FDA NewsPerspective

FDA Arthritis Advisory Committee votes in favor of biosimilar to infliximab

Members of the FDA Arthritis Advisory Committee voted positively today for the recommendation to approve the biologics license application of Celltrion’s CT-P13 biosimilar to infliximab. If approved, CT-P13 would be the first biosimilar monoclonal antibody to be approved for use in the United States.

In a 21-to-3 vote, the committee recommended CT-P13 should receive licensure as a biosimilar product for the indications for which the originator infliximab (Remicade, Janssen Biotech) is currently licensed in the United States and also be eligible for licensure for treatment of rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease and adult ulcerative colitis.

“CT-P13 met criteria for biosimilarity. As a pediatric rheumatologist, I’m forced to use infliximab for a lot of non-FDA approved indications, so the more choices we have, the better,” Mara L. Becker, MD, MSCE, director of the Division of Pediatric Rheumatology at Children’s Mercy Kansas City, said.

Jeffrey R. Curtis , MD, MS, MPH, director of the University of Alabama at Birmingham Arthritis Clinical Intervention Program, said his dissent was related to the “residual uncertainties” about the indications for inflammatory bowel disease and concerns about immunogenicity, particularly in patients with Crohn’s disease.

Ivan Fuss , MD, staff clinician of the Division of Intramural Research NIAID for the NIH, also voted no, citing concerns about long-term safety.

The hearing included a large proportion of debate about whether inflammatory bowel diseases – namely Crohn’s disease and ulcerative colitis – and pediatric use should be approved as indications for the biosimilar as the candidate has not been studied as extensively as the biosimilar has been studied in RA and ankylosing spondylitis.

Much of the contention surrounded the concept of extrapolation, or comparing data from studies of the originator infliximab and studies of the biosimilar product, to be applicable to other indications. The concerns were expressed by numerous physicians and patient advocates.

Among comments following the vote, many of the panelists, including those who voted favorably, said more study of the biosimilar is required and more information is needed on long-term safety and efficacy data. – by Shirley Pulawski

Reference: www.fda.gov

Members of the FDA Arthritis Advisory Committee voted positively today for the recommendation to approve the biologics license application of Celltrion’s CT-P13 biosimilar to infliximab. If approved, CT-P13 would be the first biosimilar monoclonal antibody to be approved for use in the United States.

In a 21-to-3 vote, the committee recommended CT-P13 should receive licensure as a biosimilar product for the indications for which the originator infliximab (Remicade, Janssen Biotech) is currently licensed in the United States and also be eligible for licensure for treatment of rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, adult and pediatric Crohn’s disease and adult ulcerative colitis.

“CT-P13 met criteria for biosimilarity. As a pediatric rheumatologist, I’m forced to use infliximab for a lot of non-FDA approved indications, so the more choices we have, the better,” Mara L. Becker, MD, MSCE, director of the Division of Pediatric Rheumatology at Children’s Mercy Kansas City, said.

Jeffrey R. Curtis , MD, MS, MPH, director of the University of Alabama at Birmingham Arthritis Clinical Intervention Program, said his dissent was related to the “residual uncertainties” about the indications for inflammatory bowel disease and concerns about immunogenicity, particularly in patients with Crohn’s disease.

Ivan Fuss , MD, staff clinician of the Division of Intramural Research NIAID for the NIH, also voted no, citing concerns about long-term safety.

The hearing included a large proportion of debate about whether inflammatory bowel diseases – namely Crohn’s disease and ulcerative colitis – and pediatric use should be approved as indications for the biosimilar as the candidate has not been studied as extensively as the biosimilar has been studied in RA and ankylosing spondylitis.

Much of the contention surrounded the concept of extrapolation, or comparing data from studies of the originator infliximab and studies of the biosimilar product, to be applicable to other indications. The concerns were expressed by numerous physicians and patient advocates.

