Recruitment is one of the biggest – and most costly – challenges facing clinical trial sponsors today, with Alzheimer’s disease (AD) trials particularly difficult to identify and enrol trial participants for. But a new adaptive trial design being tested by a major European consortium has the potential to ease the recruitment process and improve the efficiency of trials for AD, while lessons learnt from the project’s innovative recruitment and retention strategies could be applied to other disease areas too.
The development of a new drug is estimated to cost between $1 billion and $3 billion, and take as long as 15 years, with a large proportion of the time and the cost burden falling on clinical trials – much of this during the recruitment phase. Indeed, according to the Manhattan Institute for Policy Research, 90% of drug development costs are incurred in phase-III trials, while other researchers have found that up to 30% of the timeline for the drug development process is spent on suitable subject enrolment and 45% of clinical studies are delayed because of difficulty enrolling participants. Moreover, more than two thirds of trial sites fail to meet their original enrolment goals for a given trial and 15-20% of trials never manage to recruit a single patient.
AD, which is expected to affect 100 million people worldwide by 2050, is one disease area that struggles to recruit participants even more than most. As Andrew Satlin, executive vice-president at Eisai Pharmaceuticals, explains: "It’s one of those diseases where, unlike many others, many people who have AD never get a full evaluation or are given a diagnosis, in part because of physicians not being familiar enough with the disorder, and also because of some lingering hesitation on the part of physicians and patients to talk about these kinds of issues because of fear of the loss of memory as you get older.
"So, while there are a lot of people out there with the disease, there are very many fewer who are being actively followed, diagnosed and treated, and, therefore, even thought about being considered for participation in a clinical trial."
In addition, with research increasingly focusing on the prevention of the disease or the delay of the onset of its symptoms rather than the search for a cure, identifying suitable trial participants has become harder still. "We’re trying to find people that don’t even know that they have a disease," says Luc Truyen, vice-president of neuroscience external affairs and chair of J&J Global Fight Against Alzheimer’s Disease.
Building cohorts
One project focusing on precisely this area, the Innovative Medicines Initiative’s (IMI’s) European Prevention of Alzheimer’s Dementia (EPAD) Consortium, is therefore testing wider-reaching recruitment strategies as well as an innovative adaptive trial design in an attempt to overcome some of the key challenges associated with enrolling – and retaining – people at risk of developing AD. The ultimate goal of the five-year project, which is a collaboration between 36 different organisations, including Eisai, Janssen, Novartis and Pfizer, is the prevention of dementia in people with evidence of the disease, such as biomarker abnormalities, who still may have few or no complaints or clinical symptoms.
When it comes to recruitment, the major difference between EPAD and a standard clinical trial is that, before subjects are enrolled in the project’s proof-of-concept study, they will be part of what will be known as the ‘EPAD Cohort’ – an observational study that will allow researchers to follow potential subjects and their disease progression. Not only will this ensure that the final trial participants are fully characterised before being enrolled, resulting in much lower initial screening failure rates, they will also be engaged with the idea of participating in a trial, thereby minimising the chance of later dropouts.
But if EPAD’s researchers are looking for people who don’t know whether they’re at risk of developing AD, where will the cohort’s participants come from? "There are a lot of observational studies already out there, cohorts that have been in existence for ten, 15 or 20 years, some even older," explains Serge Van der Geyten, EPAD coordinator and director for neuroscience external affairs at Janssen Pharmaceutica NV. "Within those, you have subjects that are already engaged in clinical research but that are not necessarily linked to AD [cohorts of patients linked to cardiovascular diseases or metabolic diseases, for example] and, if you add the numbers up, you easily reach tens of millions of people in the EU alone."
What the EPAD team intends to do is reach out to these cohorts to see, firstly, if their scientific leads are interested in joining EPAD and, secondly, if their cohorts include any suitable subjects. "Those patients are already engaged, [their current cohorts] have acquired some data on them already and, for us, it will be pretty easy; if you’re 50 or above, it brings you into the kind of population we’re looking for," Van der Geyten notes.
From there, EPAD plans to build a registry of 24,000 potentially suitable subjects, and it’s that registry that will be used to recruit around 6,000 participants for the specific EPAD Cohort. Finally, 1,500 people from the EPAD cohort will be selected to take part in an early stage ‘adaptive’ clinical trial of drugs designed to prevent AD.
