By Deborah Borfitz 

November 14, 2023 | Time is of the essence when it comes to acute stroke trials, where investigators may have mere minutes to obtain consent—in many cases, from a loved one of the patient. Because consenting delays can impact the potential efficacy of an experimental treatment, they represent the biggest obstacle to both participant enrollment and scientific advancement in the field, according to Joseph Broderick, M.D., professor in the University of Cincinnati’s department of neurology and rehabilitation medicine and a principal investigator (PI) of the National Coordinating Center for the NIH StrokeNet. 

Many countries outside the U.S. recruit patients into acute stroke trials at a higher rate per institution, he notes, largely because their process for emergency consent is a lot easier to navigate. The “exception from informed consent” (EFIC) process of the Food and Drug Administration (FDA) requires community consultation and public disclosure prior to institutional review board (IRB) approval for a study to start. 

When the COVID pandemic struck and public gatherings were effectively banned, the EFIC process shut down some stroke studies simply because trial investigators couldn’t meet with community members, says Broderick. The requirement was intended to protect individual autonomy and preserve public trust in instances where emergency trials are allowed to enroll patients without informed consent. 

Enhancing and streamlining startup emergency consent in the U.S. is one of 12 action items for improving enrollment and completion in acute stroke trials that came out of a Stroke Treatment Academic Industry Roundtable (STAIR) meeting held earlier this year. The meeting’s review and recommendations published recently in Stroke (DOI: 10.1161/STROKEAHA.123.044149). 

EFIC does not mean investigators don’t obtain consent, only that they don’t have to get it immediately, Broderick stresses. The time window for enrollment in an acute stroke trial is often within one to two hours of stroke onset, necessitating the special allowance to enable the testing of therapies that could potentially salvage brain tissue and help prevent disability.  

Without patient enrollment and completion of trials, progress in treating strokes comes to a standstill, Broderick says. “While we may have a lot of good ideas, none of them are going to get tested without recruitment.”  

Emergency Consent

The STAIR brought together stroke physicians and researchers, members of the National Institute of Neurological Disorders and Stroke (NINDS), industry representatives, and members of the FDA to discuss strategies for improving enrollment, Broderick says. Industry generally has more resources to devote to clinical trials than the investigator-initiated, government-funded studies done by NIH StrokeNet, and are better at doing global trials because of their presence in multiple countries. But the issues faced by academic and industry-sponsored trials have “huge overlap.” 

As a PI for the National Coordinating Center for all NINDS-sponsored stroke trials conducted around the country and in some cases globally, as well as a PI on other large trials, Broderick has a lot of firsthand experience with the enrollment challenges. The U.S. has been behind other countries for more than a decade now when it comes to getting patients admitted into stroke trials, and the situation is now urgently in need of redress.  

The prerequisite of community engagement and consultation is the key difference in how emergency consent in the U.S. differs from that of other countries, says Broderick. In practical terms, that means planned events where investigators talk about a trial with groups of at-risk individuals living in the geographic area from which study participants will be drawn and, if an IRB deems it appropriate and feasible, some sort of opt-out mechanism for those who know they would not consent (e.g., a medical identification bracelet or wallet card). 

Elsewhere, IRBs might simply approve emergency consent based on the recognized need for the study provided it is judged to be ethically sound. There is consensus across most countries that consent be obtained from patients if their condition improves or at the earliest feasible opportunity from a family member or legal representative.  A few countries, including Japan and India, don’t even have an emergency consent process, he notes.  

In the U.S., a conference regarding emergency consent will be held in December for relevant parties, including the FDA, Broderick says. The published recommendation is for centralizing some of the EFIC workload and using national data in conjunction with local community events. 

Procedural differences are inevitable country to country because of the various ways trials get reimbursed, jobs are created, and healthcare systems operate, he adds. Enrollment takes a bit of a hit in places like the U.S. where studies are conducted at many different sites that aren’t necessarily interested or focused on research rather than centralized within academic centers. 

Investigators on an acute stroke trial typically have no preexisting therapeutic relationship with eligible patients and their families, highlighting the need to build community ties to understand their perspectives. Patients and their family members might even be tapped as advisors, says Broderick, pointing to a tactic deployed in the I-ACQUIRE stroke recovery trial enrolling infants and toddlers where the parents were “highly involved” in decision-making about how best to support and communicate with families. 

“This past year we added stroke survivors to our working groups that help design future trials,” he continues. They’re engaged with an assortment of questions, among them: Does this make sense to you? Do you think this would be worthwhile? How would you present this trial opportunity to a potential patient?  

Site Issues

Stroke not only happens suddenly, says Broderick, it also “doesn’t respect business hours.” Given that reality, another identified action item emerging from the STAIR meeting was for sponsors to offer financial support to investigators doing after-hours enrollment of eligible participants.  

As learned in the ongoing Multi-arm Optimization of Stroke Thrombolysis (MOST) trial, sites open for enrollment seven days a week recruited participants twice as fast as sites open only during regular weekday hours, Broderick shares. Enrollment in other acute stroke trials might similarly improve if industry sponsors, like NIH StrokeNet, routinely offered compensation to investigators and study coordinators for their after-hours efforts.  

It also makes sense to have people available at the hospital, day and night, who understand the trial—including a pharmacist who knows how to prepare the study drug.  Some sites have done this by having the research pharmacist train the pharmacist in the emergency department to prepare study medications, Broderick says. By moving investigational products to the emergency room, enrollment in acute stroke trials becomes an around-the-clock affair. 

A site champion as well as monetary incentives for meeting study startup milestones, such as getting contracts signed and IRB approvals within a certain timeframe, can make a difference with site-level obstacles, says Broderick. The reality is that sites can sometimes take many months to launch a study either because investigators aren’t doing their job, or the center lacks the infrastructure to efficiently get things done. 

Among other action items listed in the published paper are discussions with certifying agencies and leadership from national stroke research networks about how sites might demonstrate that they have adequate clinical and research infrastructure, and prior successful trial enrollment. 

Protocol Design

Acute stroke studies can be set up to answer multiple clinical questions, separately or together, says Broderick. The STAIR group recommends trial designs that allow for co-enrollment in other studies—especially those not testing another intervention. For example, a study of a medication to open blood clots acutely in stroke could logically be combined with a study predicting how well those patients will recover.  

Alternatively, a study could be designed to test more than a single intervention. A so-called factorial trial might funnel patients into one of four different groups where they receive medication A, medication B, both drugs, or neither of the two treatments. Another option is to enroll patients in one of two different studies based on the day of the week or some other agreed-upon system.   

From the standpoint of both patients and study teams, protocols that deviate too far from standard care just feel burdensome, says Broderick. Given a choice of two studies, they will invariably opt for the one that’s easier to do. The rule of thumb is to “use what you are already collecting [e.g., blood pressure checks] in a standard fashion and apply them to what you are trying to address and test [blood pressure management],” he says.  

Recommendations coming out of the STAIR meeting are not mandates, but tasks that will require the combined efforts of everyone—including investigators, sites, and patients, says Broderick. Stroke research in the future will ideally garner the same level of attention, and large-scale quest for trial participation, which today is rarely witnessed outside of oncology.