Clinical trials occur in three stages. They can make or break decades of research, and bring medicine into the market, but can also be incredibly dangerous.
In the medical and biological space, there’s no better scientific evidence than a successful clinical trial.
The process can make or break decades of research, allow medicine to be brought to market, but if something goes wrong, can be incredibly dangerous.
Clinical trials are a research study which looks at a new drug, treatment or intervention in human participants. These trials occur in three stages – phase I, II, and III.
Phase I is usually done in a small group of less than 100 healthy people to test the safety and any side effects. Phase II looks at a larger group to see if the drug or product actually works, and phase III involves up to several thousand people, to test if it’s better than standard treatment.
That’s the simple explanation, but behind the scenes, there are whole teams of scientists ensuring that the participants doing the trial are safe, and that the trial is designed in the best way possible.
“Often people think statisticians just do the analysis at the end,” says Associate Professor Patty Chondros, a biostatistician at the University of Melbourne.
“But actually, the statistician’s role starts right at the beginning – at the inception of the trial.”
“It might be how to recruit participants to minimise selection bias … or how you might set up the data collection tools, or how to refine the research question.”
Without this effort from researchers at the beginning of the trial, the data at the end can be almost unusable.
“If you haven’t collected the right data – no matter what you want to do – there’s no amount of fixing it,” she says. “It can get very costly if you do it at the endpoint, or you might not be able to answer [the question you were asking].”
Clinical trials exist broadly in two different categories.
Firstly, there’s the sort of clinical trials Chondros works with – usually run by hospitals or universities. These are low or no payment clinical trials, which look at an intervention or some other product. This could be an app for COVID symptoms, or a support tool for doctors to help them provide better care for those with severe depression.
These sorts of trials are important, but are not as high profile as the second type of trial – the multimillion-dollar, pharmaceutical drug trials.
Depending on where you live, you might have seen the advertisements – almost every capital city around Australia has a for-profit clinical trial unit. These generally enjoy government support: they provide jobs and are seen to add lustre to the reputation of a state’s health and research sector.
For profit companies pay people hundreds of dollars a day to test drugs, products or other molecules that are not yet approved for use, and they seem to always be looking for more participants.
Australia punches above its weight in one particular area: early-stage clinical trials.
According to a paper published in 2020 on best practice in clinical trials, “Australia’s research capacity, capability and quality of research is revered”, and the sector has grown steadily over the past 10 years.
In many cases this might be the first time the drug or treatment has ever been used in humans, and this means there’s the most uncertainty about risks to the patient.
Most of the biotech or pharmaceutical companies who use Australia for these phase I and II trials are doing it for high quality trials, and a lack of red tape.
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To do an early-stage clinical trial in the US, companies have to go through the US Food and Drug Administration. This involves a series of meetings and a long lengthy process to get approval.
“In Australia, we just have a little bit less red tape,” says Zoe Harrison, the Chief Business Development Officer at CMAX Clinical Research.
“The ethics committees here have the skills and experience and the authority to approve the studies, and they work really hard to turn around reviews quite quickly. We’ve just developed this little niche expertise in this area, I suppose.”
If that’s not enough of a sweetener, they also have a lot of Government support. There is a Federal Government tax rebate of up to 43.5 percent on all clinical trial related research and development costs.
Of course, Harrison is quick to point out that this doesn’t mean Australia’s regulation is less safe, just less low-level bureaucracy – not lower standards.
“The requirements that we have to meet are the international requirements,” she says.
“There are standardised preclinical batteries of tests that you must go through before the study can go forward.”
Unfortunately, despite all this, the timeframes and costs are immense. For one successful drug it can take 10 to 15 years and around US $1 billion to develop and move through all three phases. It’s been reported that up to 90% of drug trials fail, although the success rates vary greatly.
A lot of this is to do with phase III trials where even after the drug has passed phase two trials, sometimes the company can’t cough up the large amount of money needed for a large phase III trial, or when they do, the drug is found to not be more effective than a standard treatment.
