Would you ever volunteer to help test a new drug?
Your answer would probably be a resounding “No!” if you are a healthy individual.
But if you have a terminal disease like cancer, especially the types that do not have effective treatments, your outlook might be quite different.
The fact is, the process of developing new drugs and medical devices rely on human subject testing to determine their safety and effectiveness for future use in patients.
This is because of the complexity of the human body and the numerous biological process that go on in it – many of which are still not understood – that may or may not affect the drug and its intended effects.
Researchers can only make a reasonable estimation of how the new drug will react in human patients by testing them in fellow humans.
This occurs in the clinical studies stage of drug development, which begins after the molecule that is the basis of the new drug has been proven to have the desired effects in animal models.
There are three main phases to clinical studies.
Haematology-oncologist Dr Scott Fields explains that phase one studies are usually done with healthy volunteers to determine a well-tolerated dose of the new drug by monitoring the toxicity levels of a range of administered doses.
However, he says: “In oncology phase one studies, we usually don’t use healthy volunteers.
“The drugs are often too toxic – many of the drugs cause cancer themselves – and the goal is not to get to a tolerable dose.
“In fact, the goal is the maximum tolerated dose because we want to push the dose in general as much as we can, because in the old days, the cytotoxics did appear to have a threshold, so you want to push the dose as high as you can.”
He notes that this method is now changing with some of the newer drugs, which are developed hand-in-hand with an accompanying biomarker that allows researchers to accurately measure if the drug is already having its maximum impact.
The pharmaceutical company Bayer’s Oncology Strategic Business Unit Oncology Development head adds: “Sometimes, phase ones and phase twos in oncology kind of merge because in healthy volunteers, we don’t look for efficacy, but in oncology, we do look for efficacy (which is typically the goal of phase two studies).”
These efficacy trials can be of various types, including a single-arm study to see if the tumour shrinks, or a randomised study comparing the new drug to an established standard treatment for the tumour to see if the new drug provides any additional benefits like increased survival time.
Non-oncology phase two trials, he says, usually involve the testing of multiple dose levels of the drug against a control like an established standard treatment to see which one has the best effect.
Meanwhile, phase three clinical trials in oncology are similar to those in other medical conditions as they consist of a randomised study comparing the new drug against the best standard of care available for the particular cancer.
Dr Fields notes that sometimes there is no established best standard of care for the particular cancer under study; in such cases, the researchers and regulatory authority come to a consensus on which treatment they consider the best and use that for comparison against the new drug.
For cancers where there is no treatment at all, the comparison is usually a combination of the new drug and palliative care against palliative care alone.
This method can also be used for current treatments where a combination of the new drug and the chosen treatment is compared against the chosen treatment alone.
“In non-oncology, it’s often against a placebo, but we try not to use a placebo in cancer patients,” he says.
Problem With Patients
Clinical trials can be a huge endeavour, especially in phase three, involving up to thousands of patients and multiple healthcare centres, often in different countries.
According to the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) Facts and Figures 2017 report, the pharmaceutical industry in the United States spent a total of US$25.7bil (RM102.1bil), or 48.3% of their total research and development costs, on phase one to three clinical trials in 2014.
However, the success rate of a new drug making it all the way from its phase one trial to the market was 9.6%, or less than one in 10.
Compounding that are the challenges faced by researchers in the course of conducting the trials themselves.
According to Dr Fields, recruiting patients is one of them.
“The question is, why is it so hard?” he asks.
“One is cancer trials have become quite complex, and it’s getting worse.
“I’ve recently seen protocols that are 200-something pages – you can imagine the burden on patients and physicians who have to go through consent forms that are 30-plus pages.
“Sometimes, the complexity can scare off patients – and even physicians actually.”
Another two reasons are somewhat paradoxical: the lack of awareness of trials and the availability of too many trials.
“I’ve a lot of people who contact me and say, ‘I want to go on a trial, but I see like 50 trials in my disease, how do I pick?’
“And so it just becomes a bit overwhelming how to do it,” he says, adding that for some patients who have a disease with an excellent established treatment option, the answer is to skip the trial and try the current treatment first.
Distance is also another issue as most clinical trials are only run in certain large tertiary centres, and patients may have to travel long distances to get to them, which incurs extra cost and time.
As the trials are run by specific healthcare teams, “they have to leave their doctors – and cancer patients get very attached to their doctors, whom they’ve built a close relationship with – and you’re asking them to go to another doctor to get involved in a trial”, says Dr Fields, citing an emotional reason.
The requirement by regulatory authorities to strictly adhere to the eligibility criteria for clinical trials is also an issue.
In designing a clinical trial, researchers need to clearly state the criteria required of a patient to be able to participate in the trial.
However, this criteria, Dr Fields notes, can be somewhat arbitrary.
“When you try to design a trial, you have to put specific criteria, say like kidney function should be sort of like this – you have to put some number.
“Let’s say you have a creatinine clearance – i.e. how well your kidneys work – of 60 ml per minute, and you have a patient with 58, and otherwise, the patient fits all the criteria.
“In the old days, we could make an exception; today, regulatory agencies do not want exceptions – you either meet the criteria or you don’t.
“It’s really heartbreaking at times, you have to turn people away because you have a criteria that’s a bit arbitrary, and then the patient can’t go into the study.
“I can tell you when that happens, you often don’t want to look at any more studies, you’re just frustrated and it sends a bad message,” he says, adding that eligibility is really a big challenge for them.
Burden On Doctors
Another issue that Dr Fields says he hasn’t heard being talked or written much about is the burden clinical trials can place on doctors and healthcare institutions.
If the doctor is not the primary investigator (PI) on the trial, he or she has to go through the entire trial protocol and design to understand it, then explain the trial to not just the patient, but also their families or caregivers.
This can take up a lot of extra time and effort.
In addition, the doctor would have to do extra work, like collating data and filling out forms, for the trial.
“What was frustrating to me as a PI on a number of trials back when I was in academia, was that your colleagues just didn’t put patients who were eligible on trial”, due to this reason, says Dr Fields.
Less complex trial protocols, he feels, would make a big difference in this matter.
A more technical issue is the lack of suitable biomarkers to both indicate how well the drug on trial is achieving its target and to detect which patients would best benefit from the drug.
“I need a marker that can tell me whether I’m actually hitting my target, because if I’m not hitting my target, I don’t need to keep going,” he says.
“I also need a marker that can help pick which patients are going to respond,” he adds.
New Types Of Trials
There, however, have been developments in recent years to try and overcome these challenges, Dr Fields shares.
“Everybody is trying to figure out a better way to do clinical trials, and there has been a lot of progress in the last few years,” he says.
One of them is a basket trial.
This type of trial tests a therapy that targets a particular mutation in tumours, regardless of the type of cancer it is.
“It has the same multiple indications (for the different types of cancer), but you test each arm (comprising of one type of cancer each) separately.
“And then you look across the arms (for results),” he says.
Another type of trial is the umbrella trial, where you test multiple drugs against one type of tumour.
“Let’s just say you have patients with lung cancer, and you have drugs that can work against various mutations – EGFR, HAL, ROS, RET, TRKA, etc – so instead of having separate trials for each, when a lung cancer patient comes in, you sequence them and then you put them on whichever arm makes the most sense and test the different drugs to see if they work against the standard of choice,” he explains.
“These are really much more efficient trials than used to be done, and I think we will see faster development with targeted drugs,” he says.
Dr Fields was speaking at the workshop on Challenges and Opportunities of Drug Development in Oncology during the first Annual Pharmaceuticals Media Day held by Bayer at their Berlin, Germany, headquarters in December 2017.