Reality, as they say, has a surprising amount of detail, and drug trials are no exception. Even my company’s drug trial, which is about as simple as drug trials get, has a lot of moving parts behind the scenes. I thought I’d give you all a sense of what goes into it.
So, first of all, some context, which you may already be familiar with if you’ve been following our journey. We’re currently about ¼ of the way done with a trial in cats to compare our combination of cyclosporine + our metabolic inhibitor versus cyclosporine alone. Our plan is to get evidence that our combination allows for less frequent dosing, more consistent blood levels, and fewer side effects/safety issues than normal cyclosporine.
Eventually we want to get our drug to be the first approved therapeutic for feline stomatitis, a devastating autoimmune disease that affects about 1% of cats. Then we want to go onto human autoimmune disease. But, first, we’ve got to get this comparison of our combination vs. normal cyclosporine.
This is a much clearer trial outcome than the average pivotal/phase 1 trial. If we were working with more experimental drugs or trickier indications, we’d have to worry about how to dose, how to measure the dose (including potentially developing new assays), what a successful outcome would look like, and how to tell if it failed. For example, new Alzheimer’s drugs have a host of problems to deal with in phase 1 trials in healthy volunteers:
1. How much drug needs to end up in the brain?
2. If we’re dosing orally, how much do we need to dose orally to go to the bloodstream to end up in the brain?
3. How do we measure the concentration of the drug in the blood?
4. How do we measure the concentration of the drug in the brain?
5. Given that these will be healthy volunteers, what sort of biomarkers will indicate that this would have an effect in diseased patients, if any?
6. How much risk is acceptable for healthy volunteers to take when testing this new drug?
7. How can we tell if they’re getting sick from this drug?
8. What happens if our volunteers get really sick or die? How can we limit the chance of that happening?
Each of these questions has a tricky answer which is part science, part extrapolating from animal or in vitro models, and part guesswork. And there’s always the danger of getting a number wrong and trashing your whole program. Maybe your drug would have been safe and effective at 5 mg, but you decided to dose it at 10 mg because you miscalculated the amount that would pass the blood-brain barrier. That caused a brain bleed in a healthy volunteer, which caused the phase 1 trial to be stopped and your whole multimillion dollar, multiyear effort to be stopped by regulators. Whoops.
In comparison, our life is easy. We know the concentration of drug we want, how to measure it, and what safety risks to watch out for. Also, because we’re dealing with cats, it’s not as big a deal if we make a safety mistake, although we’re still incredibly careful.
However, our life is just easy in comparison. In absolute terms, our drug trial is still quite difficult.
So, here’s what we actually needed to do to get our drug trial to where it is. We needed to find 18 male, short haired cats and house them for the couple months necessary for the whole trial to run1. We needed to give them food and toys for those few months. We also needed to give them the drug, then take 28 blood samples per cat in total over the two active weeks that the trial is going.
Over this entire time, every part of every cat’s life needed to be carefully recorded: eating, pooping, breathing, etc. Anything that was off needed to be carefully noted and immediately brought to a vet, who decided whether or not any aberrations were serious enough to pull the cat from the trial. This exhaustive dosing and monitoring required multiple full-time technicians.
Each of these blood samples then needed to be safely stored, and then transported to a lab as soon as possible while it was still fresh. This lab then needed to run custom-built assays on these blood samples to test the concentration of the drugs in the cat’s bloodstream. These assays need to work on cat blood, which is different from human or dog blood.
In ye olden days (basically as recently as the 90s), we would have had to do all of this ourselves. This would have been incredibly annoying and very expensive. Buying, housing, and monitoring 18 cats alone would have been an ordeal, and building out a bioanalytical lab would have required a building, equipment, and a team who knew how to outfit and handle all of it.
Fortunately, in today’s modern economy, there are clinical research organizations (CROs) who handle this. So, we paid a company in Canada to run the cat trial. They already have cat facilities and a vet on site. We then had to pay a separate bioanalytical lab to work with the first company, so they could collaborate and get the blood samples processed at a reasonable amount of time.
This was not a “pay and forget it” process, though, by any means. The CRO in Canada, like all (good) CROs, is an expert at running cat trials in general. They do it a lot. However, they are not experts in the drugs we’re working with, the tests we’re hoping to run, or the indication.
That means there was a huge amount of back-and-forth as we had to get the logistics specific to our drug functioning. This included planning out the specifics of the trial as a 3-way discussion between us, the CRO, and the bioanalytical lab (ultimately ending up as a 60-page document); shipping the drug through customs2; providing step-by-step instructions on how to prepare the drug in formula for administration to cats; and constant communication on whether small aberrations in the trial protocol were ok.
You know, one of my hopes is that by publicly documenting all the work I’ve done to get here I can help other people follow in my footsteps. I get contacted semi-frequently by people who have great ideas for drugs of their own and aren’t sure where to start. I certainly had no idea what was required when I started on this journey 1.5 years ago. Well, this is it. It’s a lot of details.
Our trial is run by testing the metabolic inhibitor by itself first, to get baseline safety and pharmacokinetics. This takes a week. Then we pause to get bioanalytics back and give the cats time to reset from the drug and having their blood drawn. Then cyclosporine is combined with the metabolic inhibitor, and we get safety and pharmacokinetics from that. Then we need to get bioanalytical results from that too. All of this takes a couple months.
Canadian customs takes shipments of white powder through the border very seriously. It’s a whole elaborate process. I was half-tempted to just hollow out a watermelon and shove the drug in there, but I decided that would be a bad look.