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Are biosimilars as effective as their biologic counterparts?

In this Ask the Expert Q&A, FDA expectations for drug review, interchangeability, and safety are discussed.
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The Food and Drug Administration (FDA) has approved five biosimilar agents over the past 2 years to treat patients suffering from a number of chronic pain conditions, including rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis (Table 1).1 As reported in Practical Pain Management in 2016, a number of these biosimilars hold promise as cost-effective treatment alternatives to their biologic counterparts.2

But PPM readers have asked whether biosimilars are really as effective as their biologic counterparts. To answer that question, we will review the approval process for biosimilars and some of the data on their efficacy.

How Similar Are Biosimilars?

Biosimilars are FDA-approved biological products designated as “highly similar” to an already FDA approved biologic product or biological reference product. A biosimilar is not a perfect copy since drugs derived from living cells are not possible to reproduce exactly, according to the Arthritis Foundation.3 These drugs may be made from different sources but cannot deviate or differ in terms of safety, purity, and potency.

Biosimilars are comparable to generic counterparts for name-brand drugs but differ in that they are not necessarily interchangeable with the reference product. To be considered interchangeable, biosimilars require evidence that they have the “same clinical result as the reference product in any given patient.”4 An interchangeable product must also demonstrate that there is no greater risk in switching between the two drugs in terms of safety and efficacy.4

The abbreviated approval application for a biosimilar through the FDA was created by amending the Public Health Service Act (PHS Act), also known as the Biologics Price Competition and Innovation Act of 2009. In order for manufacturers to have a product reviewed as a biosimilar or interchangeable, they must submit a 351(k) biologics license application (BLA). This application validates biosimilarity through analytic studies, animal studies, and clinical studies.4

Will patients get the same clinical effect from a biosimilar form of the branded product?Will patients get the same clinical effect from a biosimilar form of the branded product?

The analytic studies need to demonstrate “high similarity” to the reference agent despite differing inactive components. Animal studies include toxicity information for the biosimilar. Lastly, clinical studies analyze immunogenicity, pharmacokinetics, pharmacodynamics, safety, purity, and potency in at least one of the conditions that the reference product is licensed for treating.4

The rationale behind creating biosimilars is similar to that behind creating generic drugs—that is, to treat patients with the same active ingredient at affordable prices. Many experts estimate that biosimilars are expected to run about one-third of the price of biologics. By 2025, it is estimated that 1.2 million US patients could have access to biologics as the result of biosimilar availability, according to a new analysis published by Avalere Health for the Biosimilars Council.5 These data also suggest that women, lower income, and elderly patients would particularly benefit from access to biosimilar medicines.5 Indeed, several patents for biological drugs soon will be expiring, which will allow manufacturers to create biosimilars without the expense of extensive research.

How Effective Are Biosimilars?

The ultimate question is, can we trust biosimilars to work as effectively for all the FDA-approved indications as their biologic counterparts? According to the approval process, a biosimilar has undergone extensive and rigorous testing comparing it to the reference product and has been shown to be highly similar structurally and “to have not clinically meaningful differences from the reference product”.4

Because of that, the FDA decided that a biosimilar could be approved for all of the reference product indications—as long as it works via the same mechanism in those diseases. The skepticism comes from the biologics potentially having different mechanisms of action among their indications.3

One Norwegian study assessed the safety and efficacy of a biosimilar versus its biological reference product. This study, the NOR-SWITCH study, compared patients who were on infliximab to those that switched to its biosimilar, infliximab-dyyb (CT-P13). All the patients had been on infliximab for 6 months prior to the start of the study.6

The NOR-SWITCH study stratified the switch among all indications of the two drugs: Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and psoriasis. The stratification via indication and assessment of clinical differences from the switch between biological reference and biosimilar had not been previously studied. The hypothesis was that CT-P13 would be noninferior regarding the proportion of patients with disease worsening by, at most, 15%. The study’s full analysis was 52 weeks, having 241 patients continue treatment with infliximab and 241 switched to CT-P13.6

The results indicated that disease worsening occurred in 26% of patients on infliximab and 30% of patients on CT-P13, the risk difference being -4.4% (-12.7% to 3.9%). These results met the study’s criteria for noninferiority. However, they could not conclude this per each approved indication considering lack of power in each subgroup. Table 2 summarizes the results from each indication according to the per-protocol analysis.6

In terms of safety, the study reported adverse events in 70% of the infliximab group and 68% in the CT-P13 group. Serious adverse events were reported in 10% of the infliximab group and 9% of the CT-P13 group. The most common adverse events were infection-related, such as nasopharyngitis, which occurred in 10% of each group, and urinary tract infections, occurring in 6% of the infliximab group and 3% of the CT-P13 group.

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