Treatment Outcomes with Biosimilars: Be Aware of the Nocebo Effect.
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ABSTRACT: Funding
Biogen.
SUBMITTER: Rezk MF
PROVIDER: S-EPMC5696297 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
Publications
Treatment Outcomes with Biosimilars: Be Aware of the Nocebo Effect.
Rezk Mourad F MF Pieper Burkhard B
Rheumatology and therapy 20171014 2
Over the years, biologic agents have proven their importance in the management of chronic autoimmune diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Biosimilars, which are biologic medicines, are highly similar to approved biologic medicines, and are comprehensively developed and rigorously tested to ensure efficacy and safety are similar to the reference product. A broader armamentarium of biosimilars is expected to improve patients' access to safe and effecti ...[more]
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Project description:Background: Nocebo refers to adverse events related to patients' negative expectations and previous experiences, mediated by several neurobiological pathways within the brain. It is common among neurological patients and affects adherence and treatment outcomes, representing a real clinical challenge. Methods: We conducted a systematic search based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE database, using several keywords for studies that can be processed to investigate the magnitude of nocebo in generics and biosimilars used in the most common neurological diseases. The aim was to estimate its size and suggest strategies to minimize its prevalence in clinical trials and practice. Results: Of a total of 2,606 identified articles, after criteria-based selection, 35 studies were included for analysis. Overall, there was vast heterogeneity across the studies concerning population, study design, and outcomes. Nocebo response could be estimated only in one double-blind randomized trial of generic glatiramer acetate in relapsing remitting multiple sclerosis that included a placebo arm. In this trial, no significant differences observed between the three arms (innovator, bioequivalent, and placebo) in favorable and unfavorable outcomes. In the open-label phase of the trial, an increased withdrawal rate was recorded in patients switched from placebo to bioequivalent (8.4%) that may be related to nocebo. In other open-label and real-world studies evaluating biosimilars or generics for brain disorders, a similar indirect nocebo effect is assuming by several investigators. Also, knowledge gaps between health-care providers and patients exist towards generics and biosimilars. Conclusions: Despite its presence, the true burden of the nocebo response and effect cannot be accurately estimated in existing studies with generics and biosimilars in neurological diseases. Targeted strategies for clinical trials' design are needed in order to measure the exact nocebo's size.
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Project description:While the placebo effect has been studied for a long time, much less is known about its negative counterpart, named the nocebo effect. However, it may be of particular importance because of its impact on the treatment outcomes and public health. We conducted a review on the nocebo effect using PubMed and other databases up to July 2014. The nocebo effect refers by definition to the induction or the worsening of symptoms induced by sham or active therapies. Examples are numerous and concerns both clinical trials and daily practice. The underlying mechanisms are, on one hand, psychological (conditioning and negative expectations) and, on the other hand, neurobiological (role of cholecystokinin, endogenous opioids and dopamine). Nocebo effects can modulate the outcome of a given therapy in a negative way, as do placebo effects in a positive way. The verbal and nonverbal communications of physicians contain numerous unintentional negative suggestions that may trigger a nocebo response. This raises the important issue of how physicians can at the same time obtain informed consent and minimize nocebo-related risks. Every physician has to deal with this apparent contradiction between primum non nocere and to deliver truthful information about risks. Meticulous identification of patients at risk, information techniques such as positive framing, contextualized informed consent, and even noninformation, is valuable.
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Project description:To identify medical phrases utilized by the critical care team that may have an unintended impact on the critically ill patient, we administered an anonymous survey to multi-professional critical care team members. We elicited examples of imprecise language that may have a negative emotional impact on the critically ill. Of the 1600 providers surveyed, 265 offered 1379 examples (912 unique) which were clustered into 5 categories. Medical jargon (eg, "riding the vent") was most prevalent (n = 549). There were 217 negative suggestions (eg, "you will feel a stick and a burn"). Hyperboles (eg, "black cloud") were common (n = 198) while homonyms (ie "he fibbed") accounted for 150 examples. Phrases such as "code brown in there" were categorized as metonyms (n = 144). 121 metaphors/similes (eg, "rearranging deck chairs on the Titanic") were provided. Phrases that have the potential to negatively impact critically ill patient perceptions are commonplace in critical care practice. Whether these everyday communication habits lead to an unintended nocebo effect on mental health outcomes of the critically ill deserves further study.
