Adverse events related to pharmaceutical or device clinical trials are fairly straightforward. If the patient has a medical issue while volunteering for a study, then it should be monitored. But how might researchers in social-behavioral studies, involving psychotherapy, monitor symptoms believed to be part of the normal therapeutic process?
This is a question researchers wanted to answer with a study of a state-of-the-art adverse event monitoring program for behavioral health clinical trials. Funded by the U.S. Department of Defense and Veterans Affairs, the effort involved testing evidence-based behavioral therapies for post-traumatic stress disorder (PTSD) in active duty military personnel.1
“Many of us come to adverse event monitoring from the FDA perspective,” says Stacey Young-McCaughan, RN, PhD, professor in the division of behavioral medicine in the department of psychiatry at University of Texas Health Science Center in San Antonio.
“I’m a nurse and I never conducted drug trials, but sitting on IRBs and chairing IRBs have shown many adverse events,” she says. “Here, we conduct clinical trials testing behavioral intervention for post-traumatic stress disorder and related conditions in military service men, women, and recently released veterans.”
Through the South Texas Research Organization Network Guiding Studies on Trauma and Resilience (STRONG STAR), there have been more than two dozen randomized, controlled trials testing various behavioral health interventions among the more than 1,000 study participants.1
Some of the adverse event (AE) classifications captured in the AE monitoring were sleep-insomnia, medical-surgery, flashback, irritability, suicide-ideation, pain-headache, and depression.1
Defining serious adverse events (SAEs) is especially challenging in behavioral science research.
“You’re living your life and develop a hernia or need a knee replacement or have an auto accident,” Young-McCaughan says. “If you have an overnight hospitalization that’s considered a SAE; although it’s not related to the study, it’s considered a SAE and is reportable to the regulatory body.”
Federal regulations require unrelated AEs to be collected. If the AEs are unrelated to study participation, they do not need expedited reporting to regulatory agencies, per Unanticipated Problems guidance.
“We just document them as unrelated to the study that’s going on,” says Young-McCaughan.
Regulations define adverse events as any unfavorable medical occurrence in human subjects, including abnormal lab or physical exam findings, symptoms, or disease that is associated with the subject’s participation in research, whether or not it’s related to the research participation.
“It’s always good to keep track of them,” Young-McCaughan says. “Remember Cox-2 inhibitors? Nobody was expecting increased incidences of myocardial infarction, and then they saw a number of those and said, ‘Wait a minute, there are too many of these MIs here — let’s go back and take a look.’”
The benefit of adverse event monitoring is that it can dispel some misconceptions. For instance, it was standard practice before to not enroll anyone who expressed any sort of suicidality, she says.
Researchers initially did not want to enroll potentially suicidal subjects for safety concerns, but they’ve discovered that enrolling them with a safety plan works to everyone’s benefit, Young-McCaughan says.
For service members with PTSD, engaging in therapy and addressing their primary concerns also has the side effect of reducing potential suicidality.
“If they get their PTSD under control, they don’t feel as hopeless and helpless,” Young-McCaughan says. “It gives us and others a lot of confidence in using behavioral therapies for people who have suicidality.”
By putting rigor and definition into an adverse monitoring program, it can help investigators develop a symptom profile so individuals can be fully informed about side effects, she says.
“We have published one article on adverse event reporting, and we didn’t find any other articles of people thinking about this,” she says.
For this study, researchers had study coordinators take careful notes of what research participants said during visits. They asked participants if anything had changed since they were last there, and explained that the coordinator wanted to make sure the person could safely participate in the study, Young-McCaughan suggests.
“We would ask the person who is writing down the information for their impression of the severity of the event and whether it was related or not to the study,” she explains. “Then we take the event or series of events to the investigator and have a group discussion about what happened and whether it was an adverse event, a serious adverse event, or related or expected.”
Setting up an adverse event monitoring system for this type of research was a challenge, Young-McCaughan notes.
“We started out with checklists, asking, ‘Do you have nausea, vomiting, headaches?’ but it felt too constraining,” she says. “So we took a broad-based approach, asking, ‘Has anything changed since we last saw you?’”
They define change as any health status change since baseline.
Helping study participants understand what to expect also was challenging. “With behavioral health, what is the chance you’ll feel worse before you’ll feel better?” Young-McCaughan asks. “What is the chance of having worse sleep or worse nightmares? We didn’t know what the answer was.”
This data-driven approach is more useful than having investigators and IRBs use their intuition to determine risks.
“Instead of letting rumors abound about how traumatic these interventions can be, let’s put data behind it so we’ll know what to expect,” Young-McCaughan says. “For people wanting to use these data in clinical practice, therapists who read the study might say, ‘This looks like a good therapy and I want to use it. I can tell my patients they’ll have some side effects, but this won’t be an overwhelming, unmanageable type of therapy for them to handle.’”
For researchers who come from a laboratory setting, the process of identifying and monitoring adverse events has been a learning curve, says Allison Hancock, PhD, assistant professor of the division of behavioral medicine in the department of psychiatry at University of Texas Health Science Center.
“I have an experimental psychiatry background, and watching this process unfold in clinical trials with less structure and control around them has been eye-opening,” Hancock says. “It’s been helpful to the investigators, and coming from a regulatory perspective, the biggest help is it allows us to inform the participants more accurately.”
For example, if investigators see that many participants have difficulty with insomnia or nightmares, they can update the informed consent to inform participants of this possible side effect, Hancock says.
REFERENCE
- Young-McCaughan S, Hancock A, Roache JD, et al. State-of-the-art adverse event monitoring for behavioral health clinical trials. Poster presented at PRIM&R’s 2016 Advancing Ethical Research Conference, Nov. 13-16, 2016, Anaheim, CA.
Researchers in Texas studied a state-of-the-art adverse event monitoring program for behavioral health clinical trials.
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