"We’re trying to cast a wider net, look at larger numbers of people who are being followed perhaps for other reasons in different registries and make sure that they get evaluation that could lead to a diagnosis," Satlin says.
Ins and outs of adaptive design
Once the trial itself starts, its adaptive design – which means that several candidate drugs are simultaneously compared with each other and with a placebo, and that researchers can adapt the trial design in response to emerging results – has several further benefits for participant retention. "If we see, for example, that a drug tends to work better in one particular sub-population or another, we will adapt the trial in such a way that we funnel more subjects of that sub-population to that compound," Van der Geyten explains. "As we will have several drugs being trialled at the same time, we can hopefully get subjects into the arm of the trial where the chances of them getting an effective drug for their particular sub-population is a lot higher."
At the same time, adaptive trial design allows researchers to expose far fewer subjects to the placebo because, while there will be several treatment groups for different drugs, they will all share a single placebo group, shrinking the number of patients only receiving placebo to around 20% of the total cohort of patients, significantly fewer than the conventional 50:50 split.
"It’s a disincentive for a participant if they go into a trial and know their chances of getting the placebo are 30 or even 50%," Van der Geyten stresses. "Depending on your disease stage, that’s a big unknown."
Furthermore, subjects will not only have the chance to participate in more than one arm of the EPAD study, they will also have a higher chance of receiving the active drug the second time round if they were on the placebo initially. "It will not be a certainty because we still need to follow the randomisation concept, but the chances will be a lot higher," Van der Geyten remarks, adding that for safety reasons, patients will be put back in the cohort for six months or more before being transferred to another arm of the study.
Talk you through it
Communicating with trial participants – they will always be known as participants rather than patients throughout the study, Van der Geyten is keen to emphasise – on an extremely regular basis is another way EPAD project researchers hope to keep them engaged and reduce dropouts.
"We will put a lot of time and effort into what we call the EPAD family or EPAD community," Van der Geyten says. "And this means asking investigators to pay a lot of attention to personal interaction so there is a good rapport between the subject and the investigators. There needs to be almost constant interaction between them, constant follow-up."
As Satlin stresses: "It’s about relationships as well as about the science."
Moreover, the team will be sharing progress made with participants as the trial advances. "We’ll share the data, let them see what their contribution was, and how it drives science and clinical practice forwards, in a way that’s easily understandable; we’re not just going to inundate them with data," Van der Geyten explains.
Finally, EPAD is also putting together a research participant panel in an effort to engage trial subjects still further.
"We will get together with the patient organisation, which in our case is Alzheimer Europe, and leading ethicists in this field to engage a number of research participants in a dialogue about how the programme is going. We will also be able to get feedback on how we design trials, what is important for them and what outcomes they would like to see.
"We also want to engage regulators in the discussion, tell them what patients think is important and ask if there is any way we can incorporate those things. It’s actually about trying to build a partnership across all stakeholders, which is very important."
Education, education, education
Beyond EPAD itself, and indeed looking more widely than only AD, Satlin thinks that one of the main things that needs to improve in order to encourage more potential trial participants to get involved with clinical studies is education.
"Industry could be doing more to educate the public about the value of clinical research and that we’re not talking about people being guinea pigs; we’re talking about them potentially getting some benefits while contributing to research," he says. "[People also need to] understand better how the system of drug approval works and how important it is for large numbers of patients to be studied to be able to get new drugs approved. There’s a huge lack of understanding by the public about this whole process, and general education about it would lay the groundwork for better understanding and participation in clinical trials."
In this area, AD certainly has lessons to learn from other disease areas, according to Truyen. "There are differences based on disease areas, and that relates to the strength of patient advocacy in that area," he explains. "For instance, for cancer trials, the level of engagement and the kind of ready acceptance to participate in research to advance new treatments is proportionally much higher than, for example, new treatments for atrial fibrillation or for diabetes. Patient advocacy is a factor that drives participation rates."
Yet, other disease areas also have much to learn from the AD research community, and particularly EPAD, Van der Geyten is keen to point out. "A platform approach, reaching out to existing cohorts and building a registry, could easily be implemented for other disease areas, greatly reducing screening failures and, potentially, also the dropout rate," he says. "Moreover, setting up a research participant panel – actually involving the people who are at the centre of this, the patients – that’s something you can do for every disease area."
