Clinical Research: Phase 1 - Phase 4

Operational Challenges of Neuroscience Clinical Trials, Part 2: High Placebo Responses   

Neuroscience clinical trials, especially those for psychiatry and analgesia indications, have always had to deal with the challenge of high placebo response. Most troubling is that the placebo response rate seems to be on the rise, at least in the U.S.  

Bigger placebo responses make it harder to show that an experimental treatment is effective. Indeed, higher placebo response has been linked to trial failure in antidepressants as well as treatments for neuropathic pain and cancer pain. Strategies to reduce the placebo response fall into three broad categories of improvement: changes to overall study design, improvement in the quality of ratings, and modulation of participants’ experience and expectancy.  

Study designs for neuroscience trials

One of the most common methods to reduce the placebo response via altered study design is to perform a placebo run-in prior to the start of the trial, and to then subsequently exclude high responders from further study drug administration. While this strategy has been successful in some cases, a number of analyses of psychiatry and analgesia trials indicate that placebo run-ins do not increase the magnitude of drug-placebo difference and can extend the timelines – and therefore increase the cost – of the study in question.  

The sequential parallel comparison design (SPCD) is a two-phase design that is increasingly being used to reduce the placebo response and improve drug-placebo differences, especially in antidepressant trials. In the first phase, subjects are randomized to receive placebo or active treatment; placebo non-responders are then randomized to receive either the active drug or placebo in the second phase. The final analysis includes pooled data from both stages. Initial indications are that the SPCD is more effective at reducing placebo response; however, continued adoption of the method – and analysis of the results – will be necessary to fully ascertain its efficacy in a wide range of CNS studies.  

Improving the quality of ratings in trials

A second way to combat high placebo responses in neuroscience clinical trials is to improve the quality of ratings. Scheduling challenges often result in a participant being assessed by different raters throughout the trial. Inconsistent raters can muddle the differences between the drug and treatment arms, so raters who are adequately trained, as well as specifically trained to be consistent, are important. This is especially key in psychiatry trials, where outcome measures are a subjective assessment resulting from a structured interview between psychiatrist and patient. Surveillance of raters is another important strategy to reduce placebo responses. We’ll discuss these and other strategies to improve the quality of ratings later in this series.  

A second method to improve ratings is to ensure that the patients to whom the scale is being administered fully understand the scale and, most importantly, that the range of potential ratings is anchored to their personal experience. This is best done via training by experienced site staff and, using analgesia as an example, helps to ensure the same level of pain that is rated as a “5” on a pain scale at the beginning of the study is still rated as a “5” (rather than a “2” for instance) at the end of the study.   

Minimizing patient expectancy of improvement

A third tactic to reduce placebo response is to modulate a participant’s trial experience and minimize their expectation of improvement. Research has shown that the mere act of receiving care can increase the placebo response, so limiting the time participants spend in treatment — by streamlining study visits as well as minimizing the total number of assessments — is one way to reduce placebo responses.  

Patients start to feel better as a result of all of the attention they are getting as well as the presence of contextual elements that suggest they are receiving a medical treatment, such as a physician’s white coat and other symbols of medicine. The longer a patient stays in a trial, the more attention they are getting, and the more they are exposed to these placebo-enhancing contexts.  

In addition, trial participants who feel like they are being cared for exhibit higher placebo responses than those who rate their clinician as uncaring, so standardizing interactions with patients is another strategy to limit the placebo response. Finally, it’s important for participants to have realistic expectations about the success of the experimental treatment. Emphasis by the site staff regarding the fact that a “Research Alliance” is being established with the patient, rather than the typical “Therapeutic Alliance” that might otherwise be in place, goes a long way to managing these expectations. Placebo responses are lower among those who are told the treatment may or may not provide benefits than those who are presented with a rosier picture of the likelihood of improvement.  

At the end of the day, placebo reduction is all about finding those sites that have mastered the ability to minimize the placebo response. That’s why it’s crucial to choose a CRO with experience in placebo response reduction. To learn more about the causes, mechanisms, and strategies to reduce high placebo responses, check out our ebook The Placebo Problem 

Read more:

Operational Challenges of Neuroscience Clinical Trials, Part 1: Overview