate toxicity testing in animals
DevelRx Ltd and The Canna Consultants are concerned over what we consider to be the scientifically unjustified, and ethically unacceptable, replicate toxicity testing of Cannabidiol (CBD) that is being proposed/demanded by the Food Standards Agency (FSA), acting under guidance provided to them by the Committee on Toxicology (COT).
The Regulatory Position
For the past 2-3 years CBD, a cannabinoid compound that is purified from hemp plants, has been added to a growing number of food products (e.g., oils, tinctures, or confectionary). These products were brought to the market in the UK and the European Union and were not considered to be subject to regulation, however, in January 2019 extracted and purified CBD was classed as a Novel Food by the EU (and hence the UK).
Under a regime introduced by the FSA in February 2020, manufacturers of food products containing CBD were asked to submit a Novel Food application to the FSA for Authorisation of their CBD ingredient and products manufactured therefrom. This Authorisation process is designed to ensure the ingredient and products manufactured therefrom have been through a thorough and independent safety assessment.
We fully endorse this approach to protecting public safety and it is something which we demanded of the regulator and market participants in advance of the announcement of the FSA decision – a Position Paper entitled “The Road to a Better Future” was provided to Stakeholders by The Canna Consultants in October 2019 and any consideration of the document will identify it as the blueprint which was adopted by the FSA in its later announcement 4 months later. The document is hyperlinked above and available at: https://www.thecannaconsultants.co.uk/wp-content/uploads/2020/02/The-Road-to-a-Better-Future.pdf.
Our Issues of Concern
Issue 1
The first issue of concern is the assessment of the safety and toxicity risks of CBD that has been conducted by the Committee on Toxicity is superficial, scientifically flawed and has placed reliance in part on a biased data-source that was clearly part of a pharmaceutical company’s lobbying campaign to the US government to restrict the non-medical use of CBD by the US public.
Based on this flawed assessment, COT has recommended that CBD needs to undergo additional and extensive toxicity and safety testing in animals before it is safe for human consumption.
The approach to Novel Food applications that has been adopted by the FSA, under guidance from COT, is to treat CBD in the same way as a potential food contaminant (e.g., a pesticide or heavy metal). They are demanding that every manufacturing company which is making an application for CBD in a food product (or products) conducts an extended 96-day, repeat dosing, rat toxicity study (Organisation for Economic Co-operation and Development; OECD-408 study) on their individual CBD ingredient to evaluate their CBD’s safety and toxicity. Furthermore, in the early feedback from the FSA on Novel Food applications, there have also been demands for justification in not conducting genotoxicity studies and other “Tier 2” toxicity studies (e.g., reprotoxicity) in animals.
Issue 2
Secondly, in its role as the approving body for every application for the use of CBD as a Novel Food, the FSA is not only mandating that every CBD ingredient undergoes additional safety and toxicity testing, but also failing to treat CBD ingredients which have virtually the same chemical composition as being Substantially Equivalent to each other, thus forcing every manufacturer of every ingredient and every user of that ingredient to pursue this 96-day repeat dosing, rat toxicity studies on what are, by any scientific assessment, the same ingredients. We acknowledge that the parameters of substantial equivalence demand limits from the mean to be identified, in order to ensure that two ingredients are actually substantially equivalent, but the insistence on separate studies for every ingredient will involve large scale, replicate animal toxicity testing.
The Origin of Our Concerns
Part of this approach might be justified if it were not for that fact that in 2018-2019, CBD was approved as a medicine (Epidyolex; GW Pharmaceuticals) to treat resistant forms of epilepsy in patients 1-2 years of age and above by the European Medicines Agency (EMA), the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and the US Food and Drug Administration (FDA). The FDA has also recently approved Epidyolex to treat tuberous sclerosis complex in children of over 1 year of age.
To gain approval of CBD for medical use in humans, GW Pharmaceuticals performed the “full regulatory package” of safety pharmacology testing in vitro, in animals and in humans, together with a full programme of toxicity testing, including genotoxicity, reproductive toxicity and general toxicity testing in animals.
Furthermore, as part of that assessment process, the pharmacokinetics (including drug-drug interaction studies), tolerability and safety of CBD were also extensively explored in human subjects. The Epidyolex database consists of 15 clinical pharmacology and double-blind, placebo-controlled clinical trials. This pharmacokinetic, safety and toxicity evidence has been reviewed by experts from the MHRA, EMA and the FDA in the US and the data and their detailed assessments are publicly available2.3.
COT have published their assessment1 on the safety of CBD using the publicly available review information from the Epidyolex European2 and US3 regulatory submissions and also from other scientific research studies. It is COT’s review of the Epidyolex safety and toxicity findings which has led to the demands by the FSA for toxicity studies to be performed on every one of the individual CBD ingredients by each CBD manufacturer that has submitted a Novel Food application.
Authors’ Involvement in the Issue
DevelRx Ltd (Professor David Heal, Dr Sharon Smith and Dr Christopher Atterwill) (https://develrx.com) were approached by The Canna Consultants (Mr Stephen Oliver and Mr Matthew Lawson) (https://www.thecannaconsultants.co.uk) and asked to advise on the issue, the latter believing that the FSA/COT’s position to be scientifically and ethically unjustified.
