In Rheumatology, Biosimilars Are Flatlining. Why?

Kari Oakes

January 29, 2020

Although biosimilar versions of tumor necrosis factor inhibitors (TNFis) have been available to U.S. rheumatologists and their patients for over 3 years, uptake has thus far been slow.

In an analysis of data from a large commercial payer, the two available biosimilars for infliximab (Remicade) accounted for less than 1% of TNFi prescribing since the first biosimilar to infliximab was approved in 2016.

The study, published in Arthritis & Rheumatology, involved a total of 1.1 million TNFi prescriptions or infusions received by 95,906 patients from 2016 to 2019. Investigators found that uptake of biosimilar infliximab was essentially flat, standing at 0.1% of prescribing in the second quarter of 2017, and topping out at 0.9% in the first quarter of 2019. For branded infliximab, prescribing was also stable, but accounted for about 20% of overall biologic dispensing in each quarter of the period studied.

Dr Seoyoung C. Kim

There are currently two biosimilar medications to the originator infliximab, which is one of five originator biologics available to treat rheumatic diseases in the United States: infliximab-dyyb (Inflectra) and infliximab-abda (Renflexis). The former was approved in 2016 and the latter in 2017, said study author Seoyoung C. Kim, MD, ScD, of the division of pharmacoepidemiology and pharmacoeconomics, Brigham and Women's Hospital, Boston, and her coauthors.

"Our paper reports a disappointingly low uptake of biosimilar infliximab since the first quarter of 2017 using claims data from a large private health plan. The main and maybe the only reason to consider using a biosimilar is cost saving," said Dr. Kim in an interview. "Our results suggest that current modest cost savings from infliximab biosimilars in the U.S. are not sufficient to promote their widespread use."

In the payer database study conducted by Dr. Kim and colleagues, the insurer paid similar mean amounts per patient per quarter for originator and biosimilar infliximab in mid-2017 ($8,322 versus $8,656). By the end of 2018, a gap appeared, with the insurer paying a mean quarterly per-patient sum of $8,111 for biosimilar infliximab compared with $9,535 for the branded biologic.

Dr Jinoos Yazdany

"The lack of market penetration and very modest price reductions for biosimilars have left policymakers, payers, physicians, and the public frustrated, particularly because sales in Europe continue to rapidly expand and robust cost-savings have materialized," wrote Jinoos Yazdany, MD, MPH, in an editorial accompanying the study.

Dr. Yazdany, professor and chief of the division of rheumatology at the University of California, San Francisco, noted that increased spending on biologics in the United States – which increased by 50% from 2014 to 2018 – has been driven by rising prices as well as increased uptake of biologic therapies.

At least in part, Europe has been able to reap cost savings where the United States hasn't because fundamental differences in health care reimbursement can ease sweeping biosimilar adoption, Dr. Yazdany noted. "Countries like Denmark and Sweden, using the negotiating and purchasing power of their single-payer systems have instituted a winner-takes-all bidding system," with Denmark seeing cost savings of up to two-thirds when bidding was combined with mandatory switching, she said.

The continued market dominance of originator infliximab means that savings from biosimilars have thus far amounted to about $91 million, far short of the $1 billion that the Congressional Budget Office had projected for this date, Dr. Yazdany said.

Dr Colin Edgerton

One problem in the adoption of biosimilars by U.S. rheumatologists may have been uneven marketing and pricing across different types of practice, Colin C. Edgerton, MD, a rheumatologist at Low Country Rheumatology in South Carolina and chair of the American College of Rheumatology's Committee on Rheumatologic Care, said in an interview.

"Rheumatologists have generally developed comfort with biosimilars, although this is not universal. The core message, that all biologics vary and that this is OK, is getting out. In general, rheumatologists also understand the problem with high drug prices and the threat to patient access," Dr. Edgerton said. But "the early marketing and pricing focus for biosimilars seemed to be on hospitals and facilities, and this did not work effectively for community rheumatologists, where the majority of care is delivered. We have been pleased to see a manufacturer pivot toward community rheumatology where additional efforts need to be made to bend the curve on biosimilar adoption. It is critical for practices with experience using biosimilars to educate peers, and this is where networks of practicing rheumatologists are important."

In Dr. Yazdany's editorial, she cited four structural factors impeding biosimilar uptake and downstream savings.

First, she cites ongoing actions by pharmaceutical companies, which create a "patent thicket" that has the effect of fencing off originator biologics from biosimilars long beyond the original 12-year exclusivity period. Supporting the notion that "patent thickets" are a common strategy, Dr. Yazdany noted that almost half of the patent applications that AbbVie has filed for adalimumab (Humira) have come in after the original exclusivity period expired in 2014. Humira's price has risen 18% yearly during this period.