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Project description:The "placebo (effect) by proxy" (PbP) concept, introduced by Grelotti and Kaptchuk (1), describes a positive effect of a patient's treatment on persons in their surrounding such as family members or healthcare providers, who feel better because the patient is being treated. The PbP effect is a complex dynamic phenomenon which attempts to explain a change in treatment outcome arising from an interaction between a patient and an effect from proxies such as parents, caregivers, physicians or even the media. By extension the effect of the proxy can also have a negative or adverse effect whereby a proxy feels worse when a patient is treated, giving rise to the possibility of a "nocebo (effect) by proxy" (NbP), and by extension can influence a patient's treatment response. While this has yet to be systematically investigated, such an effect could occur when a proxy observes that a treatment is ineffective or is perceived as causing adverse effects leading the patient to experience side effects. In this narrative review, we take these definitions one step further to include the impact of PbP/NbP as they transform to affect the treatment outcome for the patient or child being treated, not just the people surrounding the individual being treated. Following a systematic search of literature on the subject using the Journal of Interdisciplinary Placebo Studies (JIPS) database (https://jips.online) and PubMed (NCBI) resulted in very few relevant studies, especially in children. The effect of PbP per se has been studied in parents and their children for temper tantrums, acupuncture for postoperative symptoms, as well as for neuroprotection in very preterm-born infants. This paper will review the PbP/NbP concepts, show evidence for its presence in children's treatment outcome and introduce clinical implications. We will also offer suggestions for future research to further our understanding of the role of the proxy in promoting or distracting from treatment benefit in children. Increasing an appreciation of the PbP and NbP phenomena and the role of the proxy in children's treatment should improve research study design and ultimately harness them to improve clinical child healthcare.
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Project description:The nocebo effect in motor performance consists in a reduction of force and increase of fatigue following the application of an inert treatment that the recipient believes to be effective. This effect is variable across individuals and it is usually stronger if conditioning -exposure to the active effect of the treatment- precedes a test session, in which the treatment is inert. In the current explorative study we used a conditioning procedure to investigate whether subjective perception of treatment effectiveness changes between the conditioning and the test session and whether this change is related to dispositional traits and to the nocebo-induced reduction of force. Results showed that 56.1% of participants perceived the treatment as more effective in the test than in the conditioning session, had a more pronounced reduction of force, felt more effort and sense of weakness and were characterized by lower levels of optimism and higher anxiety traits compared to the other 43.9% of participants, who conversely perceived the treatment as less effective in the test session than in the conditioning. These findings highlight for the first time a link between changes in perception of treatment effectiveness, personality traits and the magnitude of the nocebo response in motor performance.
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Project description:BackgroundIn clinical practice, non-medical switching of biological medication may provoke nocebo effects due to unexplained deterioration of therapeutic benefits. Indication extrapolation, idiosyncratic reactions, and interchangeability remain challenged in clinical practice after biosimilar approval by the European Medicines Agency. The principle of "first do no harm" may be challenged in a patient when switching from originator to biosimilar biological.AimTo describe the 1-year results of a pragmatic study on infliximab biosimilar implementation in immune-mediated inflammatory disease patients on the basis of shared decision-making under effectiveness and safety monitoring.MethodsInflammatory bowel disease and rheumatology patients on infliximab originator were converted to infliximab biosimilar after providing informed consent. Nocebo response patients were monitored after switch back to originator. Linear mixed models were used to analyze continuous endpoints on effectiveness and laboratory outcomes to determine significance (P ≤ 0.05) of change over time after switching.ResultsAfter inviting 146 patients, a group of 125 patients enrolled in the project over time, respectively, 73 Crohn's disease, 28 ulcerative colitis, nine rheumatoid arthritis, ten psoriatic arthritis, and five ankylosing spondylitis patients. No statistically significant changes in effectiveness and safety were observed in any of the indications after a median of 4 infusions in 9 months of study. An overall nocebo response of 12.8% was found among the patients during a minimal observation period of 6 months after the transition to biosimilar infliximab. The overall nocebo response rate did not differ between the studied indications.ConclusionsIn inflammatory bowel disease and rheumatological patients, similar effectiveness and safety were demonstrated on the transition into infliximab biosimilar. In our series, patient empowerment and registration of treatment outcomes delineated biosimilar transition, an approach that hypothetically could reduce nocebo response rates which are relevant to account for regarding biosimilar implementation.
