Inside the ACI’s CBD Safety Trial
The UK’s CBD industry is about to hit a crossroads. In just under five months’ time, every CBD company in the country will fall on one side of a new divide: those that have submitted a novel foods application with the country’s Food Standards Agency (FSA), and those that have not.
And belonging in the latter category could quickly become costly.
The FSA became the de facto regulator of CBD foods and supplements in the UK earlier this year, after it warned that it will take CBD oils, drinks, and treats “off the shelves” come March 2021, should the manufacturers not have applied for its novel foods application. Understandably, then, many CBD companies started firing out their requests.
But, with less than five months left until the deadline, it’s thought there are still some lagging CBD businesses that have yet to submit anything. So, do these companies have enough time to make the deadline? Well, no – or at least, not if they plan on starting and finishing their own CBD toxicology study…
To learn more about these time constraints and just what a CBD toxicology is, Analytical Cannabis spoke with Dr Paul Duffy, the lead toxicologist at the Association for the Cannabinoid Industry (ACI).
“Now that [CBD] is labelled as a novel food, there are European food standards that you might need to address in terms of animal toxicology data,” Duffy told Analytical Cannabis.
While some might scoff at the idea that CBD could be toxic, regulators like the UK’s FSA don’t want to rule anything out just yet. One of the agency’s advisors, the Committee on Toxicity (COT), has even said there are significant gaps in the existing safety data for CBD, particularly around its toxicity. In a report published earlier this year, the committee cited animal studies that found certain CBD levels could be toxic to rodent fetuses.
“The COT have looked at the data that is available for CBD, including the summary information for Epidiolex, which is a pharmaceutical grade product,” Duffy said. “And their conclusion is that while that's all very relevant[…] it is insufficient for them to make a judgement about food-grade CBD.”
Following the publication of that COT report, the FSA took two key actions: it advised anyone who is pregnant, breastfeeding, or taking medication not to consume CBD due to toxicity concerns, and it made it a requirement for every novel foods applicant to produce data from a CBD toxicology study.
“Applicants will need to include details of the toxicological studies they have undertaken, or propose to undertake with clear details of the reasoning for these particular tests,” reads the FSA’s own guidance, which was updated on September 24.
“Where all information isn’t available at the time of submission, a justification for the delay and when results will be available must also be included,” the guidance continues. “Without such information it is unlikely we will be able to validate an application.”
So, a toxicology study is a must-have if a CBD manufacturer wants to keep its products on the shelves. But how exactly does one undertake a CBD toxicity study? And how much does it cost?
“The animal tox data is the big hitter,” Duffy told Analytical Cannabis, “and the big cost for a lot of the companies in the industry that would never previously have had to think about this as they put their products on the shelves.”
Far from a simple chemical analysis, a toxicology study is often a laborious animal trial that could take months to prepare for, let alone carry out.
“One of the toxicology studies recommended under the European guidelines is something called an OECD 408 rodent toxicity study, a three-month rat tox study, if you like,” Duffy said. “Sounds fine, until you realize that[…] by the time you’ve got to the three-month study you’d have to have done a lot of other work and shorter studies first.”
“This three-month study needs to be preceded by some method development to do analysis of the formulations, method development to do analysis of CBD in blood samples, and a shorter dose range finding study to pick the doses for the three month study,” Duffy explained. “So, people just say, ‘Oh, the OECD 408 study,’ as if it's something you can knock out in a week, well you can't.”
When all stacked together, the total time it takes to conduct an OECD 408 study could extend to ten months. And that’s time CBD companies just don’t have if they intend to get their results by the March 31 deadline next year.
Fortunately, as stated in the FSA’s own guidance, a toxicology study “proposal” is still acceptable. But it’s currently unclear how lenient the regulator will be to CBD companies if that proposal isn’t complemented with a firm start date for any study. Of course, manufacturers still have time to agree to a start date with a contract research organization (CRO). But thanks to the coronavirus pandemic, many of these labs just had their schedules filled up.
“So, we’re talking about ten months, but that's just a basic concept to the study,” Duffy said. “Throw on top of this Covid and competition for slots in accredited, quality contract research organizations – where you get this work done – and there's another time factor involved.”
“Pharmaceutical companies are competing for those slots. And if you know anything about working with CROs, it's a minefield of scheduling, about rooms, and people, and skill sets,” Duffy added.
And even if a CBD company did somehow manage to book an upcoming slot in a third-party lab, it wouldn’t come cheap, says Duffy.
“There is variance between different CROs, but equally you've got to pick a quality one, because otherwise you've wasted your money,” Duffy said. “But you’re looking at £300,000 [US $389,820] plus; it’s not cheap.”
So, when time and money are limitations, what can a CBD company do to make sure it eventually has this essential toxicity information? Well, it might help to share the load with a few more companies. And that’s just what Duffy and the ACI are suggesting.
The ACI’s trial
“You know, some of these cannabinoid and CBD companies aren't big companies,” Duffy told Analytical Cannabis, “and you've got to have that kind of disposable income to do one of these studies. So, at the ACI, the concept was, if we do it as a consortium, we can share the cost and it becomes a more manageable situation, especially for the smaller companies.”
As one of the major CBD industry bodies in the UK, the ACI has already helped many companies file their FSA novel foods applications. Now, to help guarantee those applications will be warmly received by the FSA, the CBD group has organized its own collaborative toxicity study.
Working with the formulated products company Advanced Development and Safety Laboratories, the ACI will analyze CBD products submitted by member companies with high performance liquid chromatography (HPLC) techniques. An Ames test and an OECD 408 study will then both be conducted, to help assess the effects different means of delivery (ingestion, absorption, and inhalation) can have on the liver, and if there are any groups (children, adolescents, pregnant women) vulnerable to CBD’s effects.
“The Ames test is a bacterial mutagenicity assay,” Duffy explained, “it’s been around for years, and people use [it] as a first screening for potential geno-toxic properties of a molecule. And depending on the outcome of that, they follow up with more work in mammalian cells rather than bacterial cells. That is also in the European FSA guidance as the kind of information you might need.”
All findings, data, and toxicology reports from these tests will then be shared with the UK’s FSA and other regulatory authorities.
“It is important that we have all the safety data in place for regulators to satisfy any concerns about the CBD,” Dr Parveen Bhatarah, the ACI’s regulatory lead, told Analytical Cannabis earlier this year. “In order to do so, it’s important that we generate all the safety data to support that information and declare that the product which we are bringing to the market is safe.”
While the original plan was to collect data from four categories – CBD isolate, narrow spectrum, broad spectrum, and full spectrum – the study has since been downscaled to include just two product types: the CBD isolate and CBD broad spectrum varieties. Initial tests will include products from all participating companies, before one of the broad-spectrum products is submitted to further toxicology tests.
Around 16 companies have already signed up to the trials so far, but more partners are still welcome.
“We are further down the track than anyone that we’re aware of,” Duffy said. “The cost shared between ten, twenty, thirty members is a lot less than doing it on your own, and I believe we’re closest[…] to having the information to support a valid novel food application by next March.”
Of course, the ACI’s trial isn’t the only route to toxicology data; those that want to forge their own path still can. But as March 31, 2021, nears, the time to do so is depleting, and so are the available testing slots with third party labs…
“We started talking to [a third-party lab] about April,” Duffy added. “The earliest they could give us a start for the pre-work was October and the main 90-day study they're not going to start until February next year.”
“So, there's a lot of companies out there who have no concept about how long it's going to take them to get something in place.”