Nocebo Effect Can Hamper Biosimilar Acceptance, Review Says

It is widely acknowledged that provider education and acceptance of biosimilars is one of the factors critical to increasing uptake of biosimilars. A recent review delved into the concept of the nocebo effect—whereby new or worsening symptoms and adverse events arise from patients’ negative expectations and not the pharmacologic action of the drug itself—in biosimilar therapy, finding that gaps in patients’ and providers’ awareness, understanding, and perception of biosimilars may contribute to the nocebo effect, reducing their clinical benefits.

Although they are not as extensively studied as placebo effects, nocebo effects are considered just a significant. The authors noted that regulatory pathways set by the FDA as well as the European Medicines Agency guard against clinically meaningful differences between reference biologics and biosimilars. Although these agencies have published educational materials about biosimilars for both clinicians and patients, these materials do not adequately address the potential for nocebo effects to occur, the researcher wrote.

Personality, psychosocial, neurobiological, and contextual/environmental factors contribute to the development of nocebo effects. Moreover, providers may introduce bias against biosimilars if they are not confident or knowledgeable about biosimilars; therefore, avoidance of negative instructions and expectations, using positive framing, and promoting shared decision-making and patient empowerment is important, the authors wrote.

When providers are confident in their biosimilar knowledge, they can help reduce the risk of nocebo effects and improve patient adherence, they said.

The potential for these effects to happen is strongest when patients with autoimmune disorders switch to biosimilars from reference products, and how this occurs is a growing field of research.

The authors undertook a scoping approach to synthesize research evidence about the topic, conducting a literature search for reviews, randomized controlled trials, and observational studies about nocebo effects and biosimilar therapy published between January 2015 and July 2018. Search terms included biosimilar, clinical, inflammatory, nocebo, placebo effect, rheumatology, and treatment.

The basic psychological mechanisms contributing to the development of negative expectations and nocebo responses are prior experience of negative therapeutic outcomes (ie, conditioning) and anticipation of negative outcomes, the authors noted.

Interestingly, nocebo effects may also be induced by exposure to information shared online, through social media, through drug advertisements, and advertised descriptions or warnings about health-related conditions. The effect can be profound; the authors said negative expectations underlying nocebo phenomena have been shown to alter activity in certain regions of the brain.

Certain subgroups may be at particular risk for nocebo effects, including women and those with anxiety.

In addition, pessimists have shown a greater chance of negative expectations than optimists when given placebos and told that the pills would have unpleasant effects.

In a finding with direct implications for biosimilar acceptance, the authors wrote that “a sense of involvement or control regarding treatment decisions may also influence nocebo effects, as individuals who are not allowed a choice of medications have reported significantly more adverse events than those allowed such a choice.”

Some of these scenarios could wind up playing out in Canada, where British Columbia has begun a program of nonmedical switching for patients on reference products, and in Alberta and Ontario, a biologic drug company is urging patients to resist such switching.

In their review, the authors noted several studies in which patients discontinued biosimilars, despite having no worsening of disease, after switching from reference drugs.

Reference

Colloca L, Panaccione R, Murphy TK. The clinical implications of nocebo effects for biosimilar therapy. [published online November 29, 2019]. Front. Pharmacol. doi: 0.3389/fphar.2019.01372.