Biosimilars in IBD: Interchangeability is the issue

This is half of a two-part debate — read the opposing argument. 

Following the introduction of infliximab in 1998, two additional tumor necrosis factor antagonists (i.e., adalimumab, certolizumab pegol), the anti- integrin vedolizumab and ustekinumab (a monoclonal directed to interleukin 12 and 23) were approved for the management of inflammatory bowel disease. Biologics have greatly improved the lives of patients with Crohn’s disease and ulcerative colitis, because these agents are safer and more effective than conventional agents (e.g., corticosteroids, immunosuppressants). However, notwithstanding their value to patients, biologics have seriously challenged the capacity of health care systems to pay for such costly medications.

Biosimilars have been approved by regulatory authorities. Specifically, two biosimilar versions of infliximab have been approved by the FDA for the treatment of Crohn’s disease and ulcerative colitis,1,2 with originator drug substitution now occurring within many insurance plans for patients starting infliximab therapy. The introduction of infliximab biosimilars into clinical practice has proceeded rapidly in many jurisdictions and, in my opinion, has outstripped the ability of regulatory authorities, clinicians, payors and patients to make informed decisions regarding the safety of these agents.

Unlike small-molecule drugs, which are produced by chemical synthesis and have well- defined structures, biologics and biosimilars are produced in living cells and are structurally heterogeneous such that each product has differences in quaternary protein structure due to variances in glycosylation. These structural changes can affect drug pharmacokinetics, pharmacodynamics, and immunogenicity.3 Accordingly, although biosimilars may be approved by regulatory authorities for the same indications as the reference product (usually on the basis of integrated evidence from underpowered “equivalency trials”4 and in vitro surrogate assays of structural and pharmacodynamic equivalence), they are not necessarily interchangeable with the originator product, meaning that the biosimilar cannot be directly “switched” for the reference product in the same manner as can be a generic small molecule drug.

Two types of such switching exist: (1) medically necessary switching due to lack of efficacy or adverse events, and (2) nonmedical switching, which is conducted with the intent of reducing cost. Disease that fails to respond to infliximab is difficult to manage, and switching a patient to another tumor necrosis factor antagonist or to an entirely different drug class is often necessary. Controlled data to inform these decisions are available for the originator infliximab but not its biosimilars. In the case of cost-driven nonmedical switching, it is imperative that we are certain that the biosimilar is fully interchangeable and has no clinically relevant differences from the originator product.

The FDA has issued guidance on biosimilar interchangeability that specifies the need for a dedicated switching study prior to approval of a biosimilar as an interchangeable product. This guidance also denotes that switching studies should feature three switches between products for at least two exposure periods with each drug.5 The rationale for this requirement is the potential risk of immunogenicity given that the quaternary structure of the biosimilar and the reference product are dissimilar and that intermittent exposure to similar, yet nonidentical proteins is a provocative maneuver for the development of antidrug antibodies and sensitization-related treatment failure. The humoral immune response is a complex process influenced by multiple factors; however, the quaternary structure of a foreign protein is a key determinant of whether T cells sensitize or tolerate it. At last count, nine infliximab biosimilars are currently in development, so it is not difficult to imagine a future in which patients are commonly switched among multiple structurally different infliximab products based on cost considerations.

Myself and colleagues recently evaluated the published literature to determine what is known about infliximab biosimilar interchangeability and identified 70 relevant citations.6 Importantly, data were available from six randomized controlled trials. In general, the limited evidence revealed no apparent risks associated with switching; however, these studies reported on single switches alone and were mostly observational in design with no control arms. Very little attention was devoted to the assessment of immunogenicity. Specifically, details regarding the operating characteristics of assays for antidrug antibodies were lacking. We concluded that additional, high-quality data are needed to fully assess the potential risks of immunogenicity before the interchangeability of infliximab biosimilars can be endorsed. Consistent with this view, the FDA, EMA and Health Canada have all indicated that the evidence is insufficient to draw conclusions regarding the interchangeability of existing biosimilars to infliximab.

Nonetheless, patients and gastroenterologists are being pressured by payors to switch to biosimilars even in those whose disease is stable on originator infliximab. To be clear, the sole reason for switching to a biosimilar is the potential for cost savings to payors. Not surprisingly, clinicians have little enthusiasm for switching a patient with stable disease to a new drug when no possible clinical benefit exists. Although it can be argued that the cost savings realized from switching stable patients to biosimilars will be passed on to society and/or individual patients, no empiric evidence exists that that this will be the case. Furthermore, the liability risk for physicians and payors implementing nonmedical switching in this setting is unknown.

In summary, although the use of biosimilars in patients who are starting infliximab has become commonplace and appears to be safe and effective, interchangeability of these products should not be endorsed until controlled studies have established the safety and risk profile of immunogenicity associated with switching.

As senior scientific officer at Robarts Clinical Trials, Inc., Dr. Feagan consults with many pharmaceutical clients. His disclosures are available here.

Dr. Ha describes why biosimilars in IBD are mostly ready for change.

1. Infliximab-dyyb [package insert]. Yeonsu-gu, Republic of Korea: CELLTRION, Inc.; 2016.
2. Infliximab-qbtx [package insert]. Ringaskiddy, Ireland: Pfizer Ireland Pharmaceuticals; 2017.
3. Schellekens, H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Disc. 2002;1:457-462.
4. Jorgensen, K.K., Olsen, I.C., Goll, G.L., et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389:2304-2316.
5. FDA. Considerations in demonstrating interchangeability with a reference product: guidance for industry. Published January 2017. https:// Guidances/UCM537135.pdf. Accessed November 19, 2018.
6. Feagan, B.G., Lam, G., Ma, C., Lichtenstein, G.R. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Aliment Pharmacol Ther. 2018. [Epub ahead of print].

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