Among comments following the vote, many of the panelists, including those who voted favorably, said more study of the biosimilar is required and more information is needed on long-term safety and efficacy data. – by Shirley Pulawski

Reference: www.fda.gov

    Perspective
    Stanley Cohen

    Stanley Cohen

    The Biologics Price and Competition Act was passed as part of the Affordable Care Act in 2010 and created an abbreviated pathway (351K) for licensure for biological products shown to be biosimilar to or interchangeable to the originator molecule. Biologic proteins are complex and differ from simple molecules, such as NSAIDs/conventional synthetic DMARDs in their higher order structure, impurities, charge isoforms, glycosylations and amino acid substitutions. Realizing that creating an identical biosimilar is not possible, the regulatory definition of a biosimilar is a biologic product that is highly similar to the reference product, notwithstanding minor differences in clinically inactive components. There are no clinically meaningful differences between the biological product and reference product in terms of safety, purity and potency of the product.

    In contrast to usual new drug development, this pathway requires the bulk of the work in the preclinical phase and relies less on clinical trials. Extensive analysis of the structure and function of the biosimilar demonstrating high similarity with the reference product is required along with pharmacokinetic (PK) and pharmacodynamic studies demonstrating equivalence between the molecules. CT-P13 was demonstrated to be highly similar in structure and function along with PK similarity to infliximab, albeit some issues were raised about small differences in FcR binding and antibody dependent cellular cytotoxicity, which could be relevant in inflammatory bowel disease (IBD). These minor differences resulted in the Canadian authorities previously approving the biosimilar for rheumatic diseases and psoriasis, but not IBD.

    In addition to the preclinical work, a clinical study is required to determine if there are any clinical meaningful differences in efficacy, safety and immunogenicity between the biosimilar and the reference product. CT-P13 was evaluated in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, and demonstrated equivalency in efficacy as required by the FDA and similar safety and immunogenicity. Based on the totality of the data, the Arthritis Advisory Committee voted 21 to 3 to recommend approval of CT-P13 for the treatment of RA, AS, psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis.

    The committee spent substantial time discussing the issue of extrapolation of the data to support the indication in diseases not studied in this new abbreviated development program based on the data presented. The pathway to extrapolation was detailed in previous FDA guidance documents and was formally addressed for the first time at this meeting. Reservations were expressed about the IBD extrapolation by several of the committee members, but ultimately approval for the indication was supported by the committee. Celltrion has an ongoing trial in Crohn’s disease that should address the concerns about efficacy and safety in these patients.

    The issue of switching or interchangeability is being evaluated in biosimilar clinical trials with a single switch from the reference product to the biosimilar with no significant changes in efficacy, safety and immunogenicity noted with the switch to CT-P13. In addition, ongoing studies in Norway — where the government has mandated switches from infliximab to CT-P13 — should provide us significant data on patients undergoing a single switch. What will happen with therapeutic substitution and multiple therapeutic switches is unknown. This will require a robust post-marketing surveillance program to determine if this will be an issue regarding loss of efficacy or toxicity. The FDA has mandated that each biosimilar will have different nomenclature which will allow for appropriate monitoring. At present, none of the biosimilars have sought approval for interchangeability and the FDA has yet to provide guidelines on the criteria for a biosimilar to receive approval for interchangeability.

    Biosimilars are actively under development not only for infliximab, but also for etanercept, rituximab and adalimumab. A biosimilar etanercept has been approved in Europe. The hope is with reduced cost there will be greater access to patients with expected improvement in patient outcomes. Some have projected a cost savings of $47 billion in the first 10 years after approval. When the therapies will get to market is unknown as the pharmaceutical companies plan to fight their approval based on multiple patents taken out since approval, which will remain in place after the initial patents lapse. Nevertheless, the introduction of biosimilars to rheumatology is coming and will have significant impact on how health care providers manage patients and hopefully improve quality of life for more rheumatic disease patients.

    • Stanley Cohen, MD
    • Clinical Professor in the Department of Internal Medicine at the University of Texas Southwestern Medical School
      Private practice, Rheumatology Associates
      Co-Director of the Division of Rheumatology at Presbyterian Hospital
      Co-Medical Director of Metroplex Clinical Research Center
      Dallas

    Disclosures: Cohen reports he is an investigator and consultant for Amgen, Boehringer-Ingelheim, Celltrion, Coherus, Pfizer and Sandoz who are developing biosimilars.