Trial and terror: 'An accident of exceptional gravity'
One man died and several others are critically ill following a clinical trial in France. Rare as such incidents are, it demonstrates that drug development is not without risk but such voluntary testers are essential if we want medicine to improve.
The six men - aged between 28 and 49 - were all pronounced perfectly healthy. They were among 90 people who were seen as ideal candidates to test a new drug developed by Portuguese firm Bial to treat mood disorders such as anxiety. And when they arrived at the Biotrial Clinic in the French city of Rennes on January 4, these paid volunteers are unlikely to have thought that anything serious could go wrong. After all, France has one of the world's most regulated drug industries and they would be spending a week at a state-of-the-art facility where they were under constant medical supervision for this Phase 1 test - the name given by the pharmaceutical industry to the initial human testing that establishes whether or not a drug is safe for consumption.
But something very serious did go wrong. At the end of the trial, the six men were taken to hospital where one died within days and four of the five others are suffering from what's likely to be irreversible neurological damage.
Investigators are frantically trying to work out what could have gone wrong with a drug that, initially, was erroneously reported as having cannabis in its make-up. In the words of France's health minister Marisol Touraine, it was "an accident of exceptional gravity... without precedent."
It's news that is likely to reverberate throughout the pharmaceutical industry for quite some time, but those at the centre of drug trialling will be hoping that it does not deter volunteers, whether completely healthy or sick, from taking part in one of the least talked about, and yet most important, areas of medicine.
Dr Graham Love is chief executive of the Health Research Board and insists that it is impossible to overestimate the importance of clinical trials. "For any medical advancement to happen there has to be very extensive clinical trials and in their own way, those volunteers who take part are every bit as vital as doctors. Without them, the drugs that have come on stream over the past couple of decades, and change lives, would not have happened.
"When I heard the news [from France] I thought, 'Oh no, just when we're trying to get more people to take part in clinical trials. I don't want to trivialise what happened there, because of course it was serious, but something like that is exceptionally rare. Of the hundreds of thousands of clinical trials conducted all over the world, you might have a minuscule number of anomalies. It's research that is very highly regulated, but you can never say that there is zero risk."
It's a sentiment shared by Eibhlin Mulroe, head of ICORG - the All-Ireland Co-operative Oncology Research Group. "You can never say that there aren't risks," she says, "but it's an area that's very well monitored by the Health Products Regulatory Body [formerly the Irish Medicines Board] and by ethics committees in the hospitals.
"The benefits are enormous, especially when you look at the drug advancements in an area like breast cancer. Those drugs, which are life-changing, were only made possible because of clinical trials."
One of those drugs, Herceptin, is now firmly established in cancer treatment. Rhona Nally, who was diagnosed with HER2-positive breast cancer in 2003, was among those who took part in the groundbreaking clinical trial to use Herceptin for the treatment of primary cancers. Back then, it was used for secondaries only. "The study showed how effective it could be to treat certain types of primary cancers," she says. "Those of us who took part had to undergo extensive checks, including our heart health, and we were told about the potential risks involved."
For many clinical trials, participants are divided into three: those who are given the drug, those given a placebo and those given nothing. Rhona Nally fell into the latter category. The following year, she developed a secondary in her spine and received a poor prognosis. She was immediately prescribed Herceptin and is in good health today, almost 12 years on.
At present an estimated 3pc of cancer patients in Ireland are taking part in clinical drug trials according to Robert O'Connor, head of research at the Irish Cancer Society. "We really need to get that number up [by contrast, 5pc of cancer patients in the US are trialling new drugs]," he says, "but then, many patients are very keen to try alternatives because they can find that their options are limited." But with strict ethical guidelines in place, not every seriously ill patient who wants to be part of a clinical study is deemed suitable.
According to Dr Graham Love, the proportion of Phase 1 trials involving perfectly healthy patients in Ireland is low. Much of that work tends to be carried out outside the EU. And, yet, a number of current Irish studies, including the acclaimed work into blood cells conducted by Dr Michael O'Dwyer, haematologist at NUI Galway, involve some healthy volunteers.
