Standing in the Beaumont Room at the Yale School of Medicine on Nov. 8, flanked by school officials and medical researchers, the significance of what was transpiring in front of Rino Ferrarese and Tom Schultz was not lost on them. It was a moment the duo had been waiting and preparing for since they first chatted with each other about launching a medical cannabis operation in the Constitution State back in 2013.
They were there that morning, in front of 40 or so members of the media, the medical community and state and regulatory officials, to announce that CTPharma, the company they co-founded, received Food and Drug Administration (FDA) approval to begin clinical trials on cannabinoid medicines in partnership with the Yale School of Medicine. The first phase of this Investigational New Drug (IND) study focuses on safety and dosing in treating symptoms related to stress and pain relief. These randomized, double-blind, placebo-controlled (RDBPC) studies now allow CTPharma to put its products through the scientific gauntlet.
“Phase I of an FDA study is relatively straightforward,” Schultz explains. “You’re trying to prove some form of safety and efficacy.”
From those early days in the state’s legal medical cannabis industry, CTPharma’s focus has been on obtaining this FDA approval to commence human studies. “To date, there hasn’t been an American company who’s been able to cultivate flower, harvest it, extract it, process it into a pharmaceutical dose, and get it through the FDA, approved in an IND protocol, and then into healthy human volunteers for a safety and efficacy study,” Ferrarese told Cannabis Business Times after the press conference. “That’s a triumph. Today will be a historic day in the annals of cannabis history.”
Now that the company has the government go-ahead to begin its research, Schultz says it feels like “we’ve crossed the starting line.”
(Editor’s note: Tom Schultz and Rino Ferrarese are CBT columnists.)
Preparing for the Race
As former executives in FDA-regulated industries, both Ferrarese and Schultz are well-suited to navigate this opportunity. Ferrarese has experience as a compliance officer working under the guidelines of Current Good Manufacturing Practices (CGMP) for the production of prescription, over-the-counter (OTC) and homeopathic human drug products. Schultz operated the last significant producer of witch hazel, Dickinson Brands Inc., until he and Ferrarese launched CTPharma.
The intent with launching a medical cannabis cultivation operation was never simply to cultivate: Research was at the forefront of their minds from day one. However, Schultz says, “when we were awarded a license [in 2014], there was no research authorized by the state’s cannabis statute. We [could] ship product for consumption to six dispensaries, but if Yale School of Medicine, to whom we were speaking, wanted to do research even in a test tube, [they] couldn’t do it. It was illegal, even in Connecticut, to ship [cannabis] to them.”
The duo knew early on that rules would need to be rewritten for them to get started on the work they wanted to complete. The CTPharma co-founders spent the better part of the business’s first two years working with regulators and elected officials (some of whom were present for the Nov. 8 announcement) to pass research-enabling legislation. Two-and-a-half years after obtaining their license, Ferrarese and Schultz helped create Connecticut’s Medical Marijuana Research Program.
Under the state’s Department of Consumer Protection (DCP)’s supervision, hospitals, higher education institutions, medical cannabis producers and dispensaries can register to conduct research “intended to increase knowledge or information regarding the growth, processing, medical attributes, dosage forms, administration or use of marijuana to treat or alleviate symptoms of any medical conditions or the effects of such symptoms,” according to the DCP’s website. This program explicitly allows CTPharma to work with groups such as Yale School of Medicine on research once the study has been registered.
Another two-and-a-half years of working for federal approval and a “significant” six-figure investment brought CTPharma to the launch of its IND studies. The company is starting with two studies focused on both safety and efficacy. During the eight-week study period, participants cycle through four of six product formulations (including a placebo) in alternating weeks—one week on one formulation, one week off any formulations, then another week with a different formulation, and so on.
“Once we can prove safety, now we can get more focused on exactly what we can do with this medication,” Schultz explains.
Back to School
CTPharma selecting Yale School of Medicine as its research partner is a product of proximity and familiarity: Yale is in Connecticut, and Schultz is an alum. The third component that made the partnership attractive was mutually recognized expertise.
“[Yale] recognized the potential for cannabinoid research before anything was even authorized in Connecticut,” Schultz says. For example, while CTPharma was working to have research legislation enacted in 2016, CTPharma and Yale co-sponsored a symposium on cannabinoids in medicine. Looking back at the event, Schultz says, “we had honestly the cutting-edge researchers in the world speak at Yale and talk about exactly where research in cannabis was at that time.”
What Yale saw in CTPharma was the company’s “pharmaceutical production orientation,” Schultz says. Many of CTPharma’s employees come from a pharmaceutical background, both in OTC and prescription medications. A handful of others come from the supplement and food industries. He adds that “from [Yale’s] point of view, … we have the capacity to produce cannabinoid medication in the same way that a pharmaceutical company would produce it.”
A good example is the products CTPharma intends to use in its IND studies: Instead of smokable flower or dosed vape pen cartridges, the company offers formulated tablets to patients involved in its research. Dosages can vary from 10 mg THC:40 mg CBD to 30 mg THC:40 mg CBD. Tablets as a delivery mechanism for these cannabinoid medications were chosen not by haphazard choice, but by slow, deliberate study.
“We did membrane permeability studies, which were designed to determine how much the body uptakes,” Ferrarese explains. In other words, “if you provide 10 milligrams of medicine in a tablet and you swallow it, how much of that 10 milligrams is getting absorbed into the body in a way that the body can utilize it as medicine, and how much is getting discarded and passed into your system as waste?”
