Research Project

The U.S. Food and Drug Administration is approving a growing number of applications from cannabis companies looking to conduct clinical trials studying medical marijuana. That development could lead to multiple cannabis-based medicines—including flower—receiving FDA approval to be commercialized and sold within the next five years.

While attitudes might be changing at the FDA, obtaining agency approval and launching cannabis studies remain extremely difficult. But it’s not impossible, as a handful of companies have demonstrated, and certain steps can smooth the way.

In June 2018, GW Pharmaceuticals’ Epidiolex, used to treat certain forms of epilepsy, became the first cannabis-plant-based medicine to receive FDA approval for commercialization (a small number of FDA-approved synthetic cannabis drugs are sold by prescription). But Cambridge, England-based GW might not be alone for long.

CT Pharma, a licensed producer in Connecticut, and Tetra Bio-Pharma, a biopharmaceutical company in Ontario, Canada, both have started FDA-approved clinical trials they hope will result in cannabis drugs approved by the agency. Other major cannabis companies, including multistate players Columbia Care and Vireo Health—plus British Columbia-based producer Tilray—also are sponsoring FDA-approved studies focused on the safety and/or effectiveness of medical cannabis.

Companies that have secured the FDA’s blessings have taken unique paths. But there are several shared strategies among them:

  • Research, rather than a focus on producing recreational products.
  • A researcher on the team who already has successfully petitioned the FDA to conduct drug-development studies.
  • Extensive testing and data collection.
  • Wide-ranging and meticulous recordkeeping

Getting FDA approval to study cannabis requires time, patience and capital. But the potential payoff that comes with having an FDA-approved pharmaceutical product on the market could rival or even dwarf what the most successful recreational marijuana companies are making. Marijuana Business Magazine spoke with two cannabis companies about what it takes to launch an FDA-approved study.

 

CT Pharma’s Cannabis-to-Tablet Breakthrough

CT Pharma is collaborating with the Yale University School of Medicine on a new study exploring the efficacy of cannabis-derived tablets to treat stress and pain. Notably, the tablets will be made from cannabis flower produced at the firm’s facilities in Connecticut.

CT Pharma Chief Operating Officer Rino Ferrarese said that, to his knowledge, this is the first time cannabis grown by a state-licensed producer in the United States has been used in an FDA-approved study. Until now, the cannabis flower and oil used in FDA-approved studies have either been grown at the University of Mississippi (the sole federally approved grower in the United States), produced synthetically or imported.

CT Pharma was founded in 2014 with pharmaceutical ambitions. Not satisfied with being a license holder in a limited market, CT Pharma’s leaders dispatched ambassadors to international cannabis science conferences while networking in a local landscape rich with universities, hospitals and pharmaceutical companies.

That networking led them to Dr. Rajita Sinha, a Yale University School of Medicine professor who already had done clinical trials with cannabinoids and had past successes getting study approval from the Institutional Review Board (IRB) of the Yale medical school. An IRB, found at many research institutions, must approve a researcher’s study proposal before it can be submitted to the FDA for consideration.

“Meeting someone with experience getting cannabinoid formulations through IRB to approval—that was a really big deal,” Ferrarese said.

CT Pharma started with an oral spray formulation that the FDA approved for study in 2017. But after several months, researchers decided that oral sprays were less than ideal for patients and health providers and tablets were deemed a better choice.

 

What the FDA Wants to See

While CT Pharma had produced thousands of cannabis tablets in its facilities and had extensive safety and efficacy records, Sinha wanted to work with tablets of different ratios—10 milligrams of THC and 40 milligrams of CBD, for example—which required CT Pharma to run a new battery of tests relating to safety, contaminants, packaging, stability and degradation.

Because the FDA was familiar with the cannabinoid formulations developed by Sinha, the agency already knew they were safe to be tested on human subjects. The FDA was more interested in CT Pharma’s cultivation, extraction, manufacturing and packaging processes—namely, ensuring that they are performed under current Good Manufacturing Practice.

“They wanted to see our batch records for our cultivation processes; they wanted to see our cleaning logs, our facility layout. That’s what they wanted from us as a manufacturer,” Ferrarese said. “To get what they needed, they requested potency and stability results. They wanted to see microbiology results (showing) that it didn’t become contaminated over time. But really they were worried about degradation and contamination, namely purity and quality.”

“What happens to this tablet after six months, after a year? Is it still the potency that we formulated? Because that’s going to impact the patient’s experience and the study outcome. We had to make sure that each formulation in the study was standardized and consistent. Compiling all the information and documentation took about a year. It took the FDA about four to six weeks to come back and say, ‘Your study may proceed,’” Ferrarese said. CT Pharma did this for both the spray and the tablets, he added.

While the FDA requested “reams and reams” of information from CT Pharma, no one from the company had to meet with FDA officials; that left the discussions up to Sinha and other Yale researchers. In early November 2019, subjects were recruited for the study, which was supposed to start in January and last eight weeks.

In addition to getting FDA approval for the study, CT Pharma needed a research license from the Connecticut Department of Consumer Protection, which conducts regular visits at CT Pharma.

“There were many moving pieces to bring this together,” Ferrarese said.

CT Pharma’s success attracted investments from private equity groups Tuatara Capital and Bonaverde Capital, which acquired the cannabis outfit about 18 months ago. “They were attracted by the research aspect of the company and the potential of a new drug application,” Ferrarese said.

