ACR Issues White Paper on Biosimilar Use in Rheumatology

Pam Harrison

March 16, 2018

The American College of Rheumatology (ACR) is reconsidering its cautionary stance on the use of biosimilars in the treatment of rheumatological diseases, as experience with these agents, especially in Europe, suggests they are safe and effective and may benefit patients at a lower cost than the drugs they were designed to mimic, an ACR white paper indicates.

"[I]t is reassuring to recognize the scientific rigor with which the [US Food and Drug Administration (FDA)] and other regulatory agencies around the world have evaluated biosimilars," Louis Bridges, Jr, MD, PhD, chair, ACR Committee on Research and Director, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, and colleagues write. "We remain optimistic that the use of biosimilars will improve patient access to biologic agents, allowing continued delivery of high quality healthcare to be realized at a lower cost to the individual patient."

The white paper was published online February 7 and in the March issue of Arthritis & Rheumatology.

As of September 2017, the FDA had approved seven biosimilars, five of which are tumor necrosis factor inhibitors.

Biosimilar Science

The white paper details the science behind the biosimilars, from how they are named to how they are manufactured and the careful, step-by-step regulatory pathway they must undergo to garner FDA approval. Once comparative studies have demonstrated that a biosimilar is indeed, biosimilar, to the original biologic (reference product), "both patients and providers should expect that clinical outcomes will parallel the accumulated experience with the use of its reference product," the authors state.

However, an important part of the approval pathway is to demonstrate that the biosimilar has comparable immunogenicity to its original, including a comparable ability to produce antidrug antibodies (ADAs). The presence of ADAs reduces the drug's efficacy and causes more infusion reactions; as there can be structural differences between the original biologic and the biosimilar, both the FDA and the European Medicines Agency insist on at least one study comparing both products' immunogenicity.

"Any candidate biosimilar that is found to be more immunogenic than its reference product will fail to meet criteria for biosimilarity," the authors note. (Biosimilars proven to be less immunogenic than the original biologic may, in contrast, be approved if they are as safe and effective as the original). To date, the frequency of patients developing ADAs when treated with a biosimilar has been similar to the ADA profile of the original biologic, so the authors do not expect any difference in ADA profiles will affect patient outcomes.

However, if patients start to fail on an original biologic because they have developed an ADA against it, they should not be started on the drug's biosimilar but, rather, receive an unrelated therapeutic agent. In addition, there is the potentially thorny issue of "extrapolation of indications." This means that if an original biologic is approved for several different indications, its biosimilar can be approved for those indications, even though the biosimilar itself has not been studied for them.

The same principle of extrapolation also appears to apply to children even though none of the biosimilars has been studied in a pediatric population.

Lower Cost?

The white paper also explores issues such as "substitution," where someone other than the prescriber changes the drug, and "nonmedical substitution," also known as payer substitution, where a drug is changed, typically in response to an insurance company's or pharmacy benefit manager's (PBM's) policies. Both issues are unresolved, but the authors anticipate they will need to be addressed as biosimilars become more widely used in the United States. Switching from one biologic to a biosimilar and then again to another biosimilar is as likely to happen in the United States as it has elsewhere. So far, "real-world" observational experience suggests switching from one biosimilar to another does not compromise efficacy or safety.

However, the real sticking point around the argument in favor of biosimilars is cost. "The only anticipated advantage of a biosimilar over its reference product is lower cost, since the two drugs should otherwise be therapeutically equivalent," the authors acknowledge. As the whole point of "switching" to a biosimilar is almost always cost, the authors question whether cost savings will ever be realized, and if so, when.

Roy Fleischmann, MD, clinical professor of medicine, University of Texas Southwestern Medical Center, Dallas, writes in an accompanying editorial that he is not convinced biosimilars will improve patient access to biologics or allow patients access at a lower cost.

Many patients in the United States get their drugs through a PBM, he explains. PBMs negotiate contracts with pharmaceutical manufacturers. "It is common practice for a PBM to obtain rebates (cash) and discounts from a manufacturer to place the manufacturers' medication high on the list of what is approved by the PBM," he states, a practice that can cause millions of dollars a year to flow directly to the PBM.

"[B]ecause of the rebate system, the argument that more biosimilars will lower the price of biologics and increase access is valid only in a payor system where the purchaser determines the price and patient access, such as in Norway, and where a rebate is not paid," Fleischmann argues. "This is not the case in the United States now or probably in the near future," he concludes. The authors do not disagree with this assessment and confirm there are ways manufacturers could "out-price" the biosimilar, causing any cost advantage a biosimilar might have to evaporate.

Nevertheless, as white paper coauthor Jonathan Kay, MD, professor of medicine, University of Massachusetts Medical School, Worcester, told Medscape Medical News, the introduction of biosimilars creates competition in the marketplace, which should cause prices of both the original biologic and its biosimilar to drop. Thus, he feels biosimilar use among rheumatologists should be encouraged.

Coauthor Angus Worthing, MD, chair, ACR government affairs committee and clinical assistant professor of medicine, Georgetown University Medical Center, both in Washington, DC, also suggested regulators could draft legislation forcing companies to provide transparency around rebates and fees that flow between PBMs and manufacturers. "The ACR supports this initiative," he told Medscape Medical News, "and if that doesn't happen, I think we'll see more of the true payers — businesses, insurance policy holders, and taxpayers — fire PBMs and simply purchase drugs directly from manufacturers," Worthing suggested.

In the final analysis, the ACR supports more widespread use of biosimilars for appropriate indications. Lead author Bridges told Medscape Medical News: "It is important to maintain a working knowledge of approved biosimilars and to monitor evolving policies and guidelines regarding the development and use of new biosimilars."

"[Still, we feel that h]ealthcare providers should now incorporate biosimilars, where appropriate, into their regimens to treat patients with rheumatic diseases," Bridges and colleagues conclude.

European Experience

Asked to comment on the ACR white paper, Peter Taylor, MA, PhD, Norman Collisson Professor of Musculoskeletal Sciences, University of Oxford, United Kingdom, pointed out that unlike healthcare economics in the United States, the payer determines access to biological therapies on the basis of price in European healthcare economies. "In Europe, there has been positive experience to date following the introduction of several biosimilars for use in rheumatology indications with accompanying evidence that this has contributed to the financial sustainability of European healthcare systems," Taylor told Medscape Medical News. That said, when the biosimilars were first introduced, patients often expressed concern that the cost pressures driving the switch to a cheaper product might mean they would end up with a drug that was inferior to the original biologic.

"Rheumatologists therefore have found it beneficial to provide patients with appropriate information to explain what a biosimilar is and why the benefits and any risks are expected to be the same as those of an originator," Taylor elaborated. "And now that biosimilar use has been successfully introduced for large numbers of patients, many patients have themselves become advocates of biosimilars in recognition of [their] cost-saving advantage to the healthcare system and in the hope that this might improve access to biological medicines for others with rheumatological diseases," he said.

Fleischmann reports he has served as a consultant to AbbVie, Amgen, BMS, Celltrion, Eli Lilly, GSK, Novartis, Pfizer, Sanofi Aventis, and UCB and has received grants from AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Genentech, Janssen, Merck, Pfizer, Roche, Samumed, Sanofi Aventis, and UCB. Taylor reports that he has received either grant or research support from Celgene, Eli Lilly and Company, Galapagos and UCB. Taylor has also served as a consultant for AbbVie, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Pfizer, UCB, Biogen, Sandoz, Novartis, Roche, and Janssen.

Arthritis Rheumatol. Published online February 7, 2018. Article, Editorial

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