Co-principal investigators Jeff Lombardo and Keith Aqua discuss the unique patient profiles of the study, future cohorts, and FDA's response to the findings.
Lombardo: I’m Jeff Lombardo, I'm an oncology pharmacist by training, a research assistant professor at the University of Buffalo and I'm a co-principal investigator on this liver toxicity study.
Aqua: My name is Keith Aqua. I'm also co-principal investigator on the study. I am a practicing physician who has been in the cannabidiol (CBD) and cannabis space for about 2-3 years, and a clinical trial investigator for over 25 years.
CBD and cannabinoids have been available for many years, and in the United States and around the world. There is a lack of regulation in the United States, except for a very exclusive company, which is some very specific indications for pediatric seizure disorders. There's not a lot of safety and efficacy data. The FDA, as well as other governing regulatory bodies, are looking to researchers and to companies to find the safety and efficacy data, so they can make claims. There are a lot of consumers and customers and patients that are taking CBD on their own, assuming that it's safe and not really having an understanding of the drug interactions, or possibly how it can affect other organ systems.
So Valid Care asked Jeff and I and some other investigators to look at a population of patients, particularly liver function tests and some other secondary endpoints that we had, to try to add to the data that exists for safety. And potentially use this data to launch other companies to do research on efficacy.
Lombardo: I think, as Dr. Aqua said, with increased utilization and uptake, and basically more people using it, safety is always the number 1 concern, and then efficacy comes second. But this was a safety study looking at liver toxicity and focusing on potential drug interactions that can occur. And some of this was based on some of the previous literature, some of the reports with elevated liver function tests with some other previously reported products.
Aqua: And briefly, these products have been around for a long time. But with the passing of the Farm Bill in December of 2018, it legalized the production of hemp. And with that it opened up the gates, as Jeff said, to CBD products being produced. And with that, that's where some very good companies, which really focused on research and development and making sure that they were producing product with the utmost detail, they were some good players in the market. And then of course, the market got flooded by individuals just producing products that maybe was not at the highest quality. And I think that's what has scared a lot of individuals, and rightfully so.
Lombardo: a lot of the products, they're marketed as dietary supplements. You can find them in supermarkets, you can find them in convenience stores, you can get direct to consumers from some of the companies. It’s a different pathway than FDA approved medications and really doesn’t have standardized dosing of how much you should take for certain indications. So, there's those questions.
When we've tested some of these products in the lab, there's really been a question about potency; of what is in the bottle isn't on the label. One important thing about this study is that we received a Certificate of Analysis (COA) for all 12 companies that participated in these studies. And these are reputable companies, so what was on the label was verified and was on the COA. And really, I would say they are some of the good players in the space.
Aqua: Just to add to what Jeff said, there are some studies out there that show that anywhere between 60 and 80% of CBD products on the market and on the shelves right now are mislabeled. So, either there's no CBD in that product or there's too much CBD in that product. So, again, re-emphasizing what Jeff said, the individual companies that work on this clinical trial really are above the standard.
Lombardo: This study, the companies that participated, chose a product that they wanted to be involved. There were products that were full spectrum, meaning a lot of cannabinoids, broad spectrum and some companies we had single isolates, maybe CBD only or cannabinol (CBN) only, certain formulations. It was kind of a variety and that was tested out in the in the results as well.
Aqua: You have to be careful on how any of these companies market their products. They can't make claims. You can't say that this particular product is going to improve your migraines or help you sleep. But you can discuss or kind of market it by saying it is well known in the industry that CBD can be an anti-inflammatory, it can help you with anxiety, it can help you sleep. How they market their own products is up to the individual companies. But they do have to be careful on the verbage. There are companies that are getting warning letters actually coming out and saying what their products are doing without the appropriate proof. And they have not gone down the drug development pathway. And as Jeff had said, they may market themselves as nutraceuticals or over the counter products, direct to consumer, or e-commerce. And so, it's a market that is continuing to develop.
Lombardo: This study was what we call this real-world. A lot of individuals are taking these products already, and in order to qualify for this study patients had to have been taking a cannabinoid product for 30 days. And if they met inclusion criteria - we originally reached out to 28,000 individuals. The trial included just under 1500 qualified individuals, who then took the products for 30 days.
They journaled, Dr. Aqua looked at their medical history to make sure they met all the criteria, they signed informed consent. And at the end of the study – so 60 days at a minimum being on a cannabinoid - we drew blood and we looked at their liver function tests. Now I can tell you that some of these individuals were on the cannabinoid products a lot longer, 6 months, even 12 months or more. We had a variety of those individuals that were just starting the study for a short period of time or on product, but also included those on CBD products for much longer.
Aqua: As Jeff mentioned, we had about 28,000 patients that had the opportunity to be in the trial, and we had over 1400 patients enrolled in the study. We did in fact, discover that many more patients were taking this for medical problems, more than we thought they would be, even though this was, again, a real-world generally healthy population.
We also discovered that when we looked at the increase in liver function tests for those patients that exhibited increased liver function, it was really not significantly increased compared to what the literature supporting other products were, again, taking into effect some of those other products - those were given to patients for pediatric seizure disorders. They were taking sometimes 5 to 10 milligrams per kilogram. In the real-world, patients are not taking that amount. We only had 3 patients that had greater than 3 times the upper limit normal of liver function tests. And in a population that we had, that is not at all greater or significant compared to the general population. And in clinical trials, we generally look at labs that are greater than 3 times the upper limit of normal as something that would be viewed as an adverse event or potentially a significant adverse event. And so, from that standpoint, we were happy to say that we didn't feel that these CBD products, each individual company’s CBD products, led to a significant increase in liver function tests or liver damage that would be associated with that.