Ferrarese believes the end result will be an FDA-approved tablet that will be on the market within five years. The estimate is based on the time between when the FDA first approved GW Pharmaceuticals’ Epidiolex product for study (2013) and when the agency approved Epidiolex for market (2018).

 

Tetra Bio-Pharma’s Smoke Study

Tetra Bio-Pharma CEO Guy Chamberland had worked with FDA regulators since 1995, but despite his professional experience, “the FDA wasn’t too happy” when he first broached the idea of bringing to market a smoked cannabis drug to treat pain in end-of-life cancer patients in June 2016. But after several meetings with FDA officials and a rule change that gave him an opening, Chamberland succeeded. How did he do it?

In November 2016, the FDA revised guidelines about drug-delivery devices that Chamberland believed would allow him to characterize pipes and vaporizers as delivery devices, with cannabis smoke and vapor (as opposed to dried flower) serving as the drug.

In a meeting with the FDA shortly after the device regulations were revised, “we laid out how we would develop and bring to market a prescription drug that was going to be smoked with a pipe and dried bud,” Chamberland said.

“We laid down our full plan for the Phase 1 trial and the trials that would be Phase 2 and 3, and then all the way to the market. We made some proposals to them on the toxicology requirements as well as further regulations (and) how we saw the device being approved,” he said, adding that the FDA provided Tetra Bio-Pharma with more than 29 pages of detailed guidance. “The FDA laid down what they expected not to see in the smoke. And they were the ones that pushed us to go out there and really quantify everything that was entering the patients’ lungs and really have a look at it. So we did achieve that, and they wanted us to relate that back to the fresh plant, which we did.”

In the Phase 1 trials, conducted in Canada, volunteers smoked and vaped three varieties of cannabis provided by Ontario-based Aphria while researchers measured what was in the smoke and vapor—and whether it was safe. Chamberland and other Canadian researchers set up their studies to comply with FDA guidelines so they can show that previous studies have been done according to the agency’s standards.

“We amassed a massive amount of clinical data in volunteers and in the lab, and it gave us a very clear insight into how cannabis works in patients. And that’s accelerated our program to where we are today,” Chamberland said.

Some of the most pivotal data had to do with smoke and vapor composition, dosing and mycotoxins.

“In that research, we ended up discovering some very unique aspects to smoke versus vapor. We described from a regulatory point of view that vaped cannabis is different than smoked cannabis. They’re two different drugs. There’s a change in the cannabinoid profile that’s different between smoked and vaporized. There’re also differences in the terpenes,” Chamberland said. Essentially, if you take one bud, break it in half, smoke one half and vape the other, the cannabinoids, terpenes and amounts they are distributed in will be different in smoke and vapor.

Tetra also studied the doses patients could handle without suffering adverse side-effects such as fainting or being too intoxicated to speak. Researchers also found that subjects rapidly developed a tolerance to cannabis and, if they slowly exposed subjects to the drug over five days, they could avert side-effects.

“That’s key, because if you’re hitting patients with cancer and palliative care, you don’t want them to stop taking the medication because of adverse events,” Chamberland said. “We were able to show in volunteers that we could eliminate that with a simple titration strategy that we now include in all of our trials.”

Tetra Bio-Pharma also discovered, shortly before they planned to submit an Investigational New Drug application (see “Steps for Cannabis Drug Studies”), that the flower they were using had developed mycotoxins during the drying and curing processes. That forced them to shut down the study.

“Until we had … a better way of ensuring that the lots were mycotoxin-free, we terminated the project. We also shared that with the FDA, so they were aware that we had done that. We voluntarily sent them all the information on the mycotoxins,” Chamberland said.

Rather than abandoning the study altogether, Tetra used the opportunity to tighten its contaminant monitoring protocols. The company also developed new mycotoxin-prevention-and-monitoring strategies, such as sterilizing grow rooms after harvests and using DNA sequencing to identify fungus genes.

When Tetra presented this data to the FDA, the agency allowed the trial to be “reactivated,” granting the company an Investigational New Drug application for a Phase 2.

“We were transparent; we showed them everything we knew about mycotoxins and how we now control them, and they came back and said you can move forward. That, to me, is really positive,” Chamberland said. “Because we were transparent, we burst the bubble. We said, ‘We discovered this quality problem, here’s how we address it, here’s how we now ensure patients are safe.’ And they said, ‘Go.’ It would have been a great time for them to say, ‘Nope, take a hike.’ But they didn’t. That shows there is an opening from the FDA to bring cannabis smoked drugs to the market.”

There are several more steps for Tetra to bring cannabis to the pharmaceutical market, including further studying the composition of cannabis vapor and testing these products against placebos. These tests will be conducted by Dr. Sue Sisley, a pioneering physician researcher based in Arizona. Chamberland is confident that cannabis will easily beat the placebo, because patients—usually sooner rather than later—figure out when they are not high that they are on the placebo.

“That creates what we call a bias. And the patients will be reporting more negatively when they realize they’re on the placebo. The FDA and its northern counterpart, Health Canada, know about this bias, but there’s no choice, you have to do that. Morphine, opioids and other drugs went through the same thing,” Chamberland said.

He believes the FDA approving cannabis to treat cancer pain is more of a question of when rather than if.

“We’ve developed this as any other drug, so when we talk to the FDA (or) Health Canada, we basically need to have data for each regulation they have. We’ve never requested a different path from the classic path for drugs,” Chamberland said. “The next stage is comparing it once and for all in the pivotal trial against placebo. And the next result, if it works, is that it’s there for patients. That, to me, is an amazing achievement for our company … and that would be a major success for the cannabis industry.”