he Food and Drug Administration is overhauling its guidance for developing treatments for major depressive disorder for the first time since 1977 — and this time around, it’s making clear that patients with a history of suicidal thoughts or behaviors can be included in clinical trials.
Drug companies often rule out potential research participants with a recent history of suicidal thoughts or behavior, citing safety concerns or other issues. In a new draft guidance, the FDA says that patients with a history of suicidal thoughts or behavior “need not be systematically excluded” from clinical trials.
“Although this [exclusion] has been and is acceptable, we would encourage sponsors to broaden their inclusion criteria as long as they are able to do so safely,” said Sandy Walsh, a spokesperson for the FDA.
Excluding patients who’ve had suicidal thoughts or have attempted suicide leaves patients and clinicians in a bind: They can’t be certain the drugs will work for patients most in need of more effective treatments at a time when the U.S. suicide rate is climbing.
“To exclude people who have one of the manifestations of the underlying illness is preposterous,” said Dr. John Greden, the director of the University of Michigan Comprehensive Depression Center.
He and others in the field who’ve wanted to see broader inclusion for years say it’s a step in the right direction.
“It’s a great statement and absolutely should be there,” said Dr. Kerry Ressler, the chief scientific officer of McLean Hospital and a psychiatry professor at Harvard Medical School. “But it’s one of those statements that seems self-evident.”
But many trials do exclude patients at risk of suicide. A STAT analysis of clinical trials of major depression disorder treatments that are listed as “currently recruiting” on ClinicalTrials.gov finds there is a wide range of exclusion criteria. Some don’t exclude patients with past or current suicidal ideation at all. Many say patients at high risk of suicidal actions aren’t eligible for the trial. Some exclude patients who have attempted suicide in the past year, or patients who’ve had “clinically significant” suicidal thoughts in the past year.
Some companies are trying to strike a balance. Alkermes — whose experimental treatment ALKS-5461 for major depressive disorder is currently being reviewed by the FDA — is recruiting for another study of the drug on patients who haven’t responded to other treatments.
The company is excluding patients at imminent risk of suicide and patients who have been hospitalized within the past three months due to their depression, out of concern for their safety. Patients with active suicidal thoughts — but without any intent to act on those thoughts — are still eligible. The company said that criteria helps prioritize both patient safety and data that’s generalizable to patients with depression.
Experts point to several reasons drug companies might be reluctant to include such patients in their trials, including liability. Drug companies wouldn’t want to be blamed if a patient dies by suicide during a clinical trial, and it might be difficult to parse whether the treatment played a role.
There also are also safety and ethical concerns about including someone with active suicidal thoughts or at imminent risk of suicide in a clinical trial, particularly one with a placebo arm. But experts say drug companies can safely monitor patients, or can design trials that compare one active treatment to the experimental drug, so that no patient receives a placebo.
“I feel the ethics dictate we study [depression] more. These illnesses kill people. And we’re losing a lot of people because we don’t have more effective treatments,” said Greden.
Drug companies that include patients in trials with past suicidal behavior or active suicidal thoughts do have to proceed with caution and put safety protocols in place. But the FDA’s Walsh said that’s not necessarily what’s driving exclusions.
“Our impression is that they have been reluctant to include these patients not because they were unable to incorporate adequate safety monitoring in their protocols, but because they believed FDA would not allow it,” Walsh said.
In that case, the FDA’s statement should clear up any confusion. While it doesn’t require companies to include patients with a past history of suicidal thoughts or behavior, the guidance says trial sponsors that set restrictive inclusion or exclusion criteria should be prepared to explain their decisions to the agency.
“To exclude people who have one of the manifestations of the underlying illness is preposterous.”
Dr. John Greden, University of Michigan Comprehensive Depression Center
The document is still a draft guidance. The FDA is taking comments on it through Aug. 20, and then will work to finalize the document, which also includes new guidance on designing trials for fast-acting antidepressants.
The FDA says past suicidal thoughts and behavior are “not uncommon” in patients with major depressive disorder — and excluding these patients from clinical trials might limit how broadly a trial’s findings can be applied.
Studies over the past two decades have documented this concern. An analysis published in 2002 in the American Journal of Psychiatry found that participants in antidepressant trials represented just a sliver of patients treated for major depressive disorder in everyday practice.
“We really don’t have a good idea of how well our medications work for patients seen in routine clinical practice, because most patients seen in clinical practice wouldn’t make it into a treatment trial,” said the study’s author, Dr. Mark Zimmerman, a clinician and psychiatry professor at Brown University.
And some evidence suggests exclusion criteria are getting even more stringent: A 2015 study by Zimmerman and his colleagues published in Mayo Clinic Proceedings scoured the data on 170 placebo-controlled antidepressant trials, 56 of which had been published in the previous five years. The more recent trials were much more likely to exclude patients who had made a suicide attempt and patients with other psychological disorders.
In its draft guidance, the FDA also said drug makers should avoid other “unnecessary restrictions,” such as excluding depressed patients who have other illnesses, patients infected with HIV or hepatitis C, or elderly patients. The agency, however, didn’t specify that clinical trials should include pregnant and lactating women, who are broadly excluded from research on antidepressants.
Ressler said he’s optimistic that the draft FDA guidance will nudge large drug companies to put more resources into inclusive research on treatments for depression.
“We’re hoping that the FDA’s interest … will bring some of pharma back in,” said Ressler. “It’s been too long since there’s been interest in depression.”