Ronan Fahey, who works as a project officer at the Health Research Board, volunteered his services for a Phase 1 study for a new malaria drug conducted by Beaumont Hospital, Dublin, in 2011. As someone with a science background, he says he was especially aware of the potential risks and those were extensively outlined to him before he began the treatment. "I had flu-like symptoms and was in bed for a day," he says. "I'd never had that before, but I'd been told it could happen so there was no surprise."
The trial lasted "between 12 and 16 weeks" and although he was paid for his contribution, he says the fee essentially covered travelling expenses and missing work on occasion, and amounted to little more than a few hundred euro. "I wasn't doing it for the money and I don't think you'd want to," he says. "Of the other volunteers I met there, one had been to countries that suffered badly from malaria and saw the sort of devastation it can cause, and another was a fireman. I think this sort of study would appeal to those who see the bigger picture and have a sense about how crucial it is in order for drugs to be developed properly."
Fahey says he would consider taking part in a similar study in future and says he would not baulk at the demands made of participants in a recent Oxford malaria study - they were required to be bitten by mosquitoes in a controlled environment.
While practically all Irish clinical trials have passed without incident, one, at the now-defunct Shandon Clinic in Cork in 2010 had to be terminated after three participants required hospital treatment after becoming ill while participating in a 12-man study on cancer medication. Each of the men made a full recovery, but the clinic went into liquidation shortly afterwards.
At the time it was Ireland's only stand-alone clinical trials facility and, it was reported, in the early years of recession it was receiving 400 applications per month for paid work, mainly from young males aged 20 to 25. Depending on the study in question, it paid up to €130 per day.
Now, the vast bulk of trials are conducted in hospitals, with the Mater and Beaumont leading the way. In the past decade, the Health Research Board has invested €100m in clinical research infrastructure and several key trials have started, or are about to start in the coming months. They include: trials to help prevent second strokes and heart attack after a first stroke episode; stem cell trials to improve blood flow in legs of diabetic patients; trials in GP surgeries to reduce inappropriate use of antibiotics for urinary tract infections and the first national drug trial in pregnancy, assessing the use of aspirin in low-risk women to prevent pregnancy complications.
Research is also being conducted in establishing whether giving 'fresher' blood versus 'older blood' in transfusions makes a difference to patients who are admitted to the Intensive Care Unit and trials in blood cancer to see if new treatments can be combined with existing medication for better outcomes.
"It's an exciting time and the groundwork is being laid for improved medication and treatments in the future," says Dr Love. "The people who volunteer are doing invaluable work and future patients will reap the benefits of. It's a bit like giving blood - you may not want to get off your ass and do it, but if you do, people you've never met can be saved by your actions.
"Hopefully what happened in that French clinic will have no detrimental effect on the numbers that put themselves forward for clinical trials." He says if prospective candidates knew just how stringent the guidelines were and how challenging it is to fulfil all the criteria to get a study off the ground, they would likely be even more assured.
"The research is very patient-focused," adds Eibhlin Mulroe. "They can stop at any time - the power is always with them, and the risks, however minor, are always explained."
Five stages of drug testing
Clinical testing of drugs can take 10 years or more, from start to completion. Here are the five stages:
Pre-clinical: testing of drugs in laboratory conditions and on animals.
Phase 1: Testing of drugs on healthy volunteers for dose-ranging - to determine the safety and effectiveness of the drug. Typically, the number of participants ranges from 20 to 100.
Phase 2: Testing of drug on patients to assess efficacy and safety - to establish if the drug can have any efficacy; at this point, the drug is not presumed to have any therapeutic effect whatsoever. Between 100 and 400 participants.
Phase 3: Testing of drug on patients to assess efficacy, effectiveness and safety - determines a drug's therapeutic effect; at this point, the drug is presumed to have some effect. At least 1,000 participants.
Phase 4: Post-marketing surveillance - monitoring drug use in public as soon as the drug has been licensed for use