First Biosimilar with Extrapolation: Interchangeability is Next

This week FDA’s Arthritis Advisory Committee recommended approval of Remsima, a biosimilar product to Remicade. Remsima was developed by South Korea’s Celltrion. Remicade is one of Janssen’s biggest products with annual revenue of about $7 billion. There are several firsts in this decision. This is the first biosimilar to a monoclonal antibody reviewed by an FDA advisory committee and most likely will be the first biosimilar monoclonal antibody product approved by FDA. The recommendation from the advisory committee to approve it is not surprising since the FDA’s reviewers publicly agreed with the company there is sufficient evidence of biosimilarity between Remsima and the Remicade. FDA’s formal approval, expected soon, will also not come as a surprise. More importantly, the advisory committee agreed with the FDA reviewers and the company that Remsima should be approved for all indications for which Remicade is approved, even though the company tested only 2 of the 6 indications for which Remicade is approved. This is the first application of the principle of “extrapolation”, described in FDA’s guidance document from last year for biosimilars. Several biosimilars are approved for multiple indications so the ability to apply “extrapolation” is certain to further promote the development of biosimilars. Other developers of biosimilars should note a few things for Remsima. Remsima was approved about 2 years ago in Europe based on data similar to that presented to the FDA. Celltrion conducted one of the most thorough characterization, analysis and clinical trial program that can be envisioned for any biosimilar. The company followed FDA’s guidance to the last word. It conducted about 11 clinical trials with anywhere from 15 to more than 600 subjects for more than an year of exposure. It characterized the biosimilar molecule to the fullest extent possible presenting FDA with detailed primary, secondary, and tertiary structure information, biological activity, stability and comparability information from about 26 lots of the biosimilar to more than 40 lots of the reference product. It conducted exhaustive studies on literally every aspect of the biomolecule. It has been said that developing biosimilars is not for the faint-hearted and Celltrion’s work demonstrate it better than anyone can. Both the company’s and FDA’s presentation at the advisory committee are excellent reference material for all developers of biosimilars. However, it is not clear which of Celltrion’s studies could have been avoided. Based on our estimates to complete the work described, it took Celltrion about 5-7 years and possibly hundreds of million dollars to develop. Other developers can use this blueprint and potentially develop biosimilars to Remicade with potentially lower cost and time than Celltrion. Possibly Celltrion would have been approved as an innovator if it had not hedged its bets to becoming a biosimilar of Remicade and hence received a higher return on its investment with 12 years of market exclusivity, compared to 1 year for the biosimilar. We can speculate on the regulatory and business strategic aspects but we have to acknowledge that Celltrion certainly did a remarkable job. Remsima shows that not only is it possible to create a biosimilar to a monoclonal antibody, it is possible to get a broad approval to cover all markets for the reference product. It also indicates that even with robust data showing successful substitution of the biosimilar for the reference product, FDA is not comfortable declaring a product interchangeable with the reference. Remsima is not interchangeable with Remicade. Remsima has its own brand name and will need to capture its own market share and cannot piggy back on Remicade. Interchangeability would mean that just like generic drugs, biosimilars could be substituted by the pharmacists without the intervention of the prescribing doctor. Interchangeability is the next big hurdle in the path of biosimilars since it would create real challenge to the market of a given reference product. And the reference product holders are scared of that. This week AbbVie, the marketer of Humaira, filed a Citizen Petition to specifically assure that the principle of extrapolation is not applied when considering interchangeability. The fight for interchangeable biosimilar or “biogenerics” is on. Extrapolation is in, interchangeability is not far behind.