One of Ferrarese’s main criticisms of most cannabis studies done to date is the lack of available information about the quality and consistency of the product used. Additionally, combusting or heating cannabis will change its phytochemistry. For example, Ferrarese says, “if you heat [cannabis] … you can have terpenes volatilized, and once they’re gone, they’re gone. So you have to be very careful with the cannabis medicine.”
CTPharma spent time and resources on stability studies—research on its products and how they change over time in different conditions. Thanks to those efforts, Ferrarese says, “we know exactly what happens to our tablets if you heat them up too much, what happens if they freeze, what are the optimum storage conditions.” This work was all done “just to make sure that when the patient takes medicine, that we know what the patient can expect and we can better understand the results we’re getting,” he continues.
All of these studies and tests were conducted by CTPharma in a formulation lab and an analytical lab that Ferrarese describes as “[rivaling] any mid-level biotech company operating in America today.”
State of Control
Another big part of CTPharma’s pharmaceutical approach is its almost neurotic data collection. “In the FDA world, if you didn’t document it, it never happened,” Ferrarese says. That’s why one of the first significant cultivation investments was for a proprietary environmental control system (ECS), and the company hasn’t operated a day without one.
Since the cultivation operation’s launch in 2014, four sensors in every cultivation room have taken snapshots every 30 seconds; throughout the facility, temperature, humidity, CO2 levels, and lighting are all measured twice per minute.
It was the co-founders’ experience in FDA-regulated industries that told them data-tracking would be crucial to their goals of setting up clinical research studies; they both learned how important ongoing process control and the creation of reproducible products are to the FDA in its role as a consumer protection agency.
The data CTPharma had been collecting before it began its FDA application “was relevant and very interesting and important to the FDA because they wanted to see that we operated in a state of control,” Ferrarese explains. As CTPharma went through its IND study application, Ferrarese estimates that roughly a month was spent answering the agency’s data requests, with new ones coming almost daily.
In addition to stability data on final products and formulations, the company documents everything in the cultivation areas. This includes “watering, taking clones, what time the lights came on and off, all the way through … how much did Blue Dream yield this year compared to when we grew it last year,” Ferrarese says.
The indoor cultivation operation is also designed to maximize control and minimize any unexpected outcomes: Peat moss and Pro-Mix make up the growing media, while a mix of different fertilizer inputs gets pumped through drip irrigation lines. In vegetation, double-ended metal halide lights are the company’s preferred choice. For flowering, double-ended HPS lights are what CTPharma feels give it the most control.
But both Ferrarese and Schultz are quick to point out that it’s not the company’s approach to cultivation that they believe sets it apart from other licensees in the state, but its overall pharmaceutical approach. They add that retained samples and stability testing are a safety precaution: if a patient comes to them complaining of poor product quality or that their medicine made them sick, CTPharma can trace the batch number and investigate what might have happened. That historical data also can be used as evidence to defend the company in case of a lawsuit.
Now that the company can begin its research projects, the co-founders expect to see a jump in the company’s value—and revenue. “If we are intelligent about the way that we work on research, then it dramatically enhances our value as a company,” Schultz says.
The first hurdle is the first phase of the IND study, which looks at safety and efficacy. Schultz isn’t worried about that first jump, given the anecdotal safety of cannabis in the U.S. (As the old industry saying goes, the only way cannabis will directly kill you is if a 60-pound bale of it falls on your head.)
Part of what CTPharma is studying in this first phase are stress and pain. Depending on the results, stress studies could transition into PTSD in phase two, and the pain research could be refocused on opioid replacement. “In any case, we see the possibility in phase two to begin to address specific problems, let’s say, for which the solutions could have very substantial economic value—and … human value,” Schultz says.
The real risk, Schultz believes, is in doing the actual research with “no guarantee that some bureaucrat somewhere won’t have a negative attitude,” and simply dismiss the work, he says. “But we think that there’s enough momentum behind the industry today so that the positives that are obviously there can overwhelm the negatives. We have faith that the plants we grow and the products we produce have the potential to really help people with disease problems.
“Either that’s a good judgment or not, but we have faith, tremendous faith, that our capacity to help people is really there.”
But CTPharma is not pinning its future on research alone. As part of a bid to be competitive in the long-term, the company is moving to a new, 173,000-square-foot facility by Q2 2020. This new site not only will increase the canopy capacity to roughly 80,000 square feet, but will also permit the addition of an on-site commercial bakery, among other new features.
Schultz says the canopy expansion will be rolled out in phases, with the first phase doubling current capacity to 20,000 square feet. “We are the smallest … producer in Connecticut, and obviously that next facility is quite large and will allow us to do a lot of things that we can’t currently do and will provide for any future space that we may need,” he says.
And while CTPharma might be the first U.S. cannabis company to get approval for an FDA study, looking forward, the co-founders know they won’t be the last.
“[Nov. 8 was] a historic day, and we’re proud to be that company that did this, and we expect that you’re going to start to see more and more companies reaching this sort of achievement,” Ferrarese says. “But in order to do it, they’re going to have to have all the things lined up that we had: the CGMPs, the partnerships with academia, and the right professionals in place within the organization.”
Schultz puts it a little more simply (and sarcastically): “This is really easy: All it takes is two and a half years to get the enabling legislation passed so we can do research, and then another two and a half to get through the FDA.”