“There’s a valley of death in there between phase two and phase three,” says Harrison.
“It’s an astonishing amount of work and money that needs to go in to get a drug approved. Really frightening actually.”
In the north-east corner of the Adelaide CBD, right across from the Royal Adelaide Hospital is a tall, modern building with the letters “CMAX” plastered across the top.
The name itself, despite sounding like a Marvel superhero, is actually a nerdy play on words. Cmax is a measurement in pharmacology specifying the maximum concentration that a drug will exist in blood.
Inside, backpackers, students, workers and retirees sit in plush green seats, mostly waiting – either to be given drugs, or to see if they feel any effects.
At 28-years-old, CMAX Clinical Trials has been around longer than most for-profit clinical trial companies in Australia. In 1999 it was even the first place in the country to do a ‘first in human’ healthy volunteer study.
To even be sitting on one of those green seats is a rigorous affair. To even apply for these trials, participants need to fit into particular parameters for health such as a certain BMI and age.
The preliminary tests are first. Volunteers go through blood tests and physicals to make sure that they are ‘healthy’, and exclude any underlying issues that could affect the patients, or the results.
A declaration is made by the participant to retain all confidential information, and they have to agree that their de-identified data might be used by researchers in other trials.
It’s worth noting that it’s only the participants who get through all these stages and into the actual trial move from a ‘volunteer’ to a ‘participant’ and start getting paid for their time.
“We have a really long and quite dynamic consent process,” says Harrison.
“The participant is required to demonstrate that they understand [the information in the consent form] before they can come on to the study – and that’s a two-way conversation.”
Ian Mannix who works at Cosmos has been doing clinical trials for the past ten years – first in an unpaid trial at Royal Adelaide Hospital, and later as a paid candidate at CMAX.
Despite experiencing painful adverse reactions twice in five trials, he’d still do it again.
“The way that I see it, scientists are trying really hard and I want to support them,” the 60-year-old says.
“I think it’s important for the community for people to put themselves out, to accept the risk of testing drugs and to be part of the scientific endeavour.”
Ian explained that when selected, they enter a hospital-like clinic on level five of the building, where about 50 beds, complete with a range of monitors, hospital style curtains and endless name tags, trolleys with dozens of blood vials, and piles of towels and face-washers, surround the nurses station.
Candidates can be asked to participate from a day to a month, in house, for which they will be paid anything from a few hundred dollars to thousands.
Of course, like many people who do these for-profit trials, money is an important factor.
“At one stage I had run out of contract opportunities, and this was a financial option for me, so that was quite good. But you couldn’t live on it.”
But this is a difficult ethical tightrope for the companies to walk. Without money, no one would be interested in doing the trials, but with too much money, people might ignore the potential risks.
Much has been written about the poorest American’s making money by donating large amounts of plasma. For backpackers and others without a social safety net in Australia, the same risk could exist.
“I’m sure there were people involved in the same trials as me who were there only for the money,” says Mannix. “And they would have changed their attitudes and behaviours in order to make sure that they got [into the] trials.”
“I’m not sure how good the English language skills of some of the participants were. [The information] can be technical, and I always do some background research.”
Mannix says he was confident with the support by provided by the CMAX team despite these episodes. For him the trials ended at the moment of the adverse reactions – although due to the circumstances he still got fully paid – and he says the patient’s health is routinely followed up after the trial has finished.
The data is then analysed, a process which can take years. The participants are never told the outcome of the trials, and are none the wiser if their contribution created a new drug on the market, or a failure.
Ian Mannix is an editor for Cosmos. This story was independently written and Ian only spoke to us on his experience as a clinical trial participant.
Originally published by Cosmos as How do clinical trials work?
Jacinta Bowler is a science journalist at Cosmos. They have a undergraduate degree in genetics and journalism from the University of Queensland and have been published in the Best Australian Science Writing 2022.