| S-EPMC5893662 | biostudies-literature
Project description:BackgroundIn the context of biosimilar use and switching, a patient's negative perception of a biosimilar might trigger a nocebo effect, where negative expectations unrelated to its pharmacologic action may lead to worsened symptoms, resulting in less perceived therapeutic benefit or worsened adverse events. Considering the crucial role biosimilars have in reducing health care costs and expanding access to safe biologics globally, it is essential to develop and implement effective strategies to mitigate the possible occurrence of such nocebo effects.ObjectiveThe aim of this systematic literature review was two-fold: (i) to review strategies that have been applied and/or tested for minimising the nocebo effect in clinical practice, within and outside the context of biosimilar switching, and (ii) to propose recommendations on useful mitigation strategies to minimise the occurrence of the nocebo effect in the context of biosimilar switching.MethodsBiomedical databases PubMed and Embase were screened up until the end of April 2023 with a search string consisting of the following search terms "nocebo", "biosimilar", "mitigation", "strategy", and "prevention" and related synonyms. The search strategy was supplemented by snowballing of the included studies. The quality of the studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Syntheses, the Scale for the Assessment of Narrative Review Articles, and the Mixed Methods Appraisal Tool.ResultsOf the 1617 identified and screened records, 60 met the inclusion criteria. Among these, 10 (17%) were conducted within the context of biosimilar switching, 7 of which specifically tested strategies to mitigate the nocebo effect. Among the remaining 50 studies conducted outside the biosimilar switching context, 46 tested mitigation strategies. Across the included studies, 13 distinct mitigation strategies were identified, which can be employed within the context of biosimilar switching: (i) open non-verbal communication, (ii) positive framing, (iii) empathic communication, (iv) validating communication, (v) shared decision making, (vi) self-affirmation, (vii) education of patients and health care professionals about the nocebo effect, (viii) education of patients and health care professionals about biosimilars, (ix) soft-skills training for health care professionals, (x) personalised information, (xi) supporting information, (xii) multidisciplinary approach, (xiii) organisation of the switch.ConclusionThis review has identified a set of strategies that have been tested to mitigate the nocebo effect, which can be applied by health care professionals in the context of biosimilar switching with the aim of mitigating the occurrence of a nocebo effect. We recommend implementing a combination of mitigation strategies for patients and health care professionals to utilise before, during, and after a switch. It should be noted that given the limited number of studies specifically testing nocebo mitigation strategies within the biosimilar switching context to date, it is not yet possible to draw definite conclusions about the effect size of each mitigation strategy individually or in combination.
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Project description:Even though previously described iron-containing structures in the upper beak of pigeons were almost certainly macrophages, not magnetosensitive neurons, behavioural and neurobiological evidence still supports the involvement of the ophthalmic branch of the trigeminal nerve (V1) in magnetoreception. In previous behavioural studies, inactivation of putative V1-associated magnetoreceptors involved either application of the surface anaesthetic lidocaine to the upper beak or sectioning of V1. Here, we compared the effects of lidocaine treatment, V1 ablations and sham ablations on magnetic field-driven neuronal activation in V1-recipient brain regions in European robins. V1 sectioning led to significantly fewer Egr-1-expressing neurons in the trigeminal brainstem than in the sham-ablated birds, whereas lidocaine treatment had no effect on neuronal activation. Furthermore, Prussian blue staining showed that nearly all iron-containing cells in the subepidermal layer of the upper beak are nucleated and are thus not part of the trigeminal nerve, and iron-containing cells appeared in highly variable numbers at inconsistent locations between individual robins and showed no systematic colocalization with a neuronal marker. Our data suggest that lidocaine treatment has been a nocebo to the birds and a placebo for the experimenters. Currently, the nature and location of any V1-associated magnetosensor remains elusive.
| S-EPMC6127160 | biostudies-literature
Project description:INTRODUCTION:To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars). METHODS:A systematic search was conducted using the Medline® and Embase® databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded. RESULTS:Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases. The great majority of the publications did not report differences in immunogenicity, safety, or efficacy. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates. CONCLUSIONS:While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine.
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