In the early days of biosimilar utilization, the nocebo effect was a clear worry of the biosimilar industry. When patients knew they were receiving a biosimilar rather than a reference product, discontinuation rates and adverse drug events were noticeably higher. On an absolute basis, nocebo rates are not alarmingly high; a 2018 study found reported nocebo-related discontinuation rates for infliximab biosimilars to be around 13%.
By definition, the biosimilar nocebo effect is the result of prescribers’ or patients’ reduced clinical expectations for biosimilars relative to reference products. Therefore, education about biosimilars provided to patients and physicians and longer-term clinician experience in their use is therefore assumed to be the solution. Researchers from Belgium and The Netherlands reviewed the available evidence and proposed several steps towards mitigating the biosimilar nocebo effect.
In an open-access paper, they described their systematic literature review to analyze studies that quantitatively or qualitatively evaluated nocebo-effect mitigation strategies. Their search revealed 60 articles that fit their research criteria (mainly from Europe [58%], Oceania [17%], and North America [12%]). Fifty-three studies utilized interventional or observational research designs. A total of 12 mitigation strategies were determined to be applicable to biosimilar and non-biosimilar prescribing or switching situations. Some of these addressed utilizing a shared decision-making strategy, nonverbal physician–patient communication during the consultation (e.g., nodding, smiling, maintaining eye contact), and use of empathic communication. Five identified strategies applied to specifically to biosimilar prescribing (Table)
| TABLE: FIVE STRATEGIES TO PREVENT A BIOSIMILAR NOCEBO EFFECT | |
| Mitigation Strategy | Description |
| Validating communication | Ensuring the healthcare provider conveys that the patient’s feelings and concerns are understandable and reasonable |
| Education on biosimilars | Offering education (general or detailed information) on biosimilars and their potential benefits |
| Soft-skills training to the health care team | Training clinicians on how to act in an empathic manner, communicate effectively, and listen actively and openly |
| Multidisciplinary approach | Taking a collaborative approach among professionals in diverse fields to address the patient’s health and other needs during the switching process |
| Coordination of the switch to the biosimilar | Ensuring a smooth transition throughout the entire medication-switching process |
Adapted from Car E, et al. Pharmaceutical Medicine 2024;38:429–455.
Shared decision making, though an important factor in attaining initial buy-in and maintaining adherence to the therapeutic plan, is of particular importance in preventing the nocebo effect. Intuitively, this approach should reduce address at least negative expectations involving biosimilar use that the clinician and/or patient may have.
Positive attribute framing, where the clinician emphasizes the similarities between the biosimilar and reference product, could effectively reduce a patient’s misconceptions before starting (or switching) therapy.
The researchers proposed a framework for mitigating the nocebo effect before, during, and after switching from the biosimilar product, utilizing these essential tactics. Without more investigation, it would be difficult to “draw definite conclusions with regard to the effect size of each [recommended] mitigation strategy,“ they stated.
Does the nocebo effect become less significant for biosimilars that have been available for many years? Arnold G. Vulto, PharmD, PhD, Professor, Erasmus University Medical Center, The Netherlands, and one of study’s authors, stated in an Email to BR&R, “Pertinent scientific valid studies on the nocebo-effect occurring under biosimilar treatment are relatively scarce. Much of the material is anecdotal, looking at drug persistence, without clearly specifying the critical conditions like how patients were informed precisely [about their treatment].
“The experience in Europe shows that nocebo effects are now virtually absent with the traditional [biologic] substitution products like pegfilgrastim, filgrastim, and epoetin, which were introduced more than five to 10 years ago,” Dr. Vulto continued. “In well-developed markets like rheumatoid arthritis, hematology, and gastroenterology, most prescribers have been well informed by now, and these healthcare providers can as a result convey trust in these products to their patients. However, with new biosimilars in new indications (e.g., lung diseases, neurology), such training will be delayed and prescribers may be hesitant, and may tell a less-convincing biosimilar story to their patients.
“So in general, with increasing clinical experience in a therapeutic area, the nocebo effect wanes.” Dr. Vulto added, “Our paper contains a number of recommendations to facilitate this process. One important lesson that we have learned is to involve patient organizations as early as possible in the education process.”
