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Mandatory, cost-driven switching from originator etanercept to its biosimilar SB4: possible fallout on non-medical switching
  1. Fabrizio Cantini1,
  2. Maurizio Benucci2
  1. 1 Department of Rheumatology, Azienda USL Toscana Centro, Hospital of Prato, Prato, Italy
  2. 2 Rheumatology Clinic, Azienda USL Toscana Centro, Nuovo S Giovanni di Dio Hospital, Florence, Italy
  1. Correspondence to Dr Fabrizio Cantini, Department of Rheumatology, Azienda USL Toscana Centro, Hospital of Prato, Prato 59100, Italy; fbrzcantini{at}gmail.com

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We read with great interest the recently published results from DANBIO registry on switching from originator etanercept (ETA) to the biosimilar SB4.1 The study includes a really impressive number of patients who underwent mandatory switching to SB4, and at first glance the results show a good evidence of efficacy and safety of the procedure. However, in our opinion, how these results may be applied on non-medical switching strategy is rather questionable. A careful reading of the paper raises several concerns related to the demographic and clinical characteristics of switchers and non-switchers, and to the timing of clinical evaluations that may generate misleading biases.

First, switchers had longer previous ETA treatment duration and fewer previous bDMARDs compared with non-switchers suggesting a less severe disease. This seems to be confirmed by the baseline lower disease activity both in switchers with rheumatoid arthritis (RA) and psoriatic arthritis (PsA).

Second, an unbalanced treatment regimen resulted with 124 (43%) out of 286 RA non-switchers who continued to receive ETA at the dose of 25 mg weekly while 887 (95%) of switchers were treated with SB4 50 mg weekly. Similarly, this difference was present in both PsA and axial spondyloarthritis groups (18% vs 1% and 36% vs 1%, respectively).

Beyond the reduced dosage, both in RA and PsA relevant differences between the two groups of treatment were appreciable regarding the concomitant methotrexate (MTX) treatment (60% vs 49% in RA and 48% vs 30% in RA and PsA, respectively). These differences seem to be statistically significant, and may have negatively influenced the results, especially in patients with RA where it has been long recognised that ETA efficacy is superior if combined with MTX with respect to monotherapy.2 Indeed, considering that the majority of withdrawals were related to lack of efficacy, the higher discontinuation rate in non-switchers (33%) as compared with switchers (18%) may be, at least in part, explained by the different treatment regimens together with the baseline higher disease activity in originator ETA continuers. The significant lower retention rate in non-switcher patients with RA in comparison with ETA historic cohort seems to confirm this issue.

Third, 101 adverse events occurred in switchers, and 39 (38.5%) were unreported. These data, together with the low number of subjective events, support the hypothesis of absence or low impact of the nocebo effect in switchers, in contrast with some recently published data.3

Fourth, it is unclear why data on disease activity were limited to 3-month visit and not to the end of follow-up, while the discontinuation rate was evaluated after 1 year.

Fifth, the strength of the results was greatly influenced by the nature of the study itself, that is to say mandatory switching without a well-structured study design, and, per se, these data do not constitute a solid base to ensure the rheumatologist for non-medical switching. In this sense, the DANBIO study does not meet any of the Food and Drug Administration guidance indicating the design elements for non-medical switching study (box 1),4 thus providing a low level of evidence, not sufficient to support the European League Against Rheumatism recommendation 6 on switching strategy.5

Box 1

List of Food and Drug Administration (FDA) recommended elements for studies on non-medical switching from biologic originators to the respective biosimilar

  • Randomised, double-blind trial ensuring the homogeneity of treatment groups and control bias.

  • Adequate control with measurement of different outcomes.

  • Adequate statistical powering and proper statistical analysis.

  • Multiple switches over the study period.

  • Evaluation of immunogenicity-related outcomes.

  • Adequate follow-up.

  • Assessment of individual patient-level outcomes.

In conclusion, due to the above underlined methodological defects, greatly limiting the grade of evidence, the results of DANBIO registry cannot be translated in clinical practice to carry out non-medical switching. As we previously stated,6 we believe that properly designed clinical studies are required to definitively address the efficacy and safety of switching from originator ETA to its biosimilar SB4.

References

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors FC and MB equally contributed to write the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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