The best approach to mitigating placebo response is to develop a strategy that has all participants measuring the same things in the same way, two experts say.
Avoiding using a placebo arm in an efficacy trial is not always realistic, WCG Analgesic Solutions chief science officer Nathaniel Katz and WCG MedAdvante-ProPhase chief research officer Mark Opler told attendees at a recent WCG webinar.
Although a placebo arm is not necessary for testing the efficacy of a drug, according to Opler, studies with no placebo comparison may raise eyebrows. “If you’re trying to invent a new scale that’s going to be immune to the effects of placebo response,” he said, “it may be a fool’s errand.”
A clinical trial is essentially a measurement system, with sites and patients doing the measuring. When the two sides aren’t in sync, the whole study is prone to error.
Katz compares a smoothly working clinical trial to a watch, a complex instrument in which many moving parts work together.
“It’s each and every patient who’s reporting their symptoms; it’s the scales we give them to measure it; it’s the sites that those subjects are immersed in; it’s the supply of the drug; it’s all the things that all of us work very hard to make sure are in calibration,” said Katz.
“As clinical trialists, I think it’s fair to say that our main job is to be aware of these sources of measurement error,” said Katz, “and expunge them to the extent possible from both the way we design our studies and also the way we conduct our studies.”
Measuring pain is particularly subjective, but training trial staff to recognize the symptoms of placebo response gives them the chance to intervene and educate patients.
“As a result of trying to make patients more aware of their own bodily pain sensations, we also were able to reduce their response to placebo dramatically,” said Katz.
“Whether you’re training patients themselves to report their own subjective states, or whether you’re training clinicians to be more reliable raters of the subjective states of their patients, if you put some work into training and more finely calibrate your rater, you not only improve the reliability of the assessment, but you also reduce the response to placebo at the same time,” said Katz.
According to Opler, it’s harder today to limit placebo response than it was a few years ago. “Every year, the level of response in the placebo arm of these trials, keeps getting bigger,” he said.
Opler warned against giving patients an unrealistic expectation of improvement for a clinical trial, to help them best objectively report their own symptoms.
“Part of our job as trialists, and what we hope investigators are doing, is to identify these unrealistic expectations at the patient level, and help to reeducate,” said Opler.
He recommended making clear to patients the difference between going to a doctor and participating in a trial, something he refers to as therapeutic misconception. The risk of therapeutic misconception is study failure, he said.
“One of the things I want to urge you all to do is to work hard with your investigators, and for your investigators to work hard with their own patients, to help really clarify, at every point, the difference between medical care and clinical research,” said Opler.
Opler added that resources in clinical trials are best spent on education rather than on details that won’t support the overall effectiveness of the trial.
“If your study budget spends more on the study logo and branding than it does on placebo response mitigation, that’s a problem,” said Opler.
