The U.S. Arrival of Biosimilars: As The Dust Begins to Settle

  • April 21, 2015

By Dr. Bob Roth

Several years ago, after the first follow-on growth hormone replacement therapeutics Omnitrope® and Valtropin® were approved by FDA under the standard drug approval pathway, we proposed that development programs for these types of products would remain very extensive despite their promise for development and cost savings. Such products, though approved as drugs, were given the moniker “biosimilars”. Recall that this was far in advance of a regulatory pathway in the U.S. which eventually became established for biosimilars based on BLA-approved biologic innovator products. As noted recently by Steve Jensen of our company, Zarxio (biosimilar version of Neupogen®, recombinant filgrastim/GCSF for febrile neutropenia and related indications) is the first FDA-approved BLA biosimilar. There now exists a regulatory route for approval of follow-on protein therapeutics via both drug and biologic pathways (505(b)(2) and 351(k), respectively), depending on the Center within the FDA which approved the innovator product.

The likely development requirements for a biosimilar BLA product seemed quite significant when FDA published a general scientific considerations guidance and accompanying quality and pharmacology guidances. However, FDA did acknowledge that data requirements would be product-specific to a certain extent, and that certain information could be deemed necessary and other data unnecessary for a particular biosimilar program with FDA’s agreement. With the approval of Zarxio it is now possible to get an initial view of FDA’s approach to approvability of biosimilar BLA products via the 351(k) pathway. It is also possible to contrast the approaches taken by FDA and the EU for this product.

Based on EPARS review of the EU submission file for Zarxio approved in 2009 (named Zarzio for the EU) and data summarized in the FDA Advisory Committee briefing package for eventual FDA approval in 2015, we can start to evaluate what a successful biosimilar BLA data package looks like:

  • Very extensive comparative chemical characterization to Neupogen showing similarity.
  • In vitro binding experiments showing equivalent affinity of the two drugs for their receptors, and several animal studies to evaluate toxicity, toxicokinetics, pharmacodynamics and local tolerance.
  • Several human comparative pharmacokinetic/pharmacodynamic studies in healthy volunteers.
  • For the EU approval, no patient efficacy studies were performed; efficacy was concluded on the basis of comparative pharmacodynamic endpoints in healthy volunteers.
  • For the US approval, a head-to-head non-inferiority trial vs. Neupogen in cancer patients provided pivotal evidence of efficacy, supplementing comparative pharmacodynamic endpoints in healthy volunteers.
  • For EU approval, a long-term non-comparative safety study in cancer patients was conducted.
  • For the US approval, comparative safety vs. Neupogen in the phase 3 cancer trial supplemented the non-comparative safety study in cancer patients.

Of particular interest to us, efficacy for the EU approval was concluded solely on the basis of comparative in vitro binding experiments and pharmacodynamic endpoints in healthy human volunteers, whereas the U.S. data package included a pivotal clinical non-inferiority study demonstrating therapeutic equivalence to Neupogen. Immunogenicity risk for Zarxio vs. Neupogen was also shown directly in the U.S. development program but could only be compared to Neupogen using historical control data. In addition, we also note with interest that the development of the biosimilar product for the U.S. approval included test drug switching data in the pivotal phase 3 trial, a recommendation from FDA’s draft guidance focused on biosimilar quality issues but not in the more general Scientific Considerations guidance.

Robert Roth, M.D., Ph.D., is Vice President and Worldwide Medical Director at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please contact us