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On Tuesday February 9th Celltrion presented its biosimilar developmental data to the FDA as they sought approval for their CT-P13 (called Inflectra), a biosimilar of infliximab (Remicade). The panel included over 20 members comprised of the Arthritis Advisory Committee with additional representation from adult and pediatric rheumatologists, dermatologists, gastroenterologists, statisticians, pharmacists and protein chemists.
The sponsor was seeking FDA approval eight indications: 1) Rheumatoid arthritis (RA), 2) ankylosing spondylitis (AS), 3) plaque psoriasis, 4) psoriatic arthritis (PsA), 5) adult Crohn’s disease (CD), 6) fistulizing CD, 7) pediatric CD and 8) adult ulcerative colitis (UC).
After extensive review of the data, voting members discussed whether sufficient biosimilarity was demonstrated between CT-P13 and Remicade and whether there are clinically meaningful differences between the two products and if there was sufficient information given to support extrapolation to all the indications afforded the US licensed Remicade. Despite the FDA officials openly stating they considered CT-P13 to be “highly similar”, the discussion of the proposed 3 questions seemed to engender reluctant concerns, rather than acceptance of biosimilarity, meaningful differences and extrapolation. Several panel members voiced concern that the observed area of differences may have the potential for unforeseen consequences, including concerns about switching (but interchangeability is not part of this application). The extrapolation of RA and AS data to other adult and pediatric indications was stalled by the EU post-marketing open-label studies in IBD that are currently ongoing.
The vote asked the 24 panel members to vote on whether the totality of evidence indicates that CT-P13 receive licensure as a biosimilar product to the US licensed Remicade for each of the indications for which Remicade is currently licensed (RA, AS, PsO, PsA, adult CD, pediatric CD, adult UC)?
There were 21 votes in favor and 3 votes against CT-P13 (no abstentions)
The manufacturer presented its evidence intended to fulfill the regulatory requirement for biosimilarity between CT-P13 and infliximab. This biologic license application (BLA) included extensive based on a large body of analytical data (PK, PD, etc.), mechanism of action similarity data, and safety, immunogenicity and clinical data.
The FDA began hearing with a review of the 351(k) regulatory pathway, also called the abbreviated licensure pathway. Biosimilarity requires comparison of a new biosimilar to the reference product (innovator drug), wherein the biosimilar must be highly similar, with no clinically meaningful differences with safety, purity and potency.
Once the biosimilar is meets standards established by the reference product, there is less need for clinical trial and safety data – since these have already been established by the reference product. Thus, one or more randomized clinical trials (with immunogenicity studies) are needed for approval. There is no defined pivotal study to establish biosimilarity. Instead of relying on numerous clinical trials, analytical similarity assumes a greater role as it forms the foundation of a biosimilar development program.
The validation of biosimilarity (focused on structure and function) dominated most of the presentations and discussion. This included similarity data on structure, folding, drug binding, peptide mapping, amino acid sequence, bioactivity, glycosylation, apoptosis, FcRn binding, FcIIIa binding, ADCC assays, PK/PD studies and clinical pharmacology.
One of the important hurdles for validation was to establish biosimilarity between European (EU) Remicade, US Remicade and the biosimilar CT-P13. These 3-way bridging analyses required direct comparisons in PK, PD and other analytical studies to thereby allow the application to move forward.
Extrapolation is a consequence of the abbreviated development program. Thus, the sponsor can perform a single indication clinical trial they can request the same indications achieved by the reference product, extrapolating their single trial efficacy and safety (e.g., in RA) to other indications (e.g., Crohns, ulcerative colitis, psoriasis, psoriasis, ankylosing spondylitis). However this requires they demonstrate biosimilarity and validation of similar mechanism of action (MOA), immunogenicity and PK. Note that extrapolation does not apply to indications achieved through orphan drug approval process.
Interchangeability is important when patients are to receive the biologic at multiple times or chronically. Proving interchangeability is important to test the efficacy and safety of transitioning or substituting the biosimilar for the reference product. In this submission, the sponsor is not seeking interchangeability, although the PLANETAS trial did demonstrate sufficient interchangeability in AS patients who transitioned from EU Remicade to the biosimilar CT-P13. Multiple switching data is not available.
The FDA and sponsor were largely in agreement over many of the benchmarks needed for biosimilarity. Biosimilarity definition was meet with structural and functional similarity, without clinically meaningful differences. Bridging criteria were also met with 3-way analytical and PK comparisons showing the equivalence between CT-P13, EU Remicade and US Remicade. Nonclinical and clinical studies also raised no red flags. Clinical trial (including PK and immunogenicity) data from patients with RA, AS and IBD showed overlapping results between CT-P13 and the reference product. The clinical similarity margin was originally proposed by Celltrion to be 15%, but was lowered to 13% by the FDA who based this window on review of existing trial data using a 90% confidence interval.
The PLANETRA trial in 606 active RA patients used an immunogenic dose of 3 mg/kg (along with background MTX). Despite a 23-27% dropout rate, they showed over lapping ACR20 results (61% vs. 59% at week 30) that was maintained for this 54 week trial. The PLANETAS trial included AS patients (n=250) treated with 5 mg/kg for 54 weeks and showed ASAS40 responses >50% with similar infusion reactions, immunogenicity and safety outcomes.
While residual uncertainties were found, none were thought to have functional or clinical significance. Anti-drug antibodies were observed and showed the same predictable effects in those treated with PT-P13 or infliximab.
Safety concerns with the CT-P13 are the same as those for TNF inhibitors in general and Remicade when specifically compared. Low rates of serious infections (<5%), opportunistic infections, malignancies and infusion reaction were equally observed between CT-P13 and EU Remicade. The frequency of anaphylaxis was so low, comparison rates were not provided. There were 4 deaths in the clinical trials – 2 on Remicade and 2 on CT-P13 with 2 dying from traumatic accidents.
The quality review by the FDA showed that TNF binding affinity analyses (ELISA) and TNFα neutralization studies demonstrated statistical equivalence between CT-P13 and US licensed Remicade. Similarly the comparative clinical pharmacology studies demonstrated PK similarity between CT-P13 and US licensed Remicade. The same results were seen in the 3-way bridging PK studies that compared CT-P13 with US and EU licensed Remicade. Congruence in primary structure was demonstrated by 2-D peptide mapping with HPLC.
Remicade (infliximab) was first approved by the FDA in 1998 and since has been used in over 4.2 million patients worldwide. The CT-P13 development program began in 2008 with guidance from the EMA on a comparison of CT-P13 and EU Remicade. The drug is approved in 66 countries and has been given to over 2000 persons post-approval (outside the USA), with 23,859 patient-years of exposure experience as of July 2015.
Currently over 1000 persons have been treated in clinical trials with CT-P13, including over 800 patients who have received >1 dose of CT-P13, >600 who have been treated for >12 months and 230 patients who have been on this biosimilar for more than 2 years. The totality of evidence was strong enough to warrant approval. Extrapolation for multiple indications is based on MOA comparisons, 3-way PK comparisons across multiple conditions and similar immunogenicity and safety profiles.