Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

The approval of a new adalimumab biosimilar this week does not change the fact that adalimumab biosimilars won’t be on the market in the United States for a couple years longer, but it does signify that the FDA is not completely stymied by its need to focus on treatments for coronavirus disease 2019 (COVID-19).

The approval of Hulio, a drug developed by Fujifilm Kyowa Kirin Biologics and commercialized in multiple countries by Mylan, marks the second biosimilar approved by the FDA in as many months, following the FDA 

 received in June for Pfizer’s pegfilgrastim biosimilar Nyvepria. It brings the grand total to 2 approved biosimilars for 2020.

This is well behind the pace from last year, which set a record of 10 biosimilar approvals, half by the midyear point. The first biosimilar (filgrastim, Zarxio) was approved in 2015. Subsequently, there were 3 approvals in 2016, 5 in 2017, and 7 in 2018.

With this week’s approval, the total number of US-approved biosimilars is now 28, and the number of commercialized biosimilars is 17.

 issued today about the adalimumab approval for Hulio, Mylan noted that although AbbVie’s Humira reference product is well protected with patent exclusivities, there is an agreed-upon scheduled launch date for Hulio, July 31, 2023. There are 6 approved adalimumab biosimilars in total and several others in the works. Biosimilar development companies have been settling with AbbVie over specific 2023 launch dates, but none of these drugs for rheumatoid arthritis and similar conditions would reach the marketplace before that time.

“This approval represents yet another date-certain launch opportunity and demonstration of our commitment to expand patients’ access to medicine thanks to the power of our global platform, including our global reach and scale, our continued demonstration of scientific excellence, and the benefits of strategic partnerships, such as the one we are proud to have with Fujifilm Kyowa Kirin Biologics,” Mylan said in its statement.

The approval for Hulio was based on the phase 3 clinical study ARABESC, which demonstrated no clinical meaningful differences in safety, efficacy, and immunogenicity for the biosimilar compared with the originator product. Hulio is indicated for patients with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn disease, ulcerative colitis, and plaque psoriasis.

The FDA has previously stated that COVID-19 has placed huge strain upon its resource structure and necessitated a realignment of priorities; however, it has attempted to keep normal operations moving forward and, in recent months, has worked to ensure that adequate funds, raised through user fees for biologics license applications, are available to meet these responsibilities.

 problems with revenue and needs misalignment that have made it necessary to downsize activities to make available funds last. Lack of a disclosure policy at the FDA regarding biosimilar candidates under review makes it difficult to pinpoint the robustness of the pipeline or determine the extent to which COVID-19 has caused biosimilar approvals to stall.

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With a couple of recent biosimilar approvals, the FDA has vastly improved on the pace from the first 5 months of this year, during which no biosimilars were approved.

FDA Biosimilar Approval Pace Picks Up

Having been stopped by court rulings in its attempt to block 2 Amgen biosimilars from coming to market, Genentech waved the white flag this week by filing a court notice of settlement with Amgen. The notice indicated that both had agreed to relinquish all claims and counterclaims.

The battles waged over separate drugs involved Amgen’s trastuzumab biosimilar Kanjinti and bevacizumab biosimilar Mvasi. Kanjinti references Genentech’s Herceptin, and Mvasi is a biosimilar to Avastin.

 to originator companies, in that they would have to become more circumspect in their timing of court actions; and the Mvasi fight came to a 

 earlier this week when a federal circuit court overruled Genentech’s claims of inadequate notice of commercialization.

Both Kanjinti and Mvasi came to market in July 2019. With Kanjinti, Genentech delayed too long—almost a month after the FDA approved the drug for sale&mdash;before filing a motion for an injunction to block commercialization of the product. When Genentech finally did file that motion, a district court judge refused to grant the injunction, which allowed Amgen to bring the trastuzumab product to market.

Similarly, an appeal of that decision was turned down by the US Court of Appeals for the Federal Circuit in March.

