Biosimilars: To Switch or Not to Switch?

Biosimilars took center stage this year as the focus of the “Great Debate” at the ACR/ARHP Annual Meeting in San Diego.

On November 5, in a well-attended session in the conference center’s largest meeting room, the “pro” argument on the usefulness of biosimilars was presented by Dr Jonathan Kay, Professor of Medicine at the University of Massachusetts.

The “con” argument, that the research surrounding biosimilars has not provided enough evidence that switching can be allowed confidently, was offered by Dr Roy Fleischmann, Clinical Professor at the University of Texas Southwestern Medical Center.

The FDA defines biosimilarity as “no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity, and potency of the product.”

The ACR Annual Meeting Program Committee chose the topic because of the large impact the emergence of biosimilars will have on rheumatologists and their patients.

Pro: Biosimilars Are Safe, Effective, and Cost-Effective
Dr Kay began by explaining that all biologics are subject to variability, including normal batch-to-batch variability, drift (unintended alterations in the manufacturing process drift), and evolution (deliberate process changes made by the manufacturer).

This variability means that commercial lots of bio-originators are not identical, as demonstrated by a slide showing slight differences in US- and EU-sourced batches of infliximab (Remicade). Dr Kay argued that an approved biosimilar is no different from the reference molecule than the reference molecule is from other batches of itself.

Approved biosimilars have been shown to be highly similar to their reference product in extensive comparative analytical studies, and the clinical efficacy and safety of the reference product have already been established through extensive data. Thus, Dr Kay argued there is no need to demonstrate efficacy of the biosimilar in all indications.

Dr Kay presented data from the NOR-SWITCH study, a 52-week randomized, double-blind, non-inferiority phase IV trial in which patients with 6 different diagnoses were randomly assigned to receive an originator or biosimilar medication. The results showed similar treatment emergent events and similar immunogenicity with and without switching, as well as comparable long-term safety and efficacy of the biosimilar after switching from the originator.

Overall, the NOR-SWITCH study showed no difference in disease activity measures except in the patient global assessment, which Dr Kay maintained could be explained by the “nocebo” effect. This refers to the misattribution of bodily symptoms to a drug in patients who expect to experience distressing adverse effects or who have experienced such adverse effects in the past. Dr Kay suggested the nocebo issue could be addressed through education, collaborative discussion, and encouragement of patients.
In addition to comparable safety and efficacy, Dr Kay continued that the availability of biosimilars should decrease the cost of treating patients and introduce market competition, provoking discounts and rebates for bio-originators. He pointed out that global competition affects not just the price of the originator but also the price of the whole product class.

In addition, if biosimilar manufacturers withdraw from the market, the originator product price will likely rise. This means it might even make sense to purchase biosimilars now at slightly higher acquisition prices to preserve the competitive market.
Overall, Dr Kay concluded that biosimilars create greater global access to effective biopharmaceuticals, which should reduce disability, morbidity, and mortality associated with inflammatory diseases.

Con: The Data on Biosimilars are Not Convincing
Dr Fleischmann chose to focus his argument primarily on the issue of cost in the United States. He emphasized that the rationale for biosimilars is not only that they should be as safe and effective but, more importantly, that biosimilars should be cheaper than the originator, giving more patients access to needed treatment. If biosimilars aren’t considerably cheaper to the patient and society, Dr Fleischmann reasoned there is no value in using a biosimilar.

Dr Fleischmann’s data showed that biosimilars may not be significantly cheaper to the provider or the patient. He cited a New York Times and ProPublica report in which patients were required to buy brand-name drugs even when cheaper generics were available, a practice driven by better margins for pharmacy benefit managers (PBMs) that leaves patients paying higher out-of-pocket costs. The article concluded that this practice appears to be spreading to biosimilars as well.

In addition, Dr Fleischmann argued that even in instances in which biosimilars do result in reduced prices, these savings generally accrue to insurers and PBMs rather than patients or even the national economy.

As for efficacy and safety, Dr Fleischmann also discussed the NOR-SWITCH study, arguing that it did not actually provide evidence that the biosimilar was noninferior to the originator biologic when the diseases are looked at individually. He also questioned the use of the “nocebo” effect as an adequate explanation for a clinically meaningful number of patients losing efficacy or developing adverse events when switched to the biosimilar. He contended that more safety data are needed, for a longer period, in many more patients to fully understand the safety of biosimilars.

Dr Fleischmann concluded that, at least in the United States, the PMB system means that biosimilars do not present cost savings to patients and thus biosimilars do not have the intended impact of reducing costs and increasing patient access.

References:

Jorgensen KK, Olsen IC, Goll GL, 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 Jun 10;389(10086):2304-2316. doi: 10.1016/S0140-6736(17)30068-5. Epub 2017 May 11.

Jackie Syrop. “Take the Generic Patients Are Told. Until They Are Not.” New York Times. August 6, 2017.