The complicated role played by pharmacy benefit managers (PBMs) is another factor in slow adoption, said Dr. Yazdany: When manufacturers offer rebates to PBMs, the price of the originator biologic may be less than its biosimilar. Further, manufacturers may sign multiyear rebate agreements just before a biosimilar launch; PBMs are also sometimes threatened with the withdrawal of rebates if they offer biosimilars, she noted.

Third, prescriber inertia may also be at play, Dr. Yazdany noted, not least because patients often see little difference in out-of-pocket costs when they make the switch to a biosimilar – PBM rebates are not necessarily passed on to patients. Payers may not reimburse a biosimilar, or formularies can be built without them, influencing prescribing, and there's usually no reimbursement incentive for biosimilar prescribing in the nonpublic sector, she said. To the contrary, infusing a drug with a higher price often means higher reimbursement for the administering clinician, since commercial insurance reimbursement is often calculated as a percent of the charge for the drug.

Further contributing to inertia is the extra time required for patient education and writing a new set of orders – all work that can't be captured for extra reimbursement. Dr. Edgerton said that rheumatologists can talk with patients about the "nocebo effect" relating to biosimilars. "This is a phenomenon in which patients are thought to experience worsening symptoms associated with negative beliefs about biosimilars. There has been a study in Arthritis Care & Research addressing this concern. The authors found that positive framing of biosimilars led to more participants being willing to switch than negative framing. This suggests that clinicians have an important role in informing patients about biosimilars, and addressing hesitancy."

Finally, Dr. Yazdany pointed out that for a pharmaceutical company pursuing biosimilar approval, the regulatory pathway itself can provide its own set of complications and confusion. Biosimilars are not exact molecular replicas of the originator biologic, and these differences can change efficacy and immunogenicity, and also affect stability. Hence, a company wishing to market a biosimilar has to show the Food and Drug Administration that safety and efficacy aren't affected by a switch to biosimilar from an originator biologic. Extrapolation from one indication to another can be made – with scientific justification.

Rheumatologists are mindful of the potential differences between biosimilars and the originator biologic, as evinced in a recent position statement from the American College of Rheumatology. The position statement advises that "extrapolation should be pursued with caution," and asks for clear labeling when biosimilars have been designated "interchangeable" with their biosimilar. Interchangeability can clear the way for pharmacy substitution of a prescribed biologic, though Dr. Yazdany noted that 40 states have passed legislation requiring prescriber notification.

The FDA is currently using postmarketing pharmacovigilance to monitor biosimilar performance in the real world, and a recent systematic review "should provide some reassurance," wrote Dr. Yazdany, citing the study, which looked at 14,000 patients who had a total of 14 disease indications for biosimilar use. The 90-article review largely found no differences in safety, efficacy, or immunogenicity between originators and their biosimilars. Dr. Yazdany recommended greater openness to incorporating the European experience in the FDA's ongoing reassessment.

A further way forward can come through tackling the patent thicket with the proposed bipartisan Biologic Patent Transparency Act, which would require publication of biologic patents in a one-stop publicly searchable database. Going further with legislation to address anticompetitive activity by pharmaceutical companies could shorten the runway to biosimilar launching considerably, she noted.

The complicated landscape of PBMs and rebates affects many sectors of health care, and new policy efforts are needed here as well, she said. Reimbursement strategies – and much-needed continuing medical education – can both ease prescriber unfamiliarity with biosimilars and provide incentives for their use, she concluded.

Dr. Kim concurred that change is needed before the United States is likely to reap significant economic benefit from biosimilars. "The uptake of biosimilars and their impact on overall health care cost needs to be reevaluated when we have more biosimilars available in the next 3-4 years. However, for now, it appears that substantial savings achieved in some European countries – for example, Denmark – may not be possible without systemic reform of the U.S. pharmaceutical market," she said.

Dr. Yazdany is supported by the Alice Betts Endowed Chair in Arthritis Research, the Russel/Engleman Research Center at the University of California, San Francisco, and the National Institutes of Health. She has received independent research grants from Pfizer and Genentech and research consulting fees from Eli Lilly and AstraZeneca.

Dr. Kim's study was supported by the division of pharmacoepidemiology and pharmacoeconomics, department of medicine, Brigham and Women's Hospital, and Arnold Ventures. Dr. Kim has received research grants to Brigham and Women's Hospital from Pfizer, AbbVie, Bristol-Myers Squibb, and Roche.

SOURCES: Kim SC et al. Arthritis Rheumatol. 2020 Jan 13. doi: 10.1002/art.41201; Yazdany J. Arthritis Rheumatol. 2020 Jan 10. doi: 10.1002/art.41203.

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