Having witnessed Genentech get singed by that ruling, other originator companies are likely to make sure they file for injunctions earlier in the process and, certainly, before the FDA issues marketing authorization to biosimilar developers, patent law attorney Ted Mathias, of Axinn, Veltrop & Harkrider of Hartford, Connecticut, concluded in a presentation earlier this year.

“We can expect some changes and, specifically, some more varied approaches to litigation based on what we saw last year with trastuzumab,” Mathias said.

What that earlier notice signifies is that originator companies will have to play stronger cards against rival biosimilar companies earlier in the patent review process, thereby revealing more about their products and exclusivity protections and, potentially, tipping their hands to competitor biosimilar companies, Mathias said. It essentially gives rivals an advantage in the legal process that they didn’t have previously.

When Does the Notice Clock Start Ticking?

Whereas timing was a critical flaw in Genentech’s attempt to block commercialization of Kanjinti, Genentech’s latest move to halt Mvasi sales hinged on whether Amgen had provided adequate notice of commercialization. The Biologics Price Competition and Innovation Act calls for at least 180 days of notice prior to marketing, but Genentech argued that some adjustments to the Biologics License Application (BLA) for Mvasi reset the clock on the notice requirement, which would have forced Amgen to start again. A district court disagreed with that argument, saying the adjustments were immaterial to the substance of the BLA, and a federal circuit court upheld that ruling.

Both the trastuzumab and bevacizumab biosimilars from Amgen have been carving an ever-increasing share of the market away from Genentech since launching in July of last year. Both launched at a 15% discount to the respective Genentech originator products, Herceptin and Avastin, which can be conceived to have been helpful in gaining sales momentum.

Kanjinti notched $226 million in 2019, and $119 million in the first quarter of this year. The respective sales figures for Mvasi were $127 million and $115 million. Here are links to the 

In court filings this week, Genentech and Amgen laid to rest their long-running dispute over the marketing of bevacizumab and trastuzumab biosimilars that challenged Genentech's dominance of the market for those products.

Genentech and Amgen Cease Fire on Biosimilar Litigation

 an adalimumab biosimilar (Hulio) from Fujifilm Kyowa Kirin Biologics, making it the sixth adalimumab biosimilar to AbbVie’s reference product Humira that has been approved and the 28th biosimilar approved by the FDA. Mylan will handle the commercialization in the United States.

AbbVie has contracted with all 6 adalimumab biosimilar developers for sequential launch dates, with Fujifilm Kyowa Kirin Biologics’s being July 31, 2023. The earliest would be Amgen’s on January 31, 2023.

Hulio is a tumor necrosis factor blocker indicated for the subcutaneous treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn disease, ulcerative colitis, and plaque psoriasis. The injectable is available in prefilled single-dose pens at 40 mg/0.8 mL and in prefilled plastic syringes at the same dose or at 20 mg/0.4 mL.

Although only just approved in the United States, Hulio was launched across major European markets in October 2018, just 1 month after the European Commission (EC) issued a positive opinion for commercialization. At the time, Mylan indicated that the product launch was a significant milestone for its progress in developing a portfolio of biosimilar products. In partnership with other pharmaceutical companies, Mylan has marketed biosimilars in dermatology, diabetes, immunology, oncology, and ophthalmology.

The EC approval for Hulio applied to all 28 EU countries as well as the European Economic Area member states of Norway, Iceland, and Liechtenstein.

In the United States, the field of adalimumab biosimilars has been growing steadily and now represents the largest group of biosimilars approved for a single drug. Only trastuzumab comes close, with 5 biosimilars approved and launched. There are currently 17 biosimilars available for use or commercialized in the United States.

AbbVie’s list of patents protecting Humira numbers over 100 and has represented a formidable obstacle to biosimilar developers seeking to bring competitor adalimumab products to market in the United States. This accounts for the 2023 launch dates, enabling AbbVie to continue capitalizing on having exclusive distribution rights in the United States for what has been the world’s most profitable drug. Humira notched 

Two recent studies of Hulio provided evidence that the drug is 

 to Humira for treating rheumatoid arthritis and confirmed the subcutaneous delivery method.

