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When to give the green light to placebo controls
Severity of illness, length of trials among factors
Despite the value that placebo controls bring to psychiatric research, they are not appropriate for all clinical trials of antidepressants and anti-anxiety medications.
Boadie Dunlop, MD, director of the Mood and Anxieties Disorder Program at the Emory University School of Medicine in Atlanta, says an IRB confronted with a proposed study that includes placebos should keep the following points in mind:
Severity of illness — Participants should not be patients who are in need of urgent treatment, such as those with marked suicidal ideation or functional impairment.
"Those folks aren't going to be offered enrollment in the study because they need immediate care and it would not be appropriate to delay them care, either through the screening and evaluation process or potential placebo treatment." Dunlop notes that researchers already routinely exclude these patients from placebo studies.
He says it might be possible to conduct a placebo-controlled trial for severely affected patients, in order to see if a drug were particularly helpful for that population. Dunlop suggests that it could take the form of a discontinuation trial, in which all patients are given the study drug, and then some are later randomly assigned to either continue the drug or switch to placebo.
Dunlop notes in his article that such a trial would require an extremely well-designed informed consent process to ensure that participants understood the risks involved.
Freedom to withdraw — It should be clear in the informed consent that participants are free to withdraw from the study if they feel they are not improving or their symptoms are getting worse.
Limited duration — Patients should only be exposed to placebo for a limited amount of time – Dunlop says Phase II and III clinical trials of new treatments for depressive and anxiety disorders typically last six to eight weeks.
"For most people with depression, it's been going on for many months, often more than a year or two," Dunlop says. "So, to receive a placebo for another six to eight weeks, even assuming the placebo is absolutely ineffective, doesn't generally put a person at increased risk."
Close contact with study team — Participants should be monitored very closely throughout the trial. Dunlop recommends that they are seen at least every one to two weeks, to be sure their condition is not worsening and to intervene quickly if necessary.
Dunlop says that it's very rare for suicidal ideation to emerge out of nowhere — it builds over time, making close monitoring the most effective means of protecting the patient. He notes that participants engaged in a placebo- controlled trial are actually monitored much more closely than they would be if treated in clinical practice.
"In clinical practice, we know these medications are ineffective in about a third of people with depression, and so they're essentially like an ineffective placebo in a third of people with depression," Dunlop says. "And they might not be seen for four weeks or more. There's greater protection to the patients participating in a clinical trial than there is in routine clinical care where they might be seen less frequently."
Informed consent — Dunlop says many patients fail to understand exactly what a randomized placebo-controlled trial involves. IRBs should be aware of this in reviewing the informed consent process. Participants need to understand that treatment will be assigned to them randomly, without considering their individual cases. They need to know exactly what a placebo is. They need to know that they can withdraw at any time.
"The main thing is there are procedures in place to take care of patients who fail to get better or who worsen during the trial," he says.