Among the most anticipated sessions at the 2017 American College of Rheumatology’s Annual Meeting in San Diego, California was “The Great Debate: Biosimilars…to Switch, or Not to Switch? That Is the Question.” Moderated by Daniel Furst, MD, and Daniel Solomon, MD, the debate featured Jonathan Kay, MD, arguing in favor of switching patients from reference products to biosimilars, and Roy Fleischmann, MD, arguing against the practice.
Switching for the Greater Good
Kay began by framing his remarks with a play on the famous “to be or not to be” question asked by Shakespeare’s Hamlet. In Kay’s version, the lines that follow are “Whether ‘tis better for bones and joints to suffer the stings and burden of outrageous prices, or try changing to a biosimilar, and by converting save costs.”
Kay outlined his position by first defining a biosimilar as a molecule that has undergone rigorous analytical and clinical assessment and has been approved by a regulatory agency. He reminded the audience that the FDA reviews analytical comparisons between the reference biologic and biosimilar along with nonclinical data, clinical pharmacology, and clinical studies in a risk-based, totality-of-the evidence approach.
He went on to argue that all biologic drugs, including reference products, are subject to variability due to protein folding variance, misfolding, aggregation, enzymatic cleavage, and degradation, and that all biologics have batch-to-batch variability. Proven acceptable ranges are established during product development, and variability within that range does not pose safety or efficacy risks. Furthermore, “drift,” or unintended alterations caused by manufacturing practices over time, as well as intended and regulated alterations created by manufacturing changes, can create variability in reference biologics.
While Kay allowed that variation may have consequences that we do not yet realize, variation is to be expected in biologics. It can be so substantial, Kay said, that the same drug may be considered a biosimilar of other batches of the same product. Variability has an impact on the extrapolation of clinical data from a study in 1 indication to other indications, said Kay. “We don’t ask each batch of a reference product to be tested in large clinical trials in all indications.”
He went on to argue that trials such as PLANETAS and PLANETRA
in ankylosing spondylitis (AS) and rheumatoid arthritis (RA), respectively, point to the feasibility of switching patients from reference infliximab to its biosimilar. He also highlighted the NOR-SWITCH
trial (a 52-week, phase 4 study in patients Crohn’s disease, ulcerative colitis, spondyloarthropathy, RA, psoriatic arthritis, and plaque psoriasis) which met its primary endpoint of non-inferiority in patients who were switched from the reference infliximab to a biosimilar.
While Kay acknowledged that NOR-SWITCH’s open-label extension showed losses in patient global assessment (PSA) among switched patients, he says that the PSA “reflects nocebo effect,” or a misattribution of bodily symptoms to a drug in patients who expect to experience side effects or other poor outcomes. Kay also attributed patient discontinuation of biosimilars in other studies, such as BIO-SWITCH
, to the nocebo effect.
Given evidence of similar safety and efficacy, Kay argued, a cheaper biosimilar should be used instead of a reference biologic “So that medications are more widely available to all members of society.” Any potential risk from switching should be weighed against potential benefits for all patients who need access to biologics.
But Where Are the Cost Savings for Patients?
Fleischmann, in arguing against switching patients to biosimilars, did not challenge Kay’s comments on the nature of biosimilarity or the approval pathway for biosimilars, which have been well defined. However, Fleischmann took issue with switching biosimilars based on data from NOR-SWITCH, saying, “The assumption was difficult. How do you define 30% [disease] worsening? It couldn’t really be accurate.” He also questioned the veracity of attributing patients’ poor outcomes to the so-called nocebo effect. “Nocebo’s a word that comes up when you don’t get what you want to see,” he said. “[Do] you want to call it nocebo, or you want to call it the data?”
More importantly, Fleischmann framed the issue of switching to biosimilars differently: “If it isn’t considerably cheaper to the patient and society, there is no value in using a biosimilar. This is where I start: cost.”
“This is truly the question,” Fleischmann went on. “Are there real, considerable cost savings realized with the use of biosimilars, which accrue to the patient, and therefore [allow them to] have greater access to biologics? If the patient doesn’t have better access, you don’t need a biosimilar.”
Despite the fact that patients and payers have seen cost savings from biosimilars, in the European experience—where single-payer systems are in place—Fleischmann said that his remarks would be grounded in “the realities of our current knowledge of biosimilars and the medical system in the United States, good or bad.”
Fleischmann referenced his own experience as a partial owner of an infusion center where no biosimilars have been used to date; insurance plans have requested physician appeals before biosimilars can be approved, he said, and patients would be responsible for roughly the same costs of treatment.
Taking aim at pharma, Fleischmann pointed to the recent AbbVie and Amgen settlement on Humira that will allow a biosimilar adalimumab to enter the US market in 2023. “The deal suggests that the industry’s long-standing strategy of using patents to ward off cheaper competition for brand-name drugs is extending into the era of biosimilars. AbbVie will grant patent licenses for the sale of the biosimilar, so when is Humira going to be cheaper?” He added that AbbVie has substantially raised adalimumab’s list price over time—the price increased by 68% between 2013 and 2016—while AbbVie says it provides rebates and discounts that lower the cost for insurers. But "what about the patient?” Fleischmann asked.
Fleischmann also criticized pharmacy benefit managers (PBMs) for their role in keeping costs for patients high: “We have a unique system in the [United States] which governs the choice of medications. It’s called the rebate system, and it’s a very sad system,” referring to the arrangement by which PBMs negotiate for lower prices while patients pay co-payments on list prices for drugs.
Regardless of the European experience with biosimilars, Fleischmann said, “I live in the [United States]. I don’t get any benefit, my government doesn’t get any benefit [from biosimilars].” The only entity that has a true advantage from biosimilars, he says, is the payer. Fleischmann underscored this position by citing an article
published in The Center for Biosimilars®
reporting that 58% of US health plans do not cover biosimilar infliximab.