New recruits: Cancer Research UK

Ryan Wilson, a 19-year old plumber from North London, had been looking for a way to make some extra cash. Participating in a clinical trial was an attractive way to achieve this, and so, after coming across an advert, he signed up for the first-in-human study of TGN2412 - a supposedly breakthrough drug for leukaemia and arthritis - with few qualms.

He and six other 'guinea pigs' would be paid £2,000 to take part in trials at Northwick Park Hospital. Easy money, they thought. But within minutes of being injected with the experimental therapy, several of the men's heads had swollen grotesquely. Four suffered from multiple organ dysfunction and were lucky to survive. Wilson was in a coma for two weeks, and afterwards, his toes and the tops of his fingers had to be amputated.

The drug, developed by TeGenero Therapeutics, and trialled in March 2006, was administered at 500 times lower than the safe dose for animals. No one had foreseen the severe problems that would affect Wilson and the other participants.

"The very fit young men were absolutely walloped with the same drug in one go and immediately fell desperately ill," says Kate Law, director of clinical and population research at Cancer Research UK. "It happened because preclinical work doesn't always predict what the toxicity will be, or what the maximum tolerated dose should be."

Luckily, the Northwick Park case was extremely rare, but it has made people even more careful about the way new therapeutics are tested. Law explains that early-phase clinical trials can be challenging because recruitment to them is slow, but for good reason. A small number of patients are given the drug and you have to wait until they've passed the point you would expect acute toxicity (usually three to four weeks). Only then can you up the dose and enrol the next few in the study.

"Even if you had 100 patients jumping up and down, you are not able, legally or ethically, to give them all your new drug and do it in one go," emphasises Law, who has overseen around 250 academically sponsored clinical trials in her 20 years at the charity.

Despite the relative risks and time-consuming nature of early-phase trials, it's not as challenging as you might think to engage volunteers, especially when trialling cancer therapies. There are many reasons why these are tricky trials, but it's not because people don't want to take part in them.

"Because they're unproven they can usually only be given to cancer patients who may have been through four or five lines of previous standard care," says Law. "They're coming toward the end of their lives, but they still need to pass criteria that they are fit to take part in a novel agent trial. And that's a big hurdle to pass - they have to have certain levels of liver, renal and cardiac function to make sure the novel agent doesn't kill them. And that screens out a huge number of advanced cancer patients.

"They may be very keen to take part, but if they just get one blood test out of line, that's them off the trial," she adds.

Late-stage recruitment

Law believes recruitment is actually a much bigger challenge further down the line, in phase II or III trials. She puts forward the example of a breast cancer patient. If caught early, the chances of being treated effectively are pretty good anyway, so it's hard to make the case for a volunteer to go down a path that isn't standard care and try an experimental therapy.

"Or, another example is that we often attempt a phase III trial comparing very different treatments," she explains. "For prostate cancer, you might be offered either surgery, radiotherapy or watchful waiting and that's a very tricky study to get your head round because most people have a preference for either being cut open or not. To ask people to sit in a room while a computer decides which treatment they have is very hard indeed."

Compared with a phase I trial, where there's likely no placebo or alternative treatment, it's an easier talk to have with patients. They know there's no treatment available to them, so their decision is seemingly more straightforward.

"Really, it's about going into palliative care or having one last go at something that might work, which is why we don't get many turndowns at the early stage," says Law.

Most professionals agree, though, that generally recruiting patients to clinical trials is a big problem and cancer studies are no exception. Research suggests that around a third of trials fail to enlist their original target within the specified time. Law believes this is often down to poor patient engagement and the difficulties approaching a vulnerable person to sign up.

"Immediately after diagnosis, when you're in a room with a doctor and told you have cancer, and then the next minute they're saying 'oh and by the way would you like to go on a trial because we're not sure what the best treatment is', that's a lot to take on board," she states. "Whereas, if you're doing a blood pressure trial you're already on medication for it, and if the doctor asks if you want to try something different that might have fewer side effects, it's a much easier conversation.