DevelRx are experts in central nervous system (CNS)-active drugs, and safety pharmacology assessments in drug discovery and development. The Canna Consultants provide policy and legislation consultancy to governments and regulators on medicinal cannabis and the cannabinoid industry.
DevelRx and The Canna Consultants have made a full evaluation of the COT safety assessment of CBD and consider that the COT analysis and conclusions are deeply flawed for reasons detailed in Annex A.
The Canna Consultants have been discussing this issue with the FSA for over 18 months, through written correspondence, videoed Q&A sessions and on-line discussions with the Regulated Products Team (Annex B).
We are of the strong opinion that the request by the FSA for multiple toxicity testing on the same Novel Food product, CBD:
- is unnecessary because this testing has already been conducted by GW Pharmaceuticals;
- is unethical because animals are being used as surrogates when the question has already been answered by studies in the relevant species, humans;
- is unscientific because no guidance has been provided by COT / FSA on how the findings will be interpreted or the implications arising from them; and,
- is contrary to the principles of the 3Rs (reduction, replacement, and refinement) to avoid unnecessary use of animals in experiments.
Signed,
Professor David Heal, BSc, MSc. PhD, DSc FRSC, FBPhS (DevelRx Ltd)
Dr Sharon Smith, BSc, PhD (DevelRx Ltd)
Dr Christopher Atterwill, BPharm, PhD, FRPharmS, FIBiol, FRCPath (DevelRx Ltd)
Mr Stephen Oliver, LLB (The Canna Consultants)
Mr Matthew Lawson, LLB, Barrister (The Canna Consultants)
Annex A The Flaws in the COT Advice to the FSA over the Safety Profile of Cannabidiol (CBD)
DevelRx and Canna Consultants have had several virtual meetings with senior members of the FSA (see also Annex B) and very clearly pointed out that what COT is proposing is:
(i) Scientifically invalid;
A fair and objective scientific assessment is totally reliant on using evidence that is free of bias. Many of the statements in the COT background document are lifted directly from a lobbying submission by GW Pharmaceuticals to the FDA with the stated aim to restrict or prevent public access to CBD products and the unrestricted use of cannabis for medicinal purposes. COT has not reviewed the data (none is presented to FDA), has taken GW Pharmaceuticals statements at face value and treated a lobbying piece designed to protect the commercial interests of the pharmaceutical industry as being neutral and objective.
GW Pharmaceuticals statements unequivocally reveal the commercial position that the company is attempting to defend:
“Since our founding in 1998, GW Pharmaceuticals has been singularly focused on unlocking the potential of cannabinoids as medicines to address serious medical conditions…”
“In opening the door for consumer-market CBD products, FDA risks further diminishing the likelihood that more cannabis-derived product will be developed into proven medicines for these patients.”
“Due to a variety of factors—including competition from unapproved products—incentives to develop and drive competition among FDA-approved cannabis medicines are weakened to begin with.”
Human safety data always takes precedence over animal data. The Epidyolex database (GW Pharmaceuticals) consists of 15 clinical pharmacology and patient double-blind, randomised clinical trials, or double-blind clinical trials. It includes 10 completed trials in healthy subjects (trials with a pharmacokinetic element), 2 supporting trials looking at the effects of Epidyolex on sleep and drug withdrawal symptoms, 2 trials in specific populations (renal-impaired or hepatic-impaired patients) and 5 trials in patients with epilepsy.
What the FSA / COT proposes is to re-initiate safety testing of CBD in animals, while ignoring the large clinical trials database that is publicly available from GW Pharmaceuticals development of Epidyolex. Safety testing data are valid whether CBD is under evaluation as a medicine or a Novel Food product. This is important because the safety and toxicity of CBD in Epidiolex was tested in animals and humans at doses that were many times higher than the daily intake of CBD as a novel food product that is recommended by the FSA / COT. Hence the safety margins are large for the consumption of CBD as a novel food product.
Epidyolex is a highly purified CBD preparation (>98%) with minor amounts of psychotropic and non-psychotropic cannabinoids. The CBD isolates / distillates which are the subject of novel food applications by our clients are of similar or greater purity than CBD in Epidyolex From a safety perspective, there is no biologically relevant difference between Epidyolex and the novel food CBD isolates / distillates in these FSA Novel Food applications.
(ii) Unethical from an animal welfare perspective; and,
(iii) Potentially in contravention of the Animals Scientific Procedures Act which precludes replicate testing without good reason.
If there is substantial evidence that unnecessary animal testing of CBD has been demanded by two government bodies, i.e. COT and FSA, it would contravene the government’s commitment to the 3R’s in animal testing, undermine the case for the use of animals in medical research and could present a major problem in respect of public opinion.
Based on the publicly available EMA2 and FDA3 clinical and non-clinical assessment of CBD, we prepared an extensive analysis of the toxicity and safety risks posed by CBD scaled from the maximum therapeutic Epidyolex oral dose (20 mg/kg/day) to the FSA recommended maximum daily CBD novel food consumption (1 mg/kg/day). That document has been made available to the FSA in various CBD Novel Food applications.
