Celltrion's Biosimilar Gets FDA Panel Nod Despite Extrapolation Concerns
This article was originally published in The Pink Sheet Daily
Executive Summary
Committee discussion reflects tension between desire for indication-specific efficacy data and recognition of benefits of 351(k) pathway.
FDA's Arthritis Advisory Committee overwhelmingly endorsed approval of Celltrion Inc.'s Inflectra (CT-P13) as a biosimilar to Janssen Biotech Inc.'s Remicade (infliximab) despite panelists' discomfort with some aspects of the 351(k) approval pathway and the lack of clinical efficacy data in all indications.
The committee voted 21-3 that based on the totality of evidence, CT-P13 should be licensed as a biosimilar to Remicade for each of the reference product's eligible indications (see box).
Inflectra's Recommended Indications
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriatic arthritis
- Plaque psoriasis
- Adult and pediatric Crohn's disease
- Adult ulcerative colitis
In their votes favoring approval, panelists generally said that Celltrion met the Biologics Price Competition and Innovation Act's statutory criteria for establishing biosimilarity, demonstrating that CT-P13 was highly similar to Remicade with no clinically meaningful differences in the two conditions of use – rheumatoid arthritis and ankylosing spondylitis – in which it was studied.
Most panelists also agreed there was adequate scientific justification to extrapolate data from comparative clinical studies in RA and AS to the other indications, even though those same committee members had some reservations about the concept of extrapolation.
"Even though I certainly saw some differences in the analytical package that are always a question mark, when I looked at the totality of evidence and all the information provided by the sponsor and the assurance of good in-process controls and also information on the impurities … I think that scientifically I am comfortable looking at that totality of evidence and voting yes for biosimilarity," said Antonio Moreira, a bioprocess engineering expert from University of Maryland-Baltimore County.
Panelists voting against approval raised concerns around data extrapolation, particularly with regard to use in the pediatric and inflammatory bowel disease indications. Some suggested that an ongoing comparative efficacy trial in Crohn's disease could help provide assurance about CT-P13's use in this setting (see related story, (Also see "Inflectra's Label Won't Depend On Continuing Study In IBD" - Pink Sheet, 9 Feb, 2016.)).
Challenging Concept …
The committee's endorsement, coming 11 months after the initial advisory committee review was postponed due to information requests pending with the sponsor, puts Inflectra on solid footing to become the second licensed biosimilar and the first biosimilar monoclonal antibody in the US.
The agency's user fee goal date for the 351(k) application is in April, according to Celltrion. Pfizer Inc. holds US marketing rights for the product.
As expected, data extrapolation was a focal point for the committee's deliberations (Also see "Celltrion Biosimilar Package Is Strong, But How Many Indications Will It Get?" - Pink Sheet, 5 Feb, 2016.). It was a concept that some panelists had great difficulty wrapping their heads around.
Division of Pulmonary, Allergy and Rheumatology Products Clinical Team Leader Nikolay Nikolov acknowledged that extrapolation is "a concept that may not be very familiar to some."
Nikolov presented the agency's review and conclusion that Celltrion had demonstrated adequate scientific justification to support extrapolating clinical data across indications.
Among the considerations supporting extrapolation were CT-P13's high similarity to US-licensed Remicade in terms of primary, second and tertiary structure, post-translational profile and in vitro functional characteristics, purity, stability and potency, including TNF-alpha binding and neutralization.
"Either you sign onto the BPCIA 351(k) pathway and you hang your hat on it, or you don't," committee member Solga said.
Additional support comes from the similar pharmacokinetics of the two products, as well as similar efficacy, safety and immunogenicity in RA and AS patient populations. Extrapolation is further supported by the known and potential mechanisms of action.
Nikolov noted the review staff's conclusion on extrapolation extended beyond the rheumatology division.
"The review of this application and the considerations for extrapolation were a collaborative effort among multiple disciplines and subject matter experts within the FDA, including our gastroenterology and dermatology colleagues," he said.
Yet, panelists struggled with the concept, asking whether indications that were licensed via extrapolation would warrant more intensive post-marketing surveillance or whether clinical studies using the 3 mg/kg dose could support extrapolation to higher doses.
… That Might Become Easier Over Time
There emerged a tension among committee members between the desire for more indication-specific clinical efficacy data – as is standard with traditional BLAs – and a recognition of the evidentiary shortcuts provided by the 351(k) pathway.
"Either you sign onto the BPCIA 351(k) pathway and you hang your hat on it, or you don't," said Steven Solga, a gastroenterologist at St. Luke's University Hospital in Bethlehem, PA. "I'm aiming for the former."
Solga noted, however, that he felt "residual uncertainty" as to whether Inflectra would provide a realizable benefit in terms of reduced cost or increased access to treatment.
Richard Siegel, immunoregulation section chief at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, voted in favor of approval but described his recommendation as a "qualified yes" due to concerns about extrapolation to other disease areas.
"I agree with Dr. Solga. You sort of have to be all in or not all in with allowing any extrapolation, because if you're not all in then it's just essentially back to the original" BLA pathway, he said.
Some panelists suggested the concepts of biosimilarity and extrapolation would be less overwhelming as more products make their way through the regulatory process.
"I think as we have also over the years become more comfortable with … sponsors making changes in their manufacturing processes, I think we will with time … become more comfortable with the concept of biosimilarity and the approach we are taking for these kinds of products," Moreira said.