Treatment Outcomes with Biosimilars: Be Aware of the Nocebo Effect

For reference biologics, the aim of the developmental process is to demonstrate de novo the risk–benefit profile of the candidate product [1]. However, during biosimilar development, the aim is to demonstrate high biosimilarity with the reference biologic in terms of structure, physicochemical attributes, and biologic activity, and to reconfirm the efficacy, safety, and immunogenicity profile as it was previously established by the reference biologic during its development process [1]. The majority of effort in establishing similarity is performed during comprehensive non-clinical comparability exercises, whereupon any potential difference in terms of critical quality attributes between the biosimilar and reference biologic are more likely to be detected (Fig. 1) [14]. Following this, and to achieve regulatory approval, a phase I pharmacokinetic clinical study in humans must be carried out to demonstrate pharmacokinetic equivalence. At least one phase III, randomized clinical trial is then performed in a sensitive patient population representative of those included in an approved indication for the reference biologic, to demonstrate equivalent efficacy and comparable safety and immunogenicity of the biosimilar and its reference biologic. Post-marketing authorization studies, together with real-world data from registries and clinical centers, provide additional confirmation for the long-term effectiveness, safety, and immunogenicity of approved biosimilars [2, 15‐21]. All this taken together comprises the totality of evidence for a biosimilar, highlighting the rigorous process in which biosimilars are developed and monitored [2].

However, despite biosimilars having been available since 2007 and, although vast amounts of preclinical, clinical, and real-world evidence confirming similar quality, equivalent efficacy, and comparable safety of the biosimilars to their reference biologic are available, a perception gap (likely due to low awareness of available data and lack of communication of these data) among physicians and patients still exists [5‐7]. Although the majority of physicians are aware of biosimilars, knowledge gaps regarding the effectiveness and safety of these molecules can sometimes exist, which may lead to uncertainties around their use in daily clinical practice [5]. Patient knowledge, understanding and perception of biosimilars also play an important role with regard to acceptance and treatment outcomes. Patients who are aware of biosimilars tend to have more positive perceptions regarding biosimilars than patients who are unaware; however, perception regarding efficacy and safety of reference biologics is higher than for biosimilars [7]. Therefore, low awareness and misconceptions of biosimilars may create, or widen, gaps in physician and patient perceptions, thereby impacting the use of biosimilars (as patients are less comfortable switching) and their outcomes [7].

In general, patient perception of treatment is also important when considering treatment adherence because a negative perception of treatment efficacy can cause non-adherence, as can lack of knowledge about a disease and its treatment [22]. In addition, drug profiles play an important role, with patients more likely to discontinue treatment due to a poor side-effect profile or lack of efficacy of a medication [23]. For example, in patients with rheumatoid arthritis, discontinuation rates due to inefficacy and adverse events were demonstrated in etanercept (17.5 and 22.4%, respectively), infliximab (44.1 and 36.7%, respectively) and adalimumab (50.4 and 31.2%, respectively) over a period of 12 years. These data highlight the importance efficacy and safety of a medication plays in patient adherence to treatment [23].

Perception gaps may be related to a nocebo effect that can lead to the induction or the worsening of symptoms induced by sham or active therapies [24, 25]. When a nocebo effect is seen with an active therapy, this is a non-specific response in that the symptoms or physiologic changes cannot be explained on the basis of the known pharmacology of the drug and is not dose-dependent [11]. Nocebo symptoms are typically generalized and diffuse, including drowsiness, nausea, fatigue, and insomnia [26].

Patients in general are highly receptive, but women, patients with psychiatric illness, or individuals with certain personality traits (e.g., aggressive or competitive) have been shown to be more susceptible to a nocebo effect [26‐28]. Psychologic mechanisms, including classic conditioning (when a neutral, inert or inactive stimulus can elicit a physiologic change if these have previously been repeatedly paired with a provocative stimulus), negative expectations and suggestibility can underlie the nocebo effect [11, 29]. A perceived increase in dose of medication, suggestions by healthcare professionals (HCPs) that the medication triggers symptoms, observations of other people experiencing symptoms and higher expectations of symptoms are also strong predictors of the nocebo effect [24]. Verbal and non-verbal communications from the HCP that may contain unintentional negative connotations [24], such as “this medication may help” or “let’s try this drug”, may also trigger a nocebo response in patients [24].

This effect has previously been observed in several therapy areas, including pain, Parkinson’s disease, and cardiovascular disease [12, 30‐33]. The nocebo effect was very recently demonstrated in patients receiving statins, where an excess rate of muscle-related adverse events were reported only when patients and their doctors were aware that statin therapy was being used, and not when its use was blinded [31]. It is also very well recognized in patients who switch from a reference medicine to chemically identical generics [34, 35].

