ARTICLE IN BRIEF
Investigators examine the reasons why recruitment is challenging for neurology trials and propose possible solutions.
For over a year now, Mark Quigg, MD, has been trying to recruit patients into a five-year, NIH-sponsored trial comparing radiosurgery with open surgery for epilepsy, also known as the ROSE trial. Three of the trial's five years were designated as recruiting years, and the trial requires 237 patients to achieve statistical validity.
At press time, Dr. Quigg and his colleagues in the multicenter trial — the only US-based, randomized prospective surgery trial in epilepsy to date — had recruited exactly 15 patients.
“Taking lessons from earlier trial experiences, we tried hard to keep the criteria for accrual very basic,” said Dr. Quigg, a neurologist at the University of Virginia Medical Center in Charlottesville. “You just had to have mesial temporal lobe epilepsy [MTLE]. If you believe the literature, MTLE is the most common type of epilepsy in adults with medically intractable epilepsy. But we've found that there isn't a flood of patients coming forward for the trial.”
Joseph Broderick, MD, professor and chairman of neurology at the University of Cincinnati in Ohio, has been having similar challenges. The IMS III trial, for which he is a principal investigator, seeks to compare the standard dosage and IV delivery of recombinant tissue plasminogen activator (rt-PA) in acute stroke with infusion of rt-PA directly to the brain at the site of the clot (intra-arterial rt-PA).
“This is the largest interventional randomized trial in stroke in the world,” said Dr. Broderick. “We've randomized a lot of patients — but recruitment has been significantly slower than we expected.”
A TOUGHER SELL
“The culture has changed,” said Walter Koroshetz, MD, deputy director of the NINDS, the funding agency for both the ROSE trial and IMS III. “Something has happened over the years to raise the bar for many people to consider participating in research trials. I suspect that well-publicized cases where trials didn't work out, or where one investigator did something he shouldn't have done, may have led to a negative overall opinion of research in people's minds. When some people hear about research, they think only about the bad headlines. Without more balanced information, it makes them suspicious of all research.”
There are particular factors that make certain types of neurology trials even more challenging when it comes to accruing patients. The time-sensitivity of recruitment for something like acute stroke or traumatic brain injury poses unique challenges, said Dr. Koroshetz.
“People who have diseases that are more slowly progressive, like Alzheimer disease or MS, have been thinking about what the alternatives are and have had time to come to the understanding that research is important to get to the next step,” he noted. “But with a stroke trial, you may have less than an hour to get consent to enroll someone, and that consent may have to come from a family member if the patient can't communicate. It's very hard to ask someone to make these kinds of decisions in such a short time frame.”
Epilepsy, of course, is a chronic condition, and patients don't generally have a “now or never” deadline hanging over their heads as they consider trial participation. But Dr. Quigg noted that his trial and the field, in general, have their own set of challenges.
“With the new generation of anticonvulsants, like lamotrigine, people feel a lot better on them. There's plenty of evidence and lots of experiential use,” Dr. Quigg said. “I think patients may feel reluctant to go in for surgery when the drugs seem to be doing well. We need to get the message out there that you don't get a linear response with seizure improvement — a 50 percent improvement in seizures doesn't get a 50 percent improvement in income, jobs, driving, or independence. You only get those improvements when you're seizure-free.”
Dr. Quigg also noted that in epilepsy — and in other neurological diseases — referral patterns may be changing. “With the spread of specialty programs in epilepsy and other conditions outside of the traditional large academic setting, and the privatization of epilepsy surgery centers, it seems that some of these subspecialty programs may be reluctant to send their patients to a teaching institution for a trial when the private centers have the ability to care for them themselves,” he said.
But perhaps the biggest burden on trial recruitment may be the current economic situation, said Petra Kaufmann, MD, NINDS director for clinical research. “Trials can create a big burden among patients. They may find it difficult to get to the study site, to take the additional time from work that can be required of trial participants.”
In the past, institutional review boards (IRBs) may have discouraged investigators from providing any reimbursement to patients to compensate for their participation, but given the constraints of the economy, Dr. Kaufmann said that thinking is changing. “We try not to discourage investigators from giving patients a little support for the hardship they undergo to participate, such as gas money. It's perfectly ethical and reasonable to provide some reimbursement for the cost of participation.”
WHAT CAN BE DONE?
In addition to minimizing that burden to patients, what else can be done to improve recruitment into neurology trials?
For stroke trials and other studies in acute conditions when there's a short time window for recruitment, such as in traumatic brain injury, centers must find a way to fund the availability of a trained trial coordinator 24-7. “You have to pay people to be on call,” said Dr. Broderick. “Maybe you can share coordinators across trials, so that they can take call and be available after hours. Otherwise, if someone comes in having had a stroke at two in the morning, they may be willing to be enrolled but if you don't have the trained personnel to go through the process with them, you've lost a participant.”
NINDS has also added a recruitment specialist to its staff. Jamie Roberts joined the institute in February with hands-on experience as a research coordinator for large trials, including the 2500-patient Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST).
“She will be developing a tool kit and a training program for recruitment, helping investigators to identify barriers and overcome them,” said Dr. Kaufmann. “From very early on, she will sit in on trial meetings and raise recruitment questions to investigators, so that they can better anticipate what the issues may be.”
Since 2008, NINDS has asked investigators to provide them with an evidence-based recruitment plan. With the addition of a recruitment specialist, Dr. Kaufmann says, the NINDS now has a full-time person who can help make sure that this information is as useful as possible. “She will help them to track recruitment and learn what the most effective interventions are, so that we can gather evidence as to what improves recruitment and what doesn't.”
Simplifying the confusing and often-onerous informed consent process could also speed up recruitment, said Dr. Koroshetz. “Consent forms have become so complex that when somebody tries to get through them, often they just give up,” he said. They're long and confusing and don't even achieve what they're supposed to, which is explaining to patients what's involved in the research and what the risks and benefits are.”
That may soon change. In July, the Department of Health and Human Services published an advance notice of proposed rulemaking entitled “Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators.” Among other changes, the proposed revision to the 20-year-old regulations governing human subjects research — known as the Common Rule — would mandate a single IRB to review multi-site trials, and provide greater specificity on the content of informed consent forms “so they can be shorter, more user-friendly, less confusing.” [For more on the proposal, see “Revised Rules for Human Research Conduct Proposed” on page 17 of this issue.]
Beyond that, said Dr. Koroshetz, a “national conversation” about the importance of clinical trials is needed to raise awareness, much as there have been national conversations about organ donation and end-of-life decision-making. “People need to understand that IRB and FDA controls on safety mean that if you enter a trial, people have done everything they possibly can do to make sure it's safe. You may not be advancing your own treatment by participating in a trial, although people who enter trials do get benefits such as much more attention to their medical care and clinical well-being than you would usually see. But people need to understand that participating in a trial is about contributing to the advancement of whatever condition they have.
“The question needs to be, do they want to be part of improving life for the people coming next with their condition — including, quite possibly, their own children and grandchildren?”