The FDA has approved Fujifilm Kyowa Kirin Biologics's Hulio adalimumab biosimilar, making it the sixth adalimumab biosimilar approved in the United States. However, none will be launched before 2023 because of the strength of AbbVie's exclusivity rights for Humira, the reference product. Hulio launched in Europe in 2018.

FDA Approves Adalimumab Biosimilar From Fujifilm Kyowa Kirin Biologics

Patients could save as much as 17% on out-of-pocket costs if they used biosimilars, but many obstacles make that difficult to achieve, noted Wayne Winegarden, PhD, director of the Center for Medical Economics and Innovation at the Pacific Research Institute, a conservative policy analysis group in California.

He believes that legislators have a lot of work to do to pull out the blocks and wedges that prevent full realization of biosimilar savings.

“Since biologic medicines are some of the most expensive drugs that are driving the affordability problem in the United States, biosimilar competition can meaningfully reduce these cost pressures and improve overall affordability,” he said in a recent interview with 

Market dynamics are differnent in Europe, where biosimilar discounts are 20% to 40% lower than in the United States, Winegarden said. That’s a lofty goal to aim for.

The IQVIA Institute for Human Data Science recently developed a 

 for biosimilar access achievement in the European Union. It showed which countries are ahead in getting biosimilars to patients and why. The country-by-country breakdown rated countries' biosimilar markets on sustainability, the degree to which drug prices have fallen since the introduction of biosimilars, the health of biosimilar competition, and potential for growth. Norway and Sweden and the United Kingdom were among the leading countries for biosimilar adoption, though none of these markets was perfect, according to the analysis. Poland was among the laggers, in part because it takes a year or longer before an approved biosimilar reaches market in that country.

"A lot of my recent research has been looking at biosimilars and specifically trying to quantify the amount of savings that are available, because we haven't had the market develop here the way you have seen biosimilars develop in Europe, nor the same way that you've seen generics developed to become 90% of market here," Winegarden 

The biosimilar savings available to Medicare could reach $6.2 billion to $10.5 billion based on Winegarden’s calculation of biosimilars representing 25% to 75% of prescriptions for 9 drug classes for which biosimilars have been approved. “Greater savings can be had if biosimilars reach a higher share and biosimilars are introduced in more drug classes,” he said.

One way to achieve this is to change the incentives that in some cases discourage the use of biosimilars. One thing that tends to happen is that formularies list the more expensive originator biologics as the preferred drug, and so patients must fail on these medications before lower-cost biosimilars can be employed.

He suggested, as a solution, the creation of a formulary tier specifically for lower-cost biosimilars with lower co-pays and coinsurance rates.

Under the current system, providers can actually lose money by prescribing the lower-cost drug, and this is a disincentive that needs to be remedied, Winegarden said. “Removing the disincentives discouraging the development of a healthy biosimilars market is essential for making this happen.”

 with Winegarden, visit managedhealthcare.com.

Wayne Winegarden, PhD, director of the Center for Medical Economics and Innovation, explains that misaligned incentives are preventing the United States from realizing full benefit from biosimilars.

Remove the Disincentives and Biosimilars Will Flourish, Policy Expert Says

 an attempt by Genentech to stop Amgen from selling a bevacizumab biosimilar (Mvasi) in the United States. The ruling was an affirmation of a district court’s earlier opinion affirming Amgen’s right to market the drug.

Genentech, which markets the reference drug Avastin, sought an injunction contending that Amgen had failed to provide adequate notice in advance of commercialization. However, the US Court of Appeals for the Federal Circuit sided with Amgen, saying the notice Amgen had provided was in accord with provisions of the Biologics Price Competition and Innovation Act (BPCIA).

