Stroke Clinical Trial Recruitment Still a Challenge

February 09, 2017

The issue of slow recruitment into randomized controlled trials in the stroke field, which has long been a problem, has not improved over the past 25 years and, if anything, is getting worse, a new study suggests.

Slow recruitment into trials "threatens the financial feasibility of studies and delays the evaluation and adoption of potentially beneficial new therapies," the authors state.

"More timely completion of trials is vital for maintaining progress in the efforts to reduce the high morbidity and mortality of stroke," they conclude.

The study, published online in Stroke on January 19, was conducted by a team led by William B. Feldman, MD, Brigham and Women's Hospital, Boston, Massachusetts.

They compared recruitment efficacy into hospital-based acute stroke trials enrolling at least 300 patients within 12 hours of symptom onset during the periods 1990–2004 and 2010–2014. They identified 10 such trials in the latter period by searching the literature and compared these to a previously published data set of 18 such trials conducted from 1990 to 2004.

Results showed that the median recruitment efficiency of trials from 1990 to 2004 was 0.41 participants per site per month compared with 0.26 participants per site per month from 2010 to 2014. The median recruitment rate of trials from 1990 to 2004 was 26.8 participants per month compared with 19.0 participants per month from 2010 to 2014.

"Recruiting patients into stroke trials is very challenging," Dr Feldman commented to Medscape Medical News. "There have been some efforts to boost recruitment in recent years — such as stroke trial networks and waivers of informed consent — but despite this we are not improving recruitment rates."

He said stroke trials face particular issues affecting recruitment, including the short time available to treat and problems with patients understanding enough to give consent.

"There is a very narrow time window for most treatments for acute stroke — investigators only have a few hours from symptom onset to enroll patients into trials. That automatically rules out the vast majority of patients who do not present in time."

Informed Consent Difficult

"Also, patients are usually incapacitated from the stroke and are incapable of giving informed consent. Waiver of consent is a big topic which has been much debated. This involves several different options, including consent after the fact, verbal consent rather than written consent, and gaining consent from relatives," he said. "However, family members are less likely to give consent for a loved one to participate in a trial than the patients themselves. This is a very difficult scenario to put a relative in.

"It is important for people to have conversations with family about whether they are willing to participate in clinical trials so that when an emergency situation arises, relatives know your wishes," Dr Feldman added. "And people need to be made aware that clinical trials are critical to the advancement of medical science."

He has two hypotheses on why recruitment is getting even more difficult. "Neurology trials have become more complex — more obstacles and red tape for both investigators and patients. And the pool of patients is getting smaller. Community hospitals — primary stroke centers — are treating more patients, and fewer patients are going to the major comprehensive stroke centers where the trials are conducted."

However, he is hopeful that the rise in endovascular therapy, which has to be delivered at a comprehensive stroke center, may improve the numbers of patients available. And he adds that the formation of stroke networks — where hospitals join up to a central organization that coordinates the personnel, design, and paperwork for the trials — is also a positive step that should encourage more hospitals to participate in trials.

Many Forces at Work

Commenting on the issue for Medscape Medical News, Pooja Khatri, MD, University of Cincinnati, Ohio, who has also conducted research in this area, said it was difficult to interpret the patterns in recruitment rates from trials in 1990–2004 vs 2010–2014 in the current study, given the different patient populations (country and stroke severity) in the sets of trials being compared.  

"That being said, there is no doubt that recruitment rates in acute stroke trials are a challenging issue," she noted. "There are many forces at work against trial recruitment success, including instability in the workforce of research coordinators, the administrative burden of regulatory and contracting paperwork and clinical care, decentralization of acute stroke care, and financial disincentives to enroll in trials."

"In my own experience, there is also a psychology that works against trials in the US, in particular for clinically available treatments; clinicians often decide to use the therapy based on the very existence of the preliminary data that support the trial concept, as opposed to allowing the patient to be randomized to build more definitive data."

She believes things are getting even more challenging now as trials have to get significantly larger based on recent advances. "We are now seeking newer therapies with smaller treatment effects compared to the key 'big wins,' such as IV [intravenous] thrombolysis and endovascular therapy. We are developing adjunctive therapies and/or novel therapies that need to be demonstrated to be incrementally better." 

Dr Khatri said she hopes the National Institutes of Health (NIH) stroke network, StrokeNET, will eliminate some of these issues with some continuity in infrastructural funding, a central institutional review board mechanism, and master trial agreements for all multicenter, NIH-funded trials.

"The network is in its infancy with the first acute trial, the DEFUSE-3 study, having started in mid-2016. This trial is recruiting ahead of projected timelines and this provides some optimism."

Another promising area is the move to build worldwide collaboration and communication, such as the recently formed GAINS (Global Alliance of Independent Networks of Stroke) group, she points out.  

She added that the work pioneering exception from informed consent for time-sensitive acute stroke treatments will be critical for future trials, given the emergent nature of acute stroke trials and the time sensitivity of therapies.

The study was supported by the NIH. The authors have disclosed no relevant financial relationships.

Stroke. Published online January 19, 2017. Abstract

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