Rheumatologist Sees Gray Areas in ACR White Paper on Biosimilars

Last week, the American College of Rheumatology released a white paper supporting the use of biosimilars in clinical practice. In an editorial in Arthritis and Rheumatology, Roy Fleischmann, MD, responded to the paper, saying that while it is appropriate for the ACR to update its position on biosimilars, the white paper contains “many clear statements (white), there are a few arguments that are open to alternative opinions (gray), and there are 2 arguments that are open to an alternative conclusion (black).”

According to Fleischmann, the white paper appropriately describes issues including the nomenclature of biosimilars, the biosimilar approval pathway, and differences between biosimilars for biologic drugs and generics for small molecule drugs. However, he takes issue with ACR's stance on substitution, extrapolation, and interchangeability.

Switching

First among the gray areas, says Fleischmann, is that, while clinical trials of switching from a reference to a biosimilar in groups of patients may show equivalency of these products, “…as rheumatologists, we don't treat groups of patients—we treat individual patients; and here the results may be different. Reports of ‘real-life’ experiences have shown that there is a consistent proportion of patients who did well clinically with a bio-original but did not when switched to the biosimilar, due to either lack of effect or an adverse event.”

Fleischmann points to Danish research that concluded that switching from originator infliximab to biosimilar CT-P13 did not appear to have a negative impact on inflammatory arthritis disease activity in 802 patients after 1 year of follow up. He highlights the fact that 132 patients in the study withdrew because of a lack of treatment efficacy (n = 71) or adverse event (n = 37). Similarly, he highlights the fact that, in the NOR-SWITCH study, disease flares occurred in 30% of patients who were switched to biosimilar infliximab, and still another study showed that 24% of patients discontinued CT-P13.

“It is highly unlikely that all of the patients who had lack of effect or an adverse event experienced a nocebo effect,” says Fleischmann, who also asks, “What about…[the patients] who did experience a negative result? Are they not important?”

Extrapolation of Indications

Fleischmann also takes issue with the NOR-SWITCH study’s failure to show noninferiority of biosimilar infliximab to the reference in treating 5 diseases: Crohn disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, and psoriasis. “This raises the question of whether extrapolation is reasonable,” he says.

Multiple Switches Among Biosimilars

Among the areas of concern that Fleischmann labels “black” areas of the white paper is that of multiple switches among various biosimilars for a single reference. While the FDA has issued guidance on how to conduct a study to prove the safety of this undertaking, no such studies have been reported. To date, the safety of switching among biosimilars remains speculative.

Cost

Fleischmann’s greatest concern is that, as discussed in ACR’s white paper, it is often the patient’s pharmacy benefit manager (PBM) that decides which medications will be available, and manufacturers' rebates can incentivize PBMs to prefer high-cost drugs.

"Thus, the argument that availability of more biosimilars will lower the price of biologics and increase access is valid only in a [payer] system in which the purchaser determines the price and accessibility to patients, such as in Norway, and where a rebate is not paid. This is not the case in the [United States] now and probably will not be in the near future," says Fleischmann. "If it is the former, [biosimilars] are a welcome addition to our armamentarium; if the latter, they are of no benefit."