Differences in US, EU Approvals for Enoxaparin Follow-Ons Highlight Regulatory Challenges

Laboratorios Farmaceuticos ROVI (ROVI), a Spanish specialty healthcare company, reportedly expects to launch a biosimilar enoxaparin, a low-molecular-weight heparin (LMWH) product, in the European marketplace by the end of 2017. ROVI requested marketing authorization for its biosimilar product in Europe in 2014.

Currently, 2 biosimilars (Inhixa and Thorinane) are approved for use in the European Union (EU) on the basis of their biosimilarity to the reference enoxaparin, Sanofi’s Lenovox. Sanofi’s originator LMWH is approved for use in the United States and in all EU member nations, where it is marketed under the names Clexane, Klexane, and Qualiop, among others. ROVI estimates that worldwide sales of enoxaparin reached $1.8 billion in 2016, and that the European market represented 63% of the total sales value. ROVI says that it seeks to leverage its biosimilar to capture a share of these earnings, particularly in emerging markets.

In the United States, a follow-on enoxaparin was approved by the FDA in 2010. Sandoz’s version of the drug was not, however, approved as a biosimilar, but as a generic. According to the Generics and Biosimilar Initiative, this seeming irregularity is due in part to the fact that the approval process for Sandoz’s product began years before the Biologics Price Competition and Innovation Act was enacted into law.

Furthermore, the originator enoxaparin had not been approved in the United States under a Biologic License Application; according to a recent review in Thrombosis Journal, in the United States, originator LMWHs were classified as drugs under the Abbreviated New Drug Application procedure, as are small-molecule drugs. As such, the FDA approved Sandoz’s product as a generic, not a biosimilar, based on:

• Its physical and chemical characteristics
• The nature of the source material and method of production
• The nature of the arrangement of components that constitute the product
• Laboratory measurements of anticoagulant activity
• The drug’s effect in patients

However, the European Medicine’s Agency, in its “Guidelines on non-clinical and clinical development of similar biological medicinal products containing low molecular weight heparin,” which came into effect in June of 2017, treats the originator LMWH as a biologic, and treats follow-on products as biosimilars. This approach, according to the Thrombosis Journal review’s authors, has been instituted despite the fact that it “…is more difficult to apply to biological substances arising from extraction from biological sources and/or those for which little clinical and regulatory experience has been gained, like LMWHs, when compared to products that are highly purified and can be thoroughly characterized.” The guidelines hold that evidence for similarity of efficacy should be derived from physicochemical, functional, and pharmacodynamic (PD) comparisons, not necessarily from comparative efficacy trials.

These variations in international approaches to the approval of LMWHs, as well as the complexity of addressing the similarity of products extracted from animal tissue, highlight lingering challenges in the regulation of such treatments, leading many, including the review’s authors, to call upon regulators to require additional safety and efficacy studies for future follow-on LMWH.