Most wanted – recruiting volunteers for clinical trials

The difficulties of recruiting volunteers for clinical trials are well documented in this magazine, but the slow progress being made on the issue means that it continues to be an important topic of coverage.

Recruitment accounts for around 30% of the trial timeline and shortfalls in the process are the most commonly cited reason for missed deadlines. According to a 2006 study, up to 50% of randomly controlled trials fail to recruit to target and only half of those that succeed do so to schedule.

This is a sadly familiar state of affairs. Estimates in the region of 50% have emerged from papers published in 1984, 2001 and 2003 (in the British Medical Journal, Journal of Clinical Epidemiology and Family Practice, respectively) with the findings of a 2009 survey by the Tufts Center for the Study of Drug Development painting an even grimmer picture. It found that two thirds of US clinical trial sites failed to meet their patient recruitment targets during 2009.

The medium-term commercial impacts of delayed clinical trials are considerable. With the cost of developing a new drug now up at around £1.15 billion ($1.90 billion), according to the Association of British Pharmaceutical Industry, a delayed or cancelled clinical trial just adds to an already gigantic cost burden - and clinical trials account for around 40% of research and development funding.

A slow time to market is not just a competitive disadvantage but can negatively impact patient well-being. A 1992 study estimated that 10,000 unnecessary deaths were caused in the US by delays in recruitment to a clinical trial of streptokinase in acute myocardial infarction. Perhaps most importantly, a lack of numbers affects the efficacy of a trial and can further discourage participation.

Too small a sample could result in clinically important effects being reported as statistically insignificant, leading to the abandonment of a clinical intervention before its true efficacy is established. It could also further discourage participation, as patients who invest their time and emotional energy in a trial are told that it will no longer go ahead.

These issues are common to clinical trials across the board, but in trials involving rare conditions or vulnerable groups of patients, such as babies, it is far more pressing.

A global recruitment and retention manager at one of the world's largest pharmaceuticals firms, who asked not to be named, focuses primarily on clinical trials that focus on rare conditions.

"In haemophilia, for example, it has been a huge problem to recruit patients for many years," she says. "It was almost impossible. We always had to postpone and exceed the period of recruitment because we were never able to recruit patients within the timeline defined in the protocol."

Rules of attraction

There are many reasons why clinical trials fail to attract the necessary participation. Firstly, there is a general lack of awareness. According to a 2011 study by the National Institutes of Health, a US-based biomedical research facility, 85% of patients were either unaware or unsure that clinical trials were an option at their time of diagnosis. A piece of research carried out the same year in Ireland found that 91 out of 100 respondents who had participated in a clinical trial were pleased to have done so, implying that just getting the message out could have a very positive effect.

Having said that, reasons for delays are multifarious and occur not just at patient level. A 2006 study found that consultants were sometimes reluctant to put patients forward for trials because the patient had a preference for a particular kind of therapy or didn't have sufficient understanding of the trial and the therapy to go ahead with it. A 'Lasagna's law' situation, as it is known, plays out, where researchers and clinicians overestimate the number of patients willing or eligible to participate in a study, and a rapid decline in enthusiasm follows.

Recruitment is affected by so many different factors that coming up with a solution is far from easy. Most seem to agree, though, that thorough long-term planning and a well-conceived feasibility study are vital, especially in a business where small details can have a huge impact in the later stages of a trial.

Realistically assessed sites and a clearly defined, succinctly expressed study protocol are vital, and in some cases it can be sensible to consider relaxing the exclusion criteria. At the same time, patients who will likely be unable to comply with the follow-up requirements - such as those of no fixed address or with possible plans to move away - should be removed from the trial at the very start. One head of recruitment told Clinical Trials Insight that creating a separate position purely to deal with such issues has been hugely beneficial for her company.

"I used to be a trial manager, for many years," she said. "When this position was created and I got hired, things changed a lot; when trial managers worked on doing amendment and budgets, I could continue to focus on recruitment and that is a true advantage. I don't think we've had any recruitment problems in the three years I've been here. It's a good track record and that's not to brag - it's just a fact."

Flexible approach

With greater planning must come a greater willingness to bend to the will of the participant, particularly those with rare diseases or who belong to vulnerable patient groups. This is a lesson that the aforementioned haemophilia specialist has learned and one she thinks can be shared throughout the industry.

"If you want a small child to participate in a clinical trial, you must interact with the entire family," she says. "You must make agreements with the sites and support them in a way that they can see the families on different terms. Maybe they can see the families late afternoon or early morning, if that's most convenient? It calls for huge flexibility and the pharmaceutical company must really support this flexibility."

She continues, "And I think it's to the benefit of the patients that these ideas are shared among companies, and countries and therapeutic areas. Recruitment is not rocket science - it's very much about focus and energy and that should be shared.

This is part of a general culture of innovation that those spoken to for this piece all emphasised. New ideas should be encouraged and tried in unison from the very start of the trial.

While new approaches, such as using social media to reach out to prospective volunteers, hold potential, the real value is in bending over backwards to meet the needs of clinicians and patients.

"More of the same gives more of the same," says one recruiter. "You have to build task forces, come up with new ideas and negotiate with management to implement them. For example, it's easy to implement networking activities and training. I'm visiting a lot of sites, doing face-to-face activities with doctors and nurses, making them feel empowered, and it works very well. You make a proper plan and then carry out all your activities in parallel; you don't take one activity and wait and see."

Time and capital

The main obstacle here is money. Or in the words of one recruiter - "it's not about saving a trial - realising after a certain amount time that you are in deep shit - but having the budget and plan up front in parallel with protocol development". Securing financial support is far more difficult than it was before the financial crisis, yet small successes can convince management to loosen the purse strings.

"A good recruitment plan requires budget. You have a proper plan and then implement it in one go. It can be difficult, but when you've proven it to be effective, it motivates management to say 'maybe they're right. Maybe this works'. The flipside is that you can never really measure what the most important bit of your strategy is if you implement a lot of activities in parallel. But I believe in the pharma industry that we cannot wait for things to happen - time is so valuable for us that we really have to try a lot of innovative ideas from the very beginning."

For this approach to work, it is important to be patient. It takes time before the true benefits of an innovative strategy become apparent and managers need to be realistic from the start. This is especially so in the case of vulnerable patient groups. "If we in our previous planning said we'd go for six months, maybe we should go for eight or nine months and not be so disappointed when it isn't working," says one recruitment head, who did not wish to be named.

"Let's be realistic up front. Vulnerable or rare populations don't work well with this huge push. They may need a little more time, and we should be ready to give them the time they need and implement it in our planning. We must design our strategy to reflect the situation and not just do the same thing that we usually do."