Clinical trials are the bedrock of medicine and medical research, a series of research studies that evaluate the safety and efficacy of new treatments. These might be new drugs, new ways to use existing treatments, new surgical procedures, or new devices.
James Lind performed the first controlled clinical trial in 1747. His experiment onboard a navy ship demonstrated that oranges and lemons were a cure for scurvy, a disease resulting from a lack of vitamin C that had been a major scourge for sailors on long voyages. Since then, many other trials have changed the course of medicine and saved and improved the quality of lives of countless millions.
In this three-part interview-based article series Dave Selkirk (CEO and founder of Whitechurch Pharma & Biotech Consulting), a pharma industry veteran with three decades of experience discusses the most significant challenges to delivering clinical trials on time and how the rapid development of COVID-19 vaccines will impact the future of clinical trial execution among other topics.
In part one, he focuses on the importance of clinical trials and the pivotal role of healthy and patient volunteers.
Every drug, device, and therapy introduced to improve humanity's health and well-being needs to be very thoroughly tested for both efficacy and safety. That is a very long process. You first have to start with animal models to demonstrate you have likely efficacy in the target organ area and target organ systems you are trying to impact and that there are no scary safety problems.
Then you move into humans and start doing first-in-human studies where you generally involve healthy volunteers who will take the medication. You are looking for any safety signal that says that what you saw in the mammalian models (typically one primate and one rodent) is essentially going to be safe in humans.
You then move onto dose-ranging studies where you are looking for the specific dose that is the correct level.
The dose is obviously important
You may have heard that expression all medicine is poison; it just depends on the dose, and that's very true. Finding the right dose or right range of doses to get a therapeutic effect without creating toxicity is important. You measure that from your animal studies and extrapolate it to the human being, but you can never be sure until you test it.
From there, you go onto phase three, which is the large pivotal study that involves larger groups of people. You expose more numbers so you can get a degree of statistical significance in your findings. And at that point, you can make a submission for marketing authorization to regulatory groups for their assessment of the efficacy and safety data you have collected. Then you ask for authorization.
That whole process can take many years, often an entire decade or more, and cost in some cases more than one billion US dollars. The time aspect is very important and can't necessarily be shrunk except in some cases where there is a breakthrough designation as an important efficacy and safety step forward. You need time to ensure you measure these things and give the drug time to demonstrate both positives and negatives that will happen in human metabolism.
Why are healthy volunteers used in clinical trials?
Healthy volunteers are absolutely vital for clinical trial progress. Unless you are doing some cytotoxic treatment, which is sometimes the case for disease indications like oncology, where perhaps it is unethical to treat a healthy volunteer. In many other cases, it is appropriate to start with healthy volunteers.
The science behind that is you need to understand the pharmacokinetics. So, what happens to the drug once it is in the body? How quickly the body metabolizes it, breaks it down, excretes it, and absorbs it. And also, the pharmacodynamics about what the drug does to the body.
You measure telemetry in terms of what is happening to blood pressure, heart rate, to all the types of homeostatic systems that regulate our health. It is absolutely critical we understand how those things function and interact, human being to molecule or therapy. Without the healthy volunteer, we simply would not have the drugs we have today.
Why do healthy volunteers participate?
It is somewhat of an altruistic action to volunteer for a clinical trial. There is not necessarily a direct health benefit for those individuals. They're really contributing to science. And of course, I think it is appropriate for those individuals to be reimbursed for their expenses to be cost-neutral to them. Sometimes they have to travel and pay parking expenses and take time off work.
These healthy volunteers are advancing science and truly enabling people with diseases to be cured in many cases. Throughout our human history, there have been several incredible achievements that have come from the fact that healthy volunteers have put themselves forward for participation in these studies.
Is there a risk to their health?
I would say, in general, the risk is quite low. We do a lot of research on animal models. You are doing a rodent and a non-rodent model, at the very least. Those models are selected based on the disease indication and how closely their metabolism matches the human being. Researchers are doing everything they can to choose animal models that are very predictive of what will happen in humans.
There is a very clear process and a very clear regulatory level of scrutiny that is looking at the data before any human being is allowed to receive the therapy. That being said, the risk is not zero, and that does depend on the type of molecule.
If it's a molecule with a mechanism of action that has been very clearly established, and perhaps there's some new dose administration format (maybe an injection is being switched to an oral capsule), the risk in those types of scenarios is much lower. Whereas if a molecule is new or has an entirely new mechanism of action, we do our best, but the risk is not zero. So, it is an important consideration.
How do the people who run clinical trials decide who can participate? Can any healthy person take part, or do they have to fit set criteria depending on what is being investigated?
For healthy volunteer studies, the individual generally needs to be healthy, and there is a set of inclusion and exclusion criteria for every clinical trial. For example, you don't have various disease conditions, you don't have various infections, and you're not actively sick right now. If any resting conditions are allowed, there can't be exacerbations.
Often people of reproductive age are asked to use methods of contraception. That's quite common to prevent anything that might alter or have a genetic effect that could be passed down to the next generation. So, yes, there are very specific inclusion and extrusion criteria in every clinical trial, whether it's a healthy volunteer or later on when they involve patients with particular disease indications.
In the next article in this three-part article series, Dave Selkirk looks at the major challenges facing clinical trials and how CenTrial can help solve the biggest of them all.