FDA Licenses a Second Biosimilar – The Parameters of Approval Come Into Better Focus

By James C. Shehan –

FDA issued it second-ever approval of a biosimilar on Tuesday, April 5, giving the nod to Celltrion’s and Pfizer’s Inflectra, a biosimilar version of J&J’s Remicade (infliximab). The approval follows some of the precedents established in FDA’s approval of the first biosimilar (i.e.,Zarxio) – specifically, reliance on clinical data to support approval and extrapolation of data to support approval of multiple indications for which the biosimilar sponsor did not submit clinical data. The approval is also noteworthy for FDA’s decision to follow some precepts that the Agency decreed in recent draft biosimilar guidances, including: (1) requiring that Inflectra’s prescribing information identifying it as a biosimilar of Remicade; (2) Inflectra being given a product name with a meaningless four syllable suffix (“infliximab-dyyb”); and (3) the prescribing information including four different means of product identification (“Inflectra,” “Remicade,” “infliximab-dyyb” and “infliximab”) as appropriate to the circumstances.

Inflectra was reviewed by FDA’s Arthritis Advisory Committee on February 9, 2016 (FDA briefing document here). The Committee recommended approval by a vote of 21-3, with the three no votes apparently tied to concerns over extrapolation.

The Inflectra NDA included the following data: 

• Extensive analytical data showing that (i) Inflectra and US-licensed Remicade are highly similar; (ii) Inflectra can be manufactured in a well-controlled and consistent manner; and (iii) that data comparing European Union (EU)-approved Remicade EU)-approved to Inflectra could be used to show biosimilarity to US-licensed Remicade.
• A single dose PK study comparing Inflectra, US-Remicade and EU- Remicade.
• A clinical study comparing Inflectra and EU-Remicade – 54 weeks, randomized, double-blind, parallel group study conducted outside the US in approximately 600 patients with moderate to severely active rheumatoid arthritis. The primary endpoint was the proportion of patients who remained in the study and achieved an American College of Rheumatology 20% (ACR20) response at Week 30.
• A 54-week randomized, double-blind, parallel-group study conducted outside the US in 250 patients with moderate to severe ankylosing spondylitis.
• An assessment of safety and immunogenicity in patients undergoing switches in an open label extension of the rheumatoid arthritis study.
• Scientific justifications for extrapolation to the six indications for which Inflectra is approved but didn’t submit clinical data.

Although clinical trials were only conducted in patients with rheumatoid arthritis and ankylosing spondylitis, FDA permitted extrapolation to six other indications for which Remicade is approved. But Inflectra was not approved for one indication held by Remicade, pediatric ulcerative colitis, because Remicade has pediatric exclusivity for that use until September 2018.

Based on recent FDA guidance (see our post here), Inflectra’s labeling contains the following statement:

INFLECTRA (infliximab-dyyb) is biosimilar* to REMICADE (infliximab) for the indications listed.  

* Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product.

It is not clear at this time whether Zarxio’s prescribing information is being changed to include a similar statement.

Per last year’s naming guidance (see our post here), the proper name assigned by FDA to Inflectra is“infliximab-dyyb.” There’s no indication whether FDA or the sponsors picked this suffix. One wonders whether this is a sign that FDA has rejected the option proposed in the guidance of these four letter suffixes being assigned to companies, as is the case with the filgrastim-sndz name assigned to Zarxio.

Because of litigation, the launch date of Inflectra is uncertain. J&J and Celltrion are in litigation over a patent that expires in 2018, but a J&J court filing indicates that Celltrion and Pfizer have agreed to not enter the market until at least June 29, 2016.

Inflectra is currently approved in numerous countries, including Korea, Canada, Japan and the EU.

Based on a slim sample of two approvals, it seems that getting a biosimilar approved will require the generation of clinical data from at least one large non-inferiority trial using patients with a condition that the reference product is approved to treat. It also appears that extrapolation will be readily permitted, that the meaningless four letter suffix may be a permanent fixture for biologics and that FDA is serious about labeling containing a statement that a biosimilar is a biosimilar. As for interchangeability, while perhaps not as mythical as El Dorado, Atlantis or the Kingdom of Prester John, it remains for the time as elusive as that next Chicago Cubs world championship.