"Nocebo Effect" and Biosimilars

Updated: Nov 22

by Natasha Troy


Recently I read a report on the Clinical effectiveness of an Infliximab biosimilar used as a switch from Remicade (infliximab) in patients with established rheumatic disease [1]. The 2015 report showed that around a quarter of patients discontinued an approved infliximab biosimilar due to a perceived loss of efficacy or an increase in side effects.


In this short piece we look at the current trends in literature for biosimilars to investigate if there’s still a high discontinuation rate across biosimilars and why.


Using our “quick article search” function we performed a broad search for “biosimilars” during the month of September 2022. Since our platform is set up to search across several databases (PubMed, DialNet, SciELO, Crossref and DOAJ) it returned ~70 articles.


Screening was based on reading the titles and abstracts of publications. To keep the review brief, only articles with full free text (selected at random) were included.


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The story of biosimilar medicines over the past decade has been one of slow acceptance. Switching from an innovator to a biosimilar is not typically triggered by clinical need but by decisions such as cost and both patients and physicians need to be satisfied that biosimilar medicines offer a safe and efficacious alternative to original biologics.


In theory if a biosimilar product is well-characterized and demonstrates a highly similar clinical pharmacology profile, it should be safe and effective yet it`s true from the literature that the medical community have expressed some reservations with the use of biosimilars, possibly with regards to the reduced clinical data requirements for these drugs. Yes, the clinical data required for market approval is less when compared to the reference product, but the approval process is no less comprehensive or rigorous.


Instead, the testing of a biosimilar includes a greater emphasis on analytical studies to demonstrate similarity with the biological reference product. Data from animal studies are still required to assess toxicity and from clinical studies to gauge efficacy, immunogenicity, and pharmacokinetics/pharmacodynamics.

During our search a reoccurring theme was evident; “the nocebo effect. The nocebo effect describes a situation where a negative outcome occurs due to a belief that the intervention will cause harm. The nocebo effect can play a role in patients’ experience with biosimilars since pre-existing scepticism may be a cause of the side effects some patients experience when changing from an innovator “branded” product to a biosimilar.


So where is the nocebo effect originating from?


Our literature review showed a high positive response to the use of biosimilars. A study in a large teaching hospital reported findings from patients (n = 227) with IBD who switched from CT-P13 to SB2 using the same standard of care [3, 7]. Overall, the switch was well received, patients were satisfied with the process, and 99.2% of patients did not report any AEs. Of minor note, two reports of AEs were attributable to changes in the rate of drug administration [6].


Studies from an article by Allocati E [2] suggests that switching from biosimilar (infliximab, adalimumab, or etanercept) to another biosimilar of the same medicinal biologic medicine in patients with chronic inflammatory diseases is safe and effective in terms of disease activity, remission rate, loss of response, adverse events, and immunogenicity (when analysed).


Authors of randomised clinical trials and observational studies noted that a part of the AEs and LOE reported by these patients matched no objective disease activity assessment (e.g., serum inflammatory markers, tender joint count, anti-drug antibodies) and therefore suggested that a part of the patients’ reported AEs and LOE were purely subjective [8].


The literature strongly suggests that there remains to be a high discontinuation rate across biosimilars, but not due to adverse side effects or lack of drug effect but instead due to lack of trust in biosimilars. Education is likely to be a key component necessary to increase confidence in biosimilars. The negative perceptions of patients and HCPs toward the safety and efficacy of biosimilars need to be actively addressed in order to optimize the communication surrounding biosimilars. Identifying highly impactful methods of improving biosimilar confidence remains a challenge.


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References

  1. Nikiphorou E, Kautiainen H, Hannonen P, et al. 2015. Clinical effectiveness of CT-p13 (infliximab biosimilar) used as switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data. Expert Opinion on Biological Therapy 15(12): 1677–83. DOI: 10.1517/14712598.2015.1103733

  2. Allocati E, Godman B, Gobbi M, Garattini S, Banzi R. Switching Among Biosimilars: A Review of Clinical Evidence. Front Pharmacol. 2022 Aug 24;13:917814. doi: 10.3389/fphar.2022.917814. PMID: 36091837; PMCID: PMC9449694.

  3. Niazi S. Scientific Rationale for Waiving Clinical Efficacy Testing of Biosimilars. Drug Des Devel Ther. 2022 Aug 24;16:2803-2815. doi: 10.2147/DDDT.S378813. PMID: 36043044; PMCID: PMC9420434.

  4. Roccuzzo G, Rozzo G, Burzi L, Repetto F, Dapavo P, Ribero S, Quaglino P. Switching from adalimumab originator to biosimilars in hidradenitis suppurativa: What's beyond cost-effectiveness? Dermatol Ther. 2022 Sep 5:e15803. doi: 10.1111/dth.15803. Epub ahead of print. PMID: 36062429.

  5. Hrin ML, Bray JK, Feldman SR. Reassurance Techniques Do Not Significantly Impact Confidence in Biosimilars for Psoriasis: A Survey of a Convenience Sample of Individuals with Self-Identified Psoriasis. Dermatol Ther (Heidelb). 2022 Sep;12(9):2173-2180. doi: 10.1007/s13555-022-00781-3. Epub 2022 Jul 28. PMID: 35900655; PMCID: PMC9464285.

  6. Cohen HP, Hachaichi S, Bodenmueller W, Kvien TK, Danese S, Blauvelt A. Switching from One Biosimilar to Another Biosimilar of the Same Reference Biologic: A Systematic Review of Studies. BioDrugs. 2022 Sep;36(5):625-637. doi: 10.1007/s40259-022-00546-6. Epub 2022 Jul 26. PMID: 35881304; PMCID: PMC9485085.

  7. Kay J, Bock AE, Rehman M, Zhang W, Zhang M, Iikuni N, Alvarez DF. Use of multibiomarker disease activity scores in biosimilarity studies for the treatment of patients with rheumatoid arthritis. RMD Open. 2022 Sep;8(2):e002423. doi: 10.1136/rmdopen-2022-002423. PMID: 36180101; PMCID: PMC9528718.

  8. Krstic M, Devaud JC, Marti J, Sadeghipour F. Exploring the Reasons Behind the Substantial Discontinuation Rate Among Patients Taking CT-P13 in a Large Tertiary Hospital in Western Switzerland: A Retrospective Cohort Study Using Routinely Collected Medical Data. Drugs Real World Outcomes. 2022 Sep;9(3):425-436. doi: 10.1007/s40801-022-00299-2. Epub 2022 May 19. PMID: 35590047; PMCID: PMC9392673.