Questions over DANBIO relevance for non-medical switching

Biosimilars/Research | Posted 22/02/2019 post-comment0 Post your comment

Italian rheumatologists Fabrizio Cantini and Maurizio Benucci commented on the paper from Glintborg and co-authors ‘To switch or not to switch’, which reported the results of biosimilar etanercept switching in Denmark [1].


Denmark implemented a national guideline mandating non-medical switching of all patients treated with the originator etanercept, Enbrel, to biosimilar etanercept, Benepali (SB4), in April 2016 [2].

The authors note that the study includes an impressive number of patients: 2,030 patients treated with etanercept were identified in the nationwide quality registry, DANBIO [2], and agree that ‘at first glance the results show a good evidence of efficacy and safety of the procedure’. However, they go on to say that ‘how these results may be applied on non-medical switching strategy is rather questionable’.

The authors point out five concerns that they identified related to the demographic and clinical characteristics of switchers and non-switchers, and to the timing of clinical evaluations, that they say ‘may generate misleading biases’.
1. Switchers had longer previous etanercept treatment duration and fewer previous biological disease-modifying anti-rheumatic drugs (bDMARDs) compared with non-switchers, suggesting less severe disease.
2. There was an unbalanced treatment regimen, resulting in 124 (43%) out of 286 rheumatoid arthritis (RA) non-switchers who continued to receive etanercept at the dose of 25 mg weekly, while 887 (95%) of switchers were treated with SB4 at 50 mg weekly. Such differences were also present in both the psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) groups (18% vs 1% and 36% vs 1%, respectively).
3. A total of 101 adverse events occurred in switchers and 39 (38.5%) were unreported. These data, say the authors, together with the low number of subjective events, support the hypothesis of the absence or low impact of the nocebo effect in switchers, in contrast with some recently published data [3]. Although other recent reports have suggested that the nocebo effect may become negligible after the first few weeks [4].
4. It is unclear why data on disease activity were limited to the 3-month visit and not to the end of follow-up, while the discontinuation rate was evaluated after one year.
5. The authors say that the ‘strength of the results was greatly influenced by the nature of the study itself’ and that the study was based on ‘mandatory switching without a well-structured study design’. These data, according to the authors, ‘do not constitute a solid base’ to reassure rheumatologists for non-medical switching.

Cantini and Benucci state that, due to the above points, the DANBIO study does not meet any of the US Food and Drug Administration guidance for non-medical switching studies. The study therefore provides ‘a low level of evidence, not sufficient to support the European League Against Rheumatism (EULAR) recommendation on switching strategy’, according to the authors.

The authors conclude that due to the ‘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’.

Related article
Biosimilars - to switch or not to switch

1. Cantini F, Benucci M. Mandatory, cost-driven switching from originator etanercept to its biosimilar SB4: possible fallout on non-medical switching. Ann Rheum Dis. 2018 Nov 28. pii: annrheumdis-2018-214757. doi:10.1136/annrheumdis-2018-214757. [Epub ahead of print]
2. GaBI Online - Generics and Biosimilars Initiative. Danish etanercept switching study investigates withdrawal rates []. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 22]. Available from: 
3. GaBI Online - Generics and Biosimilars Initiative. Biosimilars - to switch or not to switch []. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 22]. Available from:
4. GaBI Online - Generics and Biosimilars Initiative. Long-term follow-up of switching to biosimilar infliximab []. Mol, Belgium: Pro Pharma Communications International; [cited 2019 Feb 22]. Available from:

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