Bevacizumab is a treatment used for colorectal, lung, glioblastoma, kidney, cervical, and ovarian cancers. Amgen began selling 

 following marketing authorization from the FDA in 

In July 2019, Genentech filed a motion to block the sale of the product. Under the BPCIA, biosimilar developers are required to provide at least 180 days’ notice of commercialization, which Amgen did provide in October 2017. Genentech contended that notice was inadequate because of subsequent changes made to Amgen’s Biologics License Application for marketing approval.

Those changes had to do with adding a manufacturing facility and drug labeling. Genentech contended the supplements to the application represented new and distinct applications.

Genentech contended the changes technically made Mvasi a different biological product under the BPCIA than the one that was the subject of the original notice of commercialization. Amgen should have filed a second notice of commercialization and waited another 180 days before commencing its sales effort, Genentech said.

In its disagreement with that argument, the district court had stated, “the fact that Mvasi was the subject of the original application approved by the FDA in September 2017 does not make it a different biological product than the Mvasi that was the subject of the supplements to the application approved by the FDA in December 2018 and June 2019.”

In its affirmation of that opinion, the higher court stated, “Genentech…had notice of Amgen’s intent to commercially market Mvasi as required…as early as October 6, 2017.”

The circuit court added clarity to the issue of whether supplements during the application process materially affect licensees’ obligations to update notices of  commercialization, noting that a “biosimilar applicant that has already provided Section 262(

)(8)(A) notice regarding its biological product need not provide another notice for each supplemental application concerning the same biological product.”

 in the United States during the first quarter of this year, and its share of the US market for bevacizumab is 33%, according to Amgen. Global sales of Avastin topped $7 billion last year, fueled by growth in China.

In upholding a lower court ruling, a federal circuit court has decided that Amgen gave enough notice prior to launching its bevacizumab biosimilar. The court decision has frustrated an attempt by Genentech to block sales of the product.

Higher Court Sides With Amgen in Mvasi Case

When Shruti Rastogi, MPharma, and her fellow investigators published a 

 suggesting that biosimilar filgrastims have a higher incidence of certain adverse events than the originator product, Neupogen, they immediately drew fire from 2 established experts on biosimilar development, Paul Cornes, MD, and Michael Muenzberg, MD, both of the Comparative Outcomes Group.

Cornes and Muenzberg found what they described as deep flaws in the methodology used by the investigators as well as the real-world database they relied on, VigiBase, which Cornes and Muenzberg said could not reliably be used to generate the type of conclusions reached by Rastogi and her fellow investigators.

The core problem, they said, was that the study unjustly portrays multiple filgrastim biosimilars as inferior to the originator product without a truly scientific examination of the data. They have asked the journal involved, 

, to at least print a balancing statement that would expose some of the concerns about the study’s validity.

In response to a query from The Center for Biosimilars

, Rastogi defended the findings as valid with a point-by-point response to the concerns identified by Cornes and Muenzberg and contended that the study was unbiased and should serve as a starting point for further studies to investigate the findings. The “authors have emphasized that this stimulating study is just a guide for further evaluation regarding safety and comparability of filgrastim originator and biosimilars,” Rastogi said. “We have no intention to discredit biosimilars use and bolster consumer loyalty to originator products.”

“Higher” Incidence of Adverse Reactions

Specifically, the study indicates that compared with Neupogen, the biosimilar filgrastim Grasin was associated with higher reporting of pyrexia (11.5% vs 7.9%), myalgia (37% vs 2.2%), and back pain (11.3% vs 4%). Zarzio was associated with higher reporting of arthralgia (4.5% vs 2.9%) and neutropenia (11.4% vs 4%), and Nivestim was associated with a higher incidence of bone pain (14.4% vs 8.3%). The study reports instances of ineffectiveness for the biosimilars Zarzio, Nivestim, and Tevagrastim, but not for Neupogen. Further details of the study are available 

Cornes and Muenzberg, both oncologists and investigators, have credentials. They have consulted for all of the companies involved with the originator product and biosimilars included in the study. Muenzberg is former medical director of EU biosimilars for Amgen, the company that developed and markets the reference product Neupogen. Cornes presented evidence to the FDA for the first approved US biosimilar.