Lombardo: One thing that was really interesting in the study of these 28,000 individuals was that we got a really good history of what the patients felt they were taking the medication for, so what indications, which was really interesting. And also what other medications they were taking in addition to the cannabinoids. So, we have a lot of data based just on that.
It was interesting seeing those combinations and as a pharmacist and as a clinician. Dr. Aqua is really interested in drug interactions and potential drug interactions because these drugs are metabolized through the cytochrome p450 system. There are some warnings out there. There are some contraindications if you have dual metabolism through some isoenzyme 2C19384. We really don't have set recommendations on what to do. I remember when I was doing bone marrow transplant patients when they're going on immunosuppression, and they needed an antifungal. We empirically did a 50% dose reduction based on the potential drug interaction that could occur. Those are some of the questions I think that are out there to what to do in those scenarios. This very large database that we will use to do preliminary studies and follow up studies - and Dr. Aqua will mention maybe a Cohort 2 that we're actually starting this month going forward - continuing the study based on some of these interesting findings and some of the guidance we received back from the FDA when we spoke to them on our results of the study. Very interesting.
Aqua: And it's interesting that you have Jeff and I, because Jeff is coming from a pharmacy background and I'm coming from a clinical background. But I'm seeing patients come to the office every day, and they're on these products and a lot of physicians don't understand the endocannabinoid system, they do not understand some of these drug interactions. And as you get more scientists, PhDs, MDs, PhDs in biology and chemistry and pharmacy involved, we can help patients make more informed decisions.
And as Jeff alluded to, we are going to look at Cohort 2. That's going to look at several pieces of data. Number 1, the patients that had elevated liver function tests in the first cohort, we did not have a second liver function test blood drawn. Some of this was due to COVID inability to get the patients to come into the clinical trial office. This was a completely virtual decentralized trial, so Cohort 2, anybody who had elevated liver function tests, we are going to look at doing a second blood draw to see if this was just a spurious random elevation.xz e Z Was it associated with other medications they were on? Did they have alcohol intake a couple days before they had it? So, we're going to try to look at that. And then there's some other data out there looking particularly at men and testosterone production and other liver functions, things like alkaline phosphatase that we have in this database as well.
So, I think out of this second cohort, it was combined data with the first cohort, we're going to have a very large real-world sampling of patients that, as Jeff alluded to, we know that they're on this CBD product for a minimum of 60 days, a lot have been on it for a lot longer. And when we look at the literature, we see random clinical trials that'll provide information that a patient was on 800 milligrams for a week, or a patient was on 1600 milligrams for a month, but we don't have long term data on patients that have had it for a very long time. Except, again, I go back to those pediatric seizure disorders and the work that GW Pharmaceuticals did. But in the real-world, we don't have that longitudinal data. And we hope to add to that database.
Lombardo: The FDA was very happy that we were doing the trial. They were very interested in individuals trying to bring appropriate data, peer reviewed and somewhat prospective data into the database. They were not critical of the not having the second liver function tests, but they asked questions about that. And when we did the study design, we knew that we were going to be asked questions about that.
Aqua: And, certainly with COVID, over the last 14 to 15 months, minimizing the patient's exposure to labs and their possibility of not getting the data that we needed, we had to take that into consideration. But they were giving us the appropriate guidance on that. And we went to start the second cohort, submitted to do further IRB testing on those patients do have elevated liver function tests. And we did get IRB approval to do that, so I think their suggestions were very well received. They have a very large group there that want to help companies and help consumers educate and get the data, so we can kind of catch up. The horse is out of the barn, so to speak. Now the data and the science need to catch up.
Lombardo: I thought it was a very good meeting. It certainly was a collaborative environment. So this was a liver toxicity study done with the Valid Care platform, looking at liver toxicity, but they were very interested in some of the other work that Dr. Aqua is doing some of the work that that we're doing at the university.
We focus in on some of these products, we look at single dose and multi-dose PK curves, to see how much of the medication is actually being absorbed into the body. We can measure cannabinoids metabolites with some of these products and really give back some of that safety information that the FDA is interested regarding drug development. Some of those preclinical and clinical studies, all these companies, the majority of them have done a lot of work looking at the safety of their products, that they're grass certified and are taken seriously. They're very interested in the science, and I applaud them for being part of this study.
Aqua: I do want to give a shout out to Valid Care. I think the Valid Care team has done a really good job at putting together companies and really stressing the importance of getting this information. Patrick McCarthy, who's the CEO of Valid Care, has extensively networked to reach out to these companies and to help them recognize that the research that we're doing and the drug development that they're doing is important to help consumers from both safety and efficacy in the future.
Lombardo: I think their platform in this COVID environment - it's an app-based platform that they're able to do electronic consent, it's 21 CFR Part 11, decentralized clinical study platform, which is very similar to what the FDA use for some of their COVID-19 trials. I don't think we could have done this with all these companies and with all these individuals. It was a national study, and I believe we had a couple in Alaska as well. So once again, we're using this platform and working with Valid Care for some other studies that we're doing. They have a really good platform.
Editor's note: Jeff Lombardo is a member of the Editorial Advisory Board for Drug Topics®.