Recently, this nocebo effect has also been considered in patients switching from reference biologics to biosimilars [15, 18, 36]. In observational studies, 16–28% of patients were found to discontinue CT-P13 biosimilar following ≥ 3 months of treatment [15, 18, 36]. Additionally, it was suggested that these discontinuation rates might have been slightly higher than those historically reported with the reference biologic and that this difference could be partially explained by perceived loss of efficacy and minor adverse events (such as fatigue, malaise, and headache), despite no changes in efficacy, safety, or immunogenicity being observed [15, 18, 36]. The authors concluded a nocebo effect was likely; however, they recommended further investigation to fully understand this phenomenon with regard to biosimilar use. The discontinuation rates stated in these publications are higher than those seen in registries and clinical center studies in patients treated with the etanercept biosimilar, with some reporting ≤ 9% discontinuation rate following ≥ 5 months of treatment [16, 17, 19‐21]. Interestingly, these are far lower than those seen in Turkey, where medical billing records from patients with rheumatoid arthritis were analyzed, and 63 and 82% of biologic-naïve and switch patients (from INF to CT-P13), respectively, discontinued biosimilar treatment [37, 38]. However, the authors of these studies concluded further analysis was required to understand the reasons for these observations.

Considering that the nocebo effect has been shown to impact the number of adverse events experienced by a patient, result in perceived loss of efficacy, and lead to non-adherence to a medicine, the consequences to the healthcare system are far-reaching. Not only does this affect patients’ quality of life, but it can also affect how HCPs resolve these additional adverse events, which can lead to more complicated treatment regimens, or needless switching of the patient to previous treatments and possibly reducing their future treatment options. Collectively, dealing with nocebo effects results in additional patient clinic visits, which places more pressure on a healthcare system and can lead to the cost savings of biosimilars not being realized [11, 39].

Given that the nocebo effect can prompt non-adherence, which can have far-reaching consequences for a patient and healthcare systems [11], it is recommended that HCPs employ interventions to help minimize these effects from occurring. Invariably, owing to time restrictions in a busy clinic, it can be challenging to perform a thorough patient–physician discussion to ensure informed shared decision-making and reduce the likelihood of a nocebo effect from occurring. However, various strategies can be implemented in the clinic to help informed decision-making and negate the nocebo effect, including identifying patients at high risk, determining patient expectations of adverse events and providing reassurance if these are excessive, tailoring information to only provide pertinent details to the patient (Fig. 2) [7], reducing exposure of the patient to others experiencing side effects, and educating the patient on nocebo effects using case studies [25, 39]. Physicians should consider implementing motivational interviewing techniques into the clinic by subtly guiding the patient to think about and verbally express their reasons for and against change, so that the patient is making an informed and considered choice, which is likely to help reduce the nocebo effect [40]. In addition, any HCP who talks to patients about the potential use of a biosimilar must themselves feel fully confident and capable of transferring this confidence, and help a patient make an informed shared decision, without unintended negative suggestions, which may trigger an inappropriate negative bias and a nocebo response.

Information on biosimilars is now available from several distinct sources that help to inform and build HCP confidence when making informed shared treatment decisions with their patients. This includes data from clinical trials, data from large observational registries, data from individual case studies, institutional experiences, and information guides released by regulatory bodies [14]. Well-informed HCPs who are aware of these data are more likely to become confident and then be able to transfer this confidence in biosimilar medication to their patients, resulting in patient confidence regarding their choice, whether they eventually choose to switch or not, which should alleviate the nocebo effect (Fig. 3). Emerging research has shown how influential patient–physician interaction is on the perception of efficacy and safety of biosimilars, as it is with other therapies. For example, researchers at the Parker Institute, Denmark, have identified strong barriers and facilitators to the patient experience and highlighted patient–physician interaction as critical to ensure perceived treatment value for the patient. They highlighted that when treatment discussions with patients occur, it is important to appreciate that single biased words and gestures can have a significant impact and should be avoided to ensure minimal negative instructions and negative therapeutic context [39].

Similarly, a recent open-label study compared the effects of switching patients with a rheumatic disease from a reference product to a biosimilar agent (infliximab to CT-P13 in 2016 and etanercept to SB4 in 2017) using different communication strategies, including: notifying all patients at the same time; clearly informing patients about the reasons for the switch; providing ‘soft skills’ training for rheumatology and pharmacy staff to help them moderate patient concerns; and openly discussing possible nocebo effects [20]. They found that this led to higher patient acceptance and persistence rates compared with patients who did not receive this enhanced communication strategy [20]. Further real-world data also show that comprehensive patient education and support (including face-to-face discussions; provision of patient information sheets on drug switch and biosimilars; access to a helpline number and regular clinical reviews) during the switch to a biosimilar product resulted in higher acceptance of these agents by patients, which may also help reduce the nocebo effect [30, 41].