How to recruit for better outcomes

Finding and enrolling the right participants for a clinical trial is fundamental to its outcome, but the selection process is all too often the cause of delays and is a significant contributor to a trial's overall costs.

Some surveys suggest that of the 50,000 clinical trials that were conducted in the US during 2009, 80% were delayed by at least a month due to low levels of enrolment. The 20 largest drug companies spend around $30bn on R&D, with up to 40% going towards funding for clinical trials. Other surveys show that recruitment is one of the biggest cost drivers for a clinical trial. So, there is obviously a need to approach the process in a way that ensures the investment in the recruitment stage results in a more efficient and effective trial.

There is currently a debate about how to define a target group, with the approach of allowing anyone to enrol in opposition to the approach of targeting trials at patients where efficacy is more likely to be evident. The parameters for participant selection are not carved in stone.

Rethinking patient selection

One topic up for discussion is the selection of individuals for phase I studies, which usually involve healthy patients with no other standard of care or curative options. There is a growing feeling in some quarters that these early-phase trials, particularly in areas like oncology, should be open to other groups, not just healthy participants.

In oncology, this could have a dramatic effect. The US National Cancer Institute reports that fewer than 5% of cancer patients participate in clinical trials, and that if 10% participated, studies could be completed in as little as a year, rather than the three-to-five that are usually required.

"In terms of the inclusion or exclusion of patients, there are many things that companies could do differently. In early-phase oncology, for example, they could be less restrictive about allowing patients on trials. The actual inclusion/exclusion parameters could be flexible to give patients more options. End-stage cancer patients have limited options so putting them onto a clinical trial allows access to an experimental therapy," says Heather DiBenedetto, clinical operations group head for Novartis Oncology Translational Medicine.

"Treating physicians want to open trials up to more patients allowing more treatment options. But from the pharmaceutical company perspective, there is more focus on safety issues as there is limited safety information about these new agents, so they want the healthier, more stable patients in order to reduce confounding factors in the trials. For early-phase trials, the inclusion and exclusion is sometimes very specific or rigid, which does not allow in as many patients. Changing some parameters even slightly could allow more patients into these types of trials."

Giving patients the best chance

In choosing participants for a clinical trial these parameters have a significant bearing on the outcomes, but they require a careful balance of allowing access to patients and monitoring the effects of a new drug. The first step should be to follow the pre-clinical data that is available at the time and let it influence the early-stage selection process.

"On the oncology side, there has been a shift to use the science to dictate the specific patients to target, those who have the best chance of responding. Then we choose to include in the clinical trial, otherwise you might end up coming away thinking that the drug doesn't work. This targeted selection gives both the patients and the drug the best chance," says DiBenedetto.

If tests are done as part of standard medical care, the results could be already available. And, if not, then we can arrange non-routine tests to be performed at a central speciality laboratory able to identify a specific aberration. Allowing sites to do their own testing could be more efficient overall because patients can enrol faster using that established result. There are times in later drug development where central testing even for patient selection is required."

A time of change in patient recruitment

Although the pharmaceutical industry is known for its conservative approach and does not adapt its processes and techniques without thorough investigation and sound reasoning, there is a sense that approaches to clinical trials recruitment are beginning to shift. It is increasingly recognised that investing more in the early stages of the selection process should ultimately lead to a more effective outcome and more efficiency gains during the ensuing stages.

"Change is on a faster path now. Many companies have often allowed all comers onto oncology trials in order to look for any hint of efficacy in a drug, but we are moving away from that towards more targeted and personalised medicine. That makes the process of recruitment more complex, but it gives better results," says DiBenedetto.

"Early on, for example, we can make genetic components part of it to ensure the right genetic make-up, the right disease and so on by doing the genetic phase first."

Such an approach does change the cost profile. It means more expense early on, but the rationale is that there will be cost advantages from having chosen a better-defined and more appropriate population for the trial.

"The main focus of any trial is on endpoints, but both outcomes and cost are improved if you recruit the right people and match the treatment to the disease and genetic components. Pre-screening means you select the key patients to the trial. This means costs are higher in the initial phase, but it saves money overall," explains DiBenedetto.

"There is a real shift in oncology early development to personalised medicine and away from letting a heterogeneous population into a trial. There are some companies that are definitely ahead on pre-selection but most companies dedicated to oncology clinical development are moving in this direction. It moves some of the effort up front but it improves outcomes and makes the rest of the trial more efficient."