Emergency physicians have only seconds to make life-saving decisions for their patients. Those decisions, sometimes involving whether or not to administer a certain type of medication, have been passed down from one generation to the next as a solution, though little research has been done over the years to validate if those solutions are the most effective method of treatment. 

That’s because, oftentimes, patients admitted to the emergency department (ED) are unconscious, meaning the typical ethical study approaches needed to execute a clinical trial—like seeking informed consent directly from the patient—are not an option. With the help of Michelle Biros, MD, MS, FACEP, research director for the University of Minnesota Medical School’s Department of Emergency Medicine, a unique set of research regulations were proposed more than 20 years ago that created new opportunities to study life-saving practices in the ED.

“We needed a way to progress in the science, so I worked with a group to help the FDA develop the regulations that allow an exception from informed consent for some emergency and critical care trials,” Dr. Biros said.

Setting the Regulations

In 1993, the Office for Human Research Protections abruptly stopped a promising study that used an enzyme therapy, which, in preclinical studies, appeared to have benefits in preserving brain function following traumatic brain injury (TBI). Their potential patients would be unconscious, and at the time, no federal regulations existed to allow patient enrollment in trials without their informed consent. So, the Society for Academic Emergency Medicine asked Dr. Biros, who then chaired the organization’s research committee, to meet with federal regulators on the topic. After 18 months of discussion in Washington, D.C., Dr. Biros and a team of professional organizations, federal regulators, investigators, lawyers and patient advocates proposed to the FDA and the Department of Health and Human Services (DHHS) a new set of regulations to guide the ethical emrollment of incapacitated patients into acute clinical trials. 

“We published a document in 1995 that basically said this is what we would like to have the FDA and the DHHS to consider, given the fact that medicine has moved on beyond what previously existed,” Dr. Biros said. “Most of our suggestions were adopted into the FDA regulations for exemption from informed consent in 1996.”

These regulations offer alternative ways to study emergency medicine, balancing the needs of a clinical trial and the ethical considerations of a patient whose clinical condition renders them unable to participate in a meaningful research discussion, such as those who are unconscious. But, the research must meet a strict set of criteria.

“The patient has to be in a life-threatening circumstance for which current therapies are not studied or unsatisfactory,” Dr. Biros said. “Also, you have to prove that you aren’t able to get consent in a meaningful fashion from the patient because of their serious clinical condition, and because the window for opportunity to enroll a patient is so short, you frequently can’t identify a legally authorized representative.”

If the research meets these requirements, the Institutional Review Boards (IRB) will approve the research for the next step—a pre-study community consultation. This unique aspect of these studies obligates those leading the research to meet with at-risk groups and inform them about the research. For example, if the study will be focused on TBI and treatment of that in the ED, the study team may meet with local motorcycle groups or skiing clubs since their activities put them at risk for that type of injury.

“We definitely are looking for two-way communication,” Dr. Biros said. “It’s not community consent. It’s not vetoing a study. It’s discovering concerns that a community may have that we, as investigators, have never thought of, and then having the IRB weigh these concerns to see what the next step ought to be.”

Dr. Biros recalled a previous exception from informed consent trial that proposed studying the use of a blood substitute to treat patients with hypotension, or low blood pressure, after trauma. In a community consultation at a local hospital, a group of Jehovah’s Witnesses voiced their concern about the blood substitute and how it conflicted with their religious beliefs involving blood-less surgery.

“We decided not to do the study,” Dr. Biros said. “We would never be able to identify beforehand if that would be the preference of a patient in front of us, so we decided it was too risky to do this study in terms of their trust of the hospital and honoring their religious belief.” 

If the IRB approves the research after community consultation, the research team then equips the sites of clinical enrollment with information about the trial. The ED determines eligibility at the bedside when a patient arrives, and concurrently, tries to locate a legally authorized representative before enrolling them under exception from informed consent. When the patient has been resuscitated and can speak on their own behalf or the team has found a legally authorized representative, the team then asks for permission to continue the study. The trial regulations require that the study team share the results with the study participants as well as the general public—another unique element of this type of trial.

“We try to close the loop with the people who have given us that privilege to include them in research, so they can understand the importance and how grateful we are that they helped contribute to the scientific literature,” Dr. Biros said.

Leading Research at the U

Since 1996, researchers across the U.S. have published only 45 exception from informed consent studies on topics, such as TBI, cardiac arrest and neurological disease. Of those studies, Dr. Biros and the Department of Emergency Medicine have performed seven and consulted on several others.

Their most recent trial, as part of national study supported by National Institute of Neurological Disorders and Stroke, published results in the New England Journal of Medicine in November 2019. This study focused on the treatment of status epilepticus, a medical emergency defined as a continuous seizure lasting more than 30 minutes or two or more seizures without full recovery of consciousness between any of them.

“It was a little question—what is the best treatment that the ED can use when a patient has failed all of the first-line drugs for seizures? We have three drugs. The use of these three drugs as a head-to-head comparison has never been done, and the use of them in the ED has always been at the discretion of a doctor,” Dr. Biros said.

The study began in 2013, enrolling more than 400 patients nationally, including 22 patients in the Twin Cities area at M Health Fairview University of Minnesota Medical Center, M Health Fairview University of Minnesota Masonic Children’s Hospital, M Health Fairview Southdale Hospital, Regions Hospital and Hennepin County Medical Center. The study found that none of the three drugs worked better or worse when compared to one another.

“From an emergency perspective, it kind of looked like a negative study because there wasn’t one winner, but it actually was good for emergency physicians because now they can use the drug they understand the best,” Dr. Biros said. “These studies work well locally because there’s a concentrated group of individuals here that have become very good at this and have established patterns to develop community outreach appropriately and understand the ethical challenges. The goal is to respect our communities in every possible way.”