Extrapolation involves extending and applying the data from clinical studies regarding one medical condition to another medical condition. Once biosimilarity has been proven, biosimilars can also be approved for one or more additional indications held by the reference product, without the need for clinical data in those indications. Author Michinori Ogura from the Tokai Central Hospital, Gifu, Japan and colleagues from France and South Korea investigated the scientific rationale for extrapolation using the rituximab biosimilar CT-P10 as an example [1].
Extrapolation is permitted by regulatory agencies as long as it is scientifically justified. Regarding extrapolation of indications for biosimilars, the European Medicines Agency (EMA) has stated that ‘if clinical similarity can be shown in a key indication, extrapolation of efficacy and safety data to other indication(s) of the reference product may be possible’ under certain conditions [2].
Celltrion Healthcare’s (Celltrion) rituximab biosimilar Truxima (CT‑P10) was approved in Europe in February 2017 [3]. It is an anti-CD20 monoclonal antibody approved for use in autoimmune and cancer indications.
Biosimilarity of CT‑P10
CT‑P10 was approved for all indications held by the reference rituximab, Roche’s MabThera/Rituxan (rituximab), based on the totality of evidence collected in the comprehensive comparability exercise.
The biosimilarity of CT‑P10 compared to Roche’s MabThera/Rituxan was demonstrated by:
- In vitro structural, physicochemical, biological and functional analyses: ‘demonstrated that CT‑P10 and reference rituximab are highly similar’.
- Phase I and III randomized controlled trials: ‘demonstrated pharmacokinetic equivalence between CT‑P10 and reference rituximab and comparable efficacy, safety, pharmacodynamics and immunogenicity in patients with rheumatoid arthritis’.
- Pharmacokinetic equivalence of CT‑P10 and reference rituximab and comparable safety, pharmacodynamics and immunogenicity: ‘have also been shown in patients with advanced follicular lymphoma’.
Scientific rationale for extrapolation
The scientific rationale for extrapolation of CT‑P10 clinical data across indications included:
- Rheumatoid arthritis was an appropriate indication in which to compare CT‑P10 with reference rituximab as it was considered adequately sensitive to detect clinically meaningful differences in efficacy and safety between products.
- B cells play a primary role in the pathology of disease for all indications of reference rituximab. The ability of CT‑P10 and reference rituximab to deplete B cells is highly comparable.
- Depletion of B cells by rituximab has been attributed to complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and apoptosis.
- The contribution of these mechanisms across indications is uncertain. However, it has been demonstrated that CT‑P10 and reference rituximab are comparable in their ability to induce these activities.
Based on the totality of evidence, according to the authors, ‘the EMA concluded that CT‑P10 was highly similar to reference rituximab and that it was scientifically justified to approve the biosimilar for all indications held by the reference product’. The authors added that ‘extrapolation is fundamental to the biosimilar concept. It efficiently reduces the number of clinical trials that are needed, which allows the regulatory process to be expedited’. They concluded by saying that ‘it is expected that post-authorization surveillance of CT‑P10 will further support the EMA’s decision to approve the biosimilar in all indications held by [reference rituximab]’.
Conflict of interest
The authors of the research paper [1] reported conflicts of interest including being employees of Celltrion Healthcare and receiving research funding from pharmaceutical companies. For full details of the authors’ conflicts of interest, see the research paper [1].
Editor’s comment
Readers interested to learn more about extrapolation of indications for biosimilars are invited to visit www.gabi-journal.net to view the following manuscript published in GaBI Journal:
Investigating the validity of biosimilar extrapolation and interchangeability
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References
1. Ogura M, Coiffier B, Kwon HC, Yoon SW. Scientific rationale for extrapolation of biosimilar data across cancer indications: case study of CT-P10. Future Oncol. 2017;13(15s):45-53.
2. GaBI Online - Generics and Biosimilars Initiative. Extrapolation and pharmacovigilance for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jul 7]. Available from: www.gabionline.net/Reports/Extrapolation-and-pharmacovigilance-for-biosimilars
3. GaBI Online - Generics and Biosimilars Initiative. EC approval for first cancer biosimilar Truxima [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Jul 7]. Available from: www.gabionline.net/Biosimilars/News/EC-approval-for-first-cancer-biosimilar-Truxima
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