One of their chief criticisms of the study is that it relies on comparisons made using the VigiBase adverse event database from the World Health Organization (WHO), which WHO specifies is appropriate for “generating but not for testing hypotheses” because the data it contains are subject to “reporting biases, duplication, confounding issues,” in which variables distort outcomes, and other problems.

Rastogi, lead author of the study and an assistant scientist at the Indian Pharmacopoeia Commission, contended the large pool of global information in the WHO database facilitated the detection of drug safety signals and increased “the probability of detecting rate adverse drug reactions.” She said similar studies have been done using global pharmacovigilance databases like VigiBase.

Cornes and Muenzberg also found fault with the study’s application of 

 numbers, which express statistical significance, to the percentage differences given for adverse events connected with biosimilars in the study. They said use of equivalence margins, which specify the range of acceptability or nonacceptability for biosimilarity to the originator product, are standard procedure for such comparative studies and would have provided meaningful results.  

numbers helped to determine potential adverse drug reaction associations between originator and biosimilars based on pharmacological hypotheses. “The authors have not drawn any conclusion based on 

 values,” she said. “In our study we were able to demonstrate that Zarzio exposure was significantly associated with a high reporting odds ratio (ROR) value (1.59) for arthralgia as compared to innovator with ROR (1.21) using VigiBase.”

Cornes and Muenzberg also contend that the investigators wrongly declared that there is a serious lack of real-world, postmarketing data on biosimilar safety. Cornes and Muenzberg said that 1500 patients have been enrolled in head-to-head randomized trials of the filgrastim biosimilars mentioned by Rastogi and her fellow investigators. Thousands more patients have been enrolled in postmarket safety studies of filgrastim biosimilars, they said.

Rastogi responded that biosimilar developers’ lack of access to manufacturing process data for the originator product creates a “high possibility” for minor structural differences in biosimilars that may “result in a product that differs in terms of pharmacological specifications, efficacy, and safety including immunogenicity influencing the product’s benefit-risk profile.” These differences may be missed by studies that demonstrate biosimilarity to the originator product, Rastogi said.

Rastogi further defended the integrity of the study, contending that it was subject to an extensive peer review by the journal 

. Cornes and Muenzberg contended the study would have flunked what they described as an appropriately rigorous peer review.

A final criticism from Cornes and Muenzberg was that in their study the investigators appeared to inappropriately lump together biosimilars with India-approved copy biologics, which are certified for use by a different set of standards. The authors’ analysis and conclusions appear to be derived from this combination of dissimilar drugs, Cornes and Muenzberg said. However, although the study makes mention of copy biologics, those were not a part of the final analysis and conclusions, Rastogi said.

Cornes and Muenzberg said that they are not “unsympathetic” to the need to generate additional data on the safety and efficacy of biosimilars, but they contend that the findings outlined in the study are “unsustainable” and contrast with existing data provided in Periodic Safety Update Reports, which are risk-benefit pharmacovigilance reports provided by biosimilar developers at intervals following marketing authorization, and these are relied upon by regulators in their continuing assessments of biosimilars.

The controversial aspects of the study have attracted notice. Julie

Maréchal, director of Biosimilar Policy and Science for Medicines for Europe, an equal access advocacy group, said that the accumulated evidence on biosimilars in the European Union has sufficiently demonstrated that these are safe medicines. “The European Biosimilar Medicines Group, a Medicines for Europe sector group, concurs with expert opinion expressed on the merits of the Rastogi et al paper. The facts and their interpretation do not fully match nor take account of important limitations. There is no question: EU-authorised biosimilar medicines have a proven safety track record,” Maréchal said.

