Consensus Report Calls for More Research Into Biosimilars and the Nocebo Effect

The nocebo effect, whereby a patient experiences a worsening of symptoms or poor outcomes because of negative beliefs about a given therapy rather than because of the therapy itself, has been the subject of increased discussion among biosimilar stakeholders. Recent months have seen the publication of a systematic review concluding that higher-than-expected discontinuation rates of biosimilars could be due to the effect, and another paper called for strategies to address the potential for the nocebo effect to impact patient outcomes. This week, a consensus report, published in Alimentary Pharmacology and Therapeutics, calls the nocebo effect underrecognized in the area of biosimilars and says that more research is needed on this important topic.

The consensus group, comprising 19 members from 5 European countries and including 7 gastroenterologists, 3 pharmacists, 2 oncologists, 2 rheumatologists, 2 methodologists, 1 dermatologist, 1 psychologist, and 1 nurse specialist in inflammatory bowel disease (IBD), sought to review the literature on the nocebo effect and its prevention and management in patients with IBD who receive biosimilars.

Three members of the group conducted a literature search up to July 2018, and 13 members of the group participated in a meeting during which they voted on their level of agreement with statements developed by 3 of the members.

The literature review revealed that the nocebo effect occurred in 12.8% of patients in 1 study of patients with immune-mediated inflammatory diseases, and that similar rates were observed in patients with IBD and those with rheumatic diseases. Predictors for the effect that emerged from the review included “learning by social observations,” “perceived dose,” “verbal suggestions of arousal and symptoms,” “type of clinical condition,” and “baseline symptom expectations.” An additional 4 patient factors that enhanced the risk of nocebo included learning by classical conditioning,” “likelihood suggestion,” “self‐awareness,” and “negative affect.” The authors add that only limited, indirect evidence exists to describe the impact of the nocebo effect, and interventional data on the prevention and management of the nocebo effect in biosimilar-treated patients with IBD do not exist.

The group reached a consensus on 11 statements, each of which gained 77% to 100% acceptance, all on the basis of very low-quality evidence:

1. The nocebo effect is underrecognized in the era of biosimilars. The nocebo effect can occur when initiating a biosimilar or when switching to a biosimilar.
2. Nocebo responses to biosimilars are triggered by a complex interplay of patient‐related factors and psychological mechanisms.
3. When using a biosimilar, caution is needed not to attribute every side effect directly to the treatment, because some side effects may be related to the nocebo effect.
4. The nocebo effect may negatively impact the cost savings of biosimilars.
5. All healthcare providers in charge of biosimilar‐treated patients need to be aware of the nocebo effect and adopt strategies to minimize it.
6. The patient—healthcare provider relationship is a key driver of acceptance of biosimilars and limits the risk of negative bias and the nocebo effect.
7. Lack of knowledge among patients about the effectiveness and safety of biosimilars contributes to the nocebo effect and should therefore be minimized.
8. Lack of knowledge and misconceptions among healthcare providers about the effectiveness and safety of biosimilars contribute to the nocebo effect and should therefore be minimized.
9. Education about biosimilars should be tailored to the individual patient, taking into account their risk profile for the nocebo effect.
10. Positive framing is recommended to reduce the nocebo effect.
11. Due to the limited evidence of the nocebo effect in the biosimilars era, further research is needed to better estimate the magnitude of the nocebo effect, to identify risk factors associated with the nocebo effect, to measure the impact of the nocebo effect on disease outcomes as well as the healthcare system, and to design interventional studies to reduce and to prevent the nocebo effect.

Funding for the consensus group was provided by biosimilar developers Sandoz, Pfizer, Celltrion, Biogen, and Samsung Bioepis through unrestricted grants.

Reference

Pouillon L, Danese S, Hart A, et al. Consensus report: clinical recommendations for the prevention and management of the nocebo effect in biosimilar-treated IBD patients [published online April 1, 2019]. Aliment Pharmacol Ther. doi: 10.1111/apt.15223.