13 Strategies to Avoid the Nocebo Effect During Biosimilar Switching

A comprehensive systematic review has identified 13 strategies—ranging from patient and provider education to empathetic communication and shared decision-making—to effectively mitigate the nocebo effect in biosimilar switching, highlighting the critical need for a multifaceted approach to overcome negative perceptions and optimize therapeutic outcomes.1

“We believe that the available data, this systematic analysis, and the set of recommendations offer a sound basis for mitigating a potential nocebo effect with respect to administration of biosimilars,” wrote the authors.

The nocebo effect, the negative counterpart of the placebo effect, occurs when negative expectations about a treatment lead to worsened symptoms or adverse events (AEs) unrelated to the treatment's pharmacological action.2 It can be triggered by factors such as negative verbal or nonverbal communication from health care providers (HCPs), social observations, AE discussions, and media coverage. The nocebo effect is particularly relevant in biosimilar switching, where misconceptions about biosimilars' efficacy and safety may cause patients to perceive lower therapeutic effects or experience AEs.3

Although several studies have confirmed that switching between originator biologics and biosimilars is safe and effective, open-label studies report higher discontinuation rates (4.8%-28.2%) compared with double-blind studies, suggesting the influence of nocebo effects. These outcomes can lead to treatment discontinuation, reduced quality of life, economic burdens, and strained HCP-patient relationships.

Given the limited focus on mitigating nocebo effects in biosimilar switching, the review, published in Pharmaceutical Medicine, aimed to assess the impact of existing nocebo mitigation strategies and propose recommendations to minimize nocebo-related AEs during biosimilar switching.

This review identified 1617 records on strategies to mitigate the nocebo effect. Searches were performed in PubMed and Embase until April 24, 2023, using predefined terms like nocebo and biosimilar, supplemented by forward and backward snowballing. Articles were screened using Rayyan software based on eligibility criteria, which included original, peer-reviewed studies focusing on nocebo mitigation strategies in humans with full-text availability in English, Dutch, or French.

After screening titles and abstracts, 70 articles were reviewed for eligibility, with 20 excluded for reasons like insufficient information or access issues. Ultimately, 60 articles were included in the review, with 50 from PubMed and Embase and 10 from snowballing.

The included studies primarily came from Europe (58%), with smaller contributions from Oceania (17%), North America (12%), and Eurasia (3%). The majority (93%) were original research, including 73% interventional studies. Approximately half (48%) focused on pharmacological interventions, with 12% specifically involving biosimilars. Many studies were in pain research (30%), followed by rheumatology (13%) and oncology (7%). Half of the studies received public funding.

Quality appraisal revealed that most studies were of high quality, with 4 randomized controlled trials rated medium and a qualitative study rated low. The nocebo mitigation strategies identified included 15 distinct approaches, 5 of which were specific to biosimilars, while others applied both within and outside the biosimilar context.

The strategies for mitigating the nocebo effect during biosimilar switching were categorized into 3 phases: preswitch, during switch, and post switch, as well as by their target group (patients, HCPs, or both) and implementation modality (tools, human interaction, or educational initiatives). The effectiveness of these strategies depends on proper training of the HCP team.

The 13 biosimilar strategies were:

• Open nonverbal communication
• Positively framing the likelihood of experiencing an effect
• Empathic communication involving understanding a patient’s situation, perspective and feelings, communicating and verifying that understanding, and acting on it in a helpful way
• The recipient (often HCP) validating communication that the patient’s thoughts and feelings are understandable and reasonable
• Shared decision-making strategy between the patient and the physician
• Self-affirmation interventions
• Education about the nocebo effect
• Education about biosimilars
• Soft-skills training for the HCP team, such as how to act in an empathic way, communicate effectively (verbal, non-erbal, and written), and listen actively and openly
• Providing personalized information considering factors like their preferences, age, literacy, medical history, and personal characteristics
• Providing supporting information to support patients throughout the switching process
• A collaborative approach involving professionals from diverse fields working together to address comprehensively patient’s health and other needs
• A smooth, organized transition process

Seven quantitative studies focused on biosimilar switching. These studies examined various strategies like shared decision-making, combining it with other strategies such as enhanced communication and multidisciplinary approaches. Key findings showed that shared decision-making, particularly with opt-in methods, had mixed results on retention rates, while combining shared decision-making with education and training improved patient acceptance. Other strategies, such as positive attribute framing in educational videos, were found to increase willingness to switch and improve perceived efficacy.

Three qualitative studies examined strategies to mitigate the nocebo effect in the context of biosimilar switching. Communication strategies, including positive framing, empathic communication, and transparency, were emphasized as key approaches. HCPs were advised to use clear, reassuring language, highlight the safety and efficacy of biosimilars, and foster a supportive, empathetic dialogue with patients. Education and training for HCPs about biosimilars and the nocebo effect were also identified as essential, ensuring they are well equipped to guide patients.

A multidisciplinary approach, involving various health care professionals, was recommended, with nurses playing a central role in personalized patient education. The importance of shared decision-making and providing tailored, understandable information was highlighted, particularly for patients at higher risk of nocebo effects. Organizational aspects, such as structured switch plans and follow-up sessions, were also stressed to ensure smooth transitions.

Limitations on these findings include the small number of studies in the biosimilar context, differences in terminology, and potential underrepresentation of some strategies. The review's language restriction also limited the inclusion of relevant studies.

References

1. Car E, Vandenplas Y, Lacosta TB.Mitigating the nocebo effect in biosimilar use and switching: a systematic review. Pharmaceut Med. 2024;38(6):429-455. doi:10.1007/s40290-024-00541-y

2. Jeremias S. Nocebo effect is difficult to diagnose in patients switched to biosimilars. The Center for Biosimilars®.March 17, 2020. Accessed December 17, 2024. https://www.centerforbiosimilars.com/view/nocebo-effect-is-difficult-to-diagnose-in-patients-switched-to-biosimilars

3. Inserro A. Nocebo effect can hamper biosimilar acceptance, review says. The Center for Biosimilars. December 6, 2019. Accessed December 17, 2024. https://www.centerforbiosimilars.com/view/nocebo-effect-can-hamper-biosimilar-acceptance-review-says