Literature Review Finds Insufficient Evidence for Biosimilar Nocebo Effect

October 1, 2018
The Center for Biosimilars Staff

In explaining why some patients who switch to biosimilars from reference biologics discontinue their therapy at a higher rate than those who remain on a therapy without interruption, some authors have referenced the so-called “nocebo” effect. This effect, whereby a patient experiences disease worsening or adverse events due to negative beliefs about a drug, has been controversial, however, and not all clinicians agree that the effect is to blame for differences in discontinuation.

In explaining why some patients who switch to biosimilars from reference biologics discontinue their therapy at a higher rate than those who remain on a therapy without interruption, some authors have referenced the so-called “nocebo” effect. This effect, whereby a patient experiences disease worsening or adverse events (AEs) due to negative beliefs about a drug, has been controversial, however, and not all clinicians agree that the effect is to blame for differences in discontinuation.

Read more about the nocebo effect and biosimilars.

A newly published review sought to investigate the nocebo effect; the review’s authors assessed studies reporting the efficacy and safety outcomes of a switch from a reference drug to an FDA-approved biosimilar. A total of 31 trials were included; 28 involved infliximab, and 3 involved etanercept. Among these studies, only 2 studies of infliximab were double-blinded randomized controlled trials (RCTs), and 2 publications on etanercept evaluated different time points of the same double-blinded RCT.

Results for 3271 patients were reported in total. The most common indications for treatment were inflammatory bowel disease, rheumatoid arthritis, and psoriasis. The mean followup after a switch to a biosimilar was 48 weeks (range, 16-80 weeks).

The analysis revealed that the median discontinuation rates for any reason were 14.3% in open-label studies (range, 0.0%-33.3%) versus 6.95% in double-blinded RCTs (range, 5.2%-11.0%). Discontinuation rates resulting from AEs were 5.6% in open-label studies (range, 0.0%-24.2%) versus 3.1% (range, 2.0%-5.2%) in double-blinded RCTs. A subgroup analysis revealed that antidrug antibody development and infusion reactions were similar between patients in open-label and double-blind RCTs of infliximab.

“Some evidence from the comparison of biosimilar discontinuation rates supports the hypothesis that this outcome measure is highly susceptible to the nocebo effect,” write the authors, but they add that “current evidence is insufficient to confirm a biosimilar nocebo effect.” More studies will be needed to evaluate whether the nocebo effect does in fact impact patients who switch to biosimilars and to identify mitigation strategies—such as patient education—that could help to overcome such an effect.

However, the authors point out that provider education may well play a role in mitigating a nocebo effect, if indeed it is present. Physicians’ knowledge gaps around biosimilars or hesitancy to use these agents may either create or reinforce patients’ negative expectations, so appropriate framing of discussions about biosimilars will be key.

Reference

Odinet JS, Day CE, Cruz JL, Heindel GA. The biosimilar nocebo effect? A systematic review of double-blinded versus open-label studies. J Manag Care Spec Pharm. 2018;24(10):952-959. doi: 10.18553/jmcp.2018.24.10.952.