In response to an inquiry from The Center for Biosimilars

, Pfizer commented that the study findings do not weaken its faith in its own filgrastim biosimilar, Nivestym. “We are confident in the safety and efficacy profile of our filgrastim biosimilar, and the comprehensive data package and totality of evidence which demonstrates a high degree of similarity of this medicine compared to its reference product.”

Amgen, which distributes Neupogen and could potentially benefit from the study owing to the conclusion that Neupogen is superior to its biosimilars based on adverse drug reactions, did not respond to a request for comment.

In the study, Rastogi and fellow investigators state that they had no conflicts of interest to report and that their funding source was not involved in study design or data collation, analysis, or interpretation.

Rastogi S, Shukla S, Sharma AK, et al. Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: trends from decades of data. 

. 2020;15(395):114976. doi:10.1016/j.taap.2020.114976

After a study from India suggested a higher incidence of adverse reactions in patients using biosimilar filgrastims, 2 European biosimilar consultants and oncologists raised objections to the study’s methodology.

Study of Neupogen vs Biosimilars Draws Fire

Fujifilm Kyowa Kirin Biologics said it has received Japanese regulatory 

 to manufacture and market the first adalimumab biosimilar in the island country.

The company said the approval was received June 29 for the product, which was identified as Hulio. It references AbbVie’s Humira.

The product is indicated for rheumatoid arthritis, psoriasis vulgaris, arthritic psoriasis, pustular psoriasis, ankylosing spondylitis, entero-behcet’s disease, Crohn disease, and polyarticular-course juvenile idiopathic arthritis.

Fujifilm Kyowa Kirin Biologics said it partnered with Mylan in 2018 to commercialize the product in Europe and expand sales across the globe. To date the product is available in 20 countries in Europe, and Fujifilm Kyowa Kirin Biologics is working to obtain marketing approvals in other countries.

"We are proud to be a leader by providing the first adalimumab biosimilar in Japan," said Atsushi Matsumoto, Fujifilm Kyowa Kirin Biologics president and CEO.

The biologics company was established by Fujifilm and Kyowa Kirin in 2012 for the purpose of developing, manufacturing, and marketing biosimilars. Its pipeline includes a biosimilar for the anti-VEGF humanized monoclonal antibody bevacizumab, which is used for colorectal and non—small cell lung cancers.

Biosimilar market growth in Japan has been described as slow but poised for growth. The biosimilar market in Japan grew by 25% a year from 2015 to 2017, which was slow compared with worldwide market growth of 72%, according to a McKinsey 

 last year. Although “in 2017 Japan’s biologics market accounted for 13% of the worldwide market, excluding the United States, its biosimilar market, valued at $140 million, accounted for just 5%,” the report said.

McKinsey explained that the Japanese co-pay system can make the originator product cheaper for patients than the biosimilar, which it said was the chief reason why biosimilars have not taken root at a faster pace in Japan. 

One of the most recent new launches in Japan in 2018 when Daiichi Sankyo began 

Japanese authorities have given marketing approval for the first adalimumab biosimilar in that country.

First Adalimumab Biosimilar Gains Approval in Japan

It is often stated that Europe is ahead of the United States in its acceptance of biosimilars, but each country in Europe is a separate market and differs in its own way on biosimilar success, based on local policies and practices.

In an ambitious attempt to understand how well each of these markets is bringing biosimilars to patients, the IQVIA Institute for Human Data Science developed a scorecard 

for rating countries on various measures of biosimilar success and came up with ratings-based profiles of 12 countries across the European zone.

The project was done in cooperation with Medicines for Europe, a trade industry association representing manufacturers of generic and biosimilar products.

For biosimilar aficionados in the United States, it may be the clearest look so far at how these countries—from Norway to Poland to the United Kingdom&mdash;compare with one another in their policies on biosimilar acceptance.

“The importance of biosimilar medicines’ role is greater than ever, and the systematic tracking of their contribution is a critical means for policymakers and stakeholders to measure progress and achievement of goals for patients and