DENVER – In a debate over whether headache trials are representative of patients, one neurologist declared that they tend to leave out a variety of subjects with many types of headaches – the young, the old, the pregnant, and those without migraines, among others. But her counterpart defended migraine trials in particular, arguing that they’re evolving to become more valuable as researchers address their limitations.
At the core of the debate at the annual meeting of the American Headache Society were sharp divisions over how much the limitations of headache clinical trials matter. Both neurologists – Jan Brandes, MD, of Nashville (Tenn.) Neuroscience Group, and Amy Gelfand, MD, of the University of California at San Francisco, agree that they exist. But they diverged on how much they matter.
Exclusion/inclusion criteria are good
Dr. Brandes argued that randomized controlled trials “remain the single best study design,” and she said migraine headache trials have improved over the past couple of decades.
Eligibility criteria, for example, have expanded to allow patients with more subtypes of migraines to participate, she said. “Another change has been the establishment of guidelines or inclusion criteria that allow patients who have stable and treated hypertension, stable depression, and stable anxiety disorders that are controlled and treated and not interfering with the disease you’re studying.”
In essence, she said, “the exclusion/inclusion criteria are good.”
It’s also a positive change that longer patient-reported outcomes are included in trials, she said.
Exclusion/inclusion criteria are too restrictive
But Dr. Gelfand criticized the inclusion criteria in migraine trials, noting it includes “a lot of amazing complexity.” Trials often will limit participation to subjects aged 18-65, even though people have high rates of headaches, she said, and they frequently overrepresent men. Pregnant and lactating women are often omitted, too, even if a trial is examining a behavioral intervention. In some cases, lactating women may be breastfeeding for a year or two, she noted.
“The vast majority of births in the United States, 92%, are to females who are between the ages of 20 and 39. That is also the age range where migraine is most prevalent,” she said. Yes, certain new agents shouldn’t be tested for the first time in pregnant women because of the risk, she said, “but we need to grapple with the fact that migraine is affecting people who are also going to be pregnant and lactating.”
Many other criteria limit the subjects in headache trials, she said. The studies are “almost exclusively” of drugs for migraines, leaving out many people with other types such as adolescents with new persistent headaches. “Where are the trials for them?” she asked.
Other groups that are left out include those whose headaches that are due to a head injury, a viral infection such as COVID-19, or even vaccination against COVID-19, she said. “There are an infinite number of questions here that we are currently not even attempting to answer.”
Non-Whites are also poorly represented in trials, she said, and studies often don’t include data about non-Whites. “Race data exists. Where do we get off not even reporting it?”
Room for improvement
For her part, Dr. Brandes said less-common headache disorders are best studied in pragmatic trials until they can be better understood. “We need to understand pathophysiology better for some of these other disorders, particularly things like continuous headache and posttraumatic headache. Then we can begin to expand that.”
She added that randomized clinical trials are now underway regarding secondary headache related to COVID-19.
Dr. Brandes did not report disclosures. Dr. Gelfand had no disclosures.