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Research without consent puts ethics to test

OHSU drug trial will study unconscious trauma victims

Photo Credit: COURTESY OF OHSU - Tranexamic Acid (TXA) administered when paramedics arrive may lessen brain damage in survivors. But it has to be given immediately--before victims have an opportunity to consent.Oregon Health & Science University is looking for a few good men (and women) for a clinical trial. Unconscious men and women, ideally. And by the way, readers, you’re all enrolled, sort of.

The new study is called “Prehospital Tranexamic Acid Use for Traumatic Brain Injury.” Tranexamic Acid (TXA) is a drug used to treat people in shock, usually people who have just been in a major car crash and who are unconscious because they have lost massive amounts of blood. It decreases bleeding and can save lives.

But TXA needs to be studied in unconscious accident victims who have specifically suffered major brain injuries. Two small studies suggest that used in those victims, it might lessen bleeding in the brain, reduce brain swelling and decrease brain damage in survivors.

“That’s why this study needs to be done,” says Dr. Susan Rowell, an OHSU trauma surgeon in charge of the trial.

But TXA must be administered to accident victims immediately to have effect. The sooner the better. Wait three hours before delivering TXA and the drug might actually worsen the patient’s condition. No waiting for the hospital, no waiting for a patient to wake up and consent to be given for TXA as part of an experiment.

To determine if paramedics should be giving TXA as soon as they arrive at scenes with unconscious accident victims, a large-scale study is needed comparing TXA against the current standard of care, which is a simple saline solution. Experimental studies require patients sign informed consent waivers, but unconscious accident victims can’t do that.

The federal Food and Drug Administration allows such studies citywide under its Exception To Informed Consent rules. Basically, the rules require investigators to notify the public about the studies. Anyone who doesn’t want to participate can contact the research team and request a bracelet which says “No Study.”

If paramedics arrive at an accident and find an unconscious, brain trauma patient wearing the bracelet, they’ll know to treat him or her with the standard saline solution, not with one of the IV trial bags that contain different levels of TXA and, for a blind control group, saline. The TXA study begins here in December. So far, one Portland-area resident has requested a No Study bracelet.

Portland residents have participated in about eight previous communitywide informed consent exception trials during the past eight years. One study that looked at two different drugs to stop seizures changed the standard of care used by paramedics across the country. Another tested whether a higher salt level in the paramedics’ saline solution would help accident victims in shock and with brain injuries. It turned out the higher salt concentration didn’t help at all.

A third looked at a new device to help revive trauma victims whose hearts had stopped. That study was halted because midpoint data returns showed the new device wasn’t increasing survival. A trial for giving less saline solution to trauma victims with low blood pressure showed the new approach might be a good idea and if another, larger study confirms the findings, the new approach should become standard of care.

No Study bracelets

The lack of Portlanders requesting No Study bracelets for the TXA study might be odd, since the 2008 communitywide study testing different saline solutions (Hypertonic Saline Trial) had more than 600 people request the bracelets — more by far than were requested in the other 10 participating cities. Or, it might be a sign that very few people know this new study is going to take place.

Understanding whether TXA helps victims of brain trauma is crucial, says principal investigator Rowell. Among the study’s funders is the U.S. Department of Defense, which wants to know if TXA can help soldiers who suffer brain injuries on the battlefield. Brian injuries are the No. 1 reason soldiers die in battle, Rowell says.

The FDA maintains strict rules for allowing communitywide exception to informed consent studies, Rowell says. First, a life-threatening situation has to be present. Second, the new drug or therapy has to be one in which there is no possible way to wait for subjects to give their consent. Also, Rowell says, “There has to be some data that says you actually have a chance of benefiting from this.” All those criteria are in place for the TXA study.

Also, all study participants will receive an added benefit in that they will be followed by Rowell’s team for six months after their accident and injury — a closer monitoring than they might otherwise get.

The primary community notification for the TXA study has involved researchers addressing 337 people who were required to attend high-risk driving courses, most after drunken driving convictions. News releases were sent out to media outlets, though publicity has been almost nonexistent.

OHSU regulatory expert Denise Griffiths says the first Exception from Informed Consent studies in the Portland metro area raised concerns that don’t appear as great today.

“People were not happy about it,” Griffiths says about the hypertonic saline trial. As a result, extensive community consultation took place. Several communitywide meetings and news conferences were advertised and held. A random phone survey was done. Letters were sent to community leaders and neighborhood associations. Griffith says there may yet be additional publicity about the TXA study that will take place in Multnomah and Clackamas counties. And, she points out, more than 800 Portland-area residents already have No Study bracelets from previous studies, so they don’t need to request new bracelets if they want to opt out of the TXA study.

Community consultation

Few Portland residents may know about the upcoming study at this point, but a bioethicist who has studied the issue of communitywide exception to informed consent trials says that if all Portlanders were properly informed and educated about the trials, most would undoubtedly agree to participate.

Most members of the public, when asked straight out if they want to participate in such studies, say no, says Rosamond Rhodes, director of Bioethics Education at the Mt. Sinai Icahn School of Medicine in New York City. Rhodes is co-investigator of a series of studies that include interviews with people who had been part of research conducted without informed consent. Most of those people initially rejected the idea of being guinea pigs.

But once those same people attended meetings where the studies were fully explained, Rhodes says, almost all changed their minds. “By the end of 90 minutes they’re saying if it will help people, they’ll participate,” Rhodes says.

Rhodes says in some cities, researchers performing Exception to Informed Consent studies erected billboards, took out large newspaper ads, and set up booths at county fairs in order to inform the public. But Rhodes says, the more grant money researchers spend on community consultation, the less there is left over for the actual research. And, she says, though it is a controversial point among medical ethicists and researchers, there are no federal guidelines for how much public consultation must take place.

Rhodes points out that with trauma research such as the TXA study, it would never be possible to notify every potential participant. “What is the relevant community?” she says. “If you’re talking about accident victims on the highway, that could be New Yorkers driving through Portland.”

The essential ethical point, Rhodes says, is that if there is reason to believe TXA could lead to better treatment for all trauma victims, the burden on researchers to let everybody know about the study is lighter.

“If you start with the approach that we should all be participants because we don’t know and we should be willing to do our fair share, you have a different perspective on how far they have to go to let people know,” she says.

People who do not want to be enrolled in the TXA study can request a No Study bracelet by calling 503-494-4315, or emailing traumare@ohsu.edu.