"For cancer, you're getting a whammy of a diagnosis. Some people run for the hills at the whole notion, while others are happy to go ahead with it."

And in cases when recruitment is really poor, the trial might have to be stopped altogether. Law reveals this is rare - it's probably every two years the Cancer Research UK team has to do this - but it does happen.

"If a trial's going to take 20 years to finish because recruitment is poor, that would be really unethical," she says. "So with the agreement of the investigator and the trial's steering committee we do occasionally say let's call it quits, but it's rare. Mostly we try and find another way around it."

A lack of participants can have dire consequences. It means studies take longer and require more resources, at considerable expense to the sponsor. There's also the risk that the greater the study duration, the less relevant it becomes. With new drugs coming through all the time, how can you be sure the therapy you're testing is still going to beat the competition?

"You get it into the journal to report it, but nobody's bothered because the next drug has come through in that time," says Law. "That's rare but it does happen and who can predict it? Because you never quite know when a new therapy is going to pop up and derail the drug you've been working on." However, sometimes it's worth persevering, even if it's going to take a longer time to complete than expected.

"If we think it is still a worthwhile question, even if it's going to take twice as long as we'd hoped, we will keep funding it because it would be unethical not to," Law says. "Hundreds of patients who already agreed to go onto a trial thinking that they are not going to only hopefully benefit themselves, but will also benefit future cancer patients. You're kind of obliged to stick with it."

Design for life

One strategy for improving recruitment is engaging patients when the trial is in its design phase. If you can troubleshoot during the development of the study, you can locate the aspect of the trial that may put off potential participants. Law reveals that doing just this has vastly improved Cancer Research trials over the last few decades. Patients on the organisation's funding committees are particularly helpful with redrafting the volunteer information sheet, so it's written in the clearest way possible, meaning people that do sign up really know what they're letting themselves in for.

One trial Law has been heavily involved with is ProTecT (Prostate Testing for Cancer and Treatment). Men are asked to have either watchful active monitoring, radiotherapy or surgery. It wasn't recruiting well at first, but two key actions made a difference. The first was a change to the volunteer information sheet, making it clear the study was supported by patient groups and that the trial was asking a valid question.

"The other thing is they took the doctors out of the informed consent process and got nurses to do it," reveals Law. "Nurses aren't going to be the ones treating the patients, so they were far more neutral when they were describing the options. That's quite clever. It's very difficult for the doctors to do when they were either a surgeon or a radiotherapist. They're just used to treating it one way."

As Law points out, while recruiting cancer patients to clinical trials is challenging, learning from previous failures is the key to overcoming the hurdles. And though improving patient engagement is important, she is not convinced it's a sponsor's place to do this directly when it comes to cancer participants.

"If you're a student and you want to earn a few bob, you can easily make the decision to go on a trial, but certainly from a cancer point of view, you are extremely vulnerable when you've had your diagnosis," she stresses. "I think you have to be very cautious how the sponsor engages directly with the patient."

Cancer Research UK tries to include every cancer trial that's open in the country on its website. The organisation encourages pharmaceutical companies to give it details of their recruiting studies for inclusion on the page. For Law, that's a great model. Specialists translate the very difficult protocols into plain English, where people can see it and perhaps discuss it with their doctor. It gives patients an ownership of their illness. It could be the way forward, not only for cancer, but other disease areas.

After all, clinical development of a new therapeutic is a huge undertaking and requires vast amounts of money, so making sure studies are palatable to potential volunteers is important. Cooperating with an organisation that can more effectively and appropriately reach out to patients could be a good place to start.

Kate Law is director of clinical and population research at Cancer Research UK, the world's largest independent charity dedicated to scientific research to help prevent, diagnose and treat cancer. Law has worked for the organisation for 20 years, during
which time she has overseen around 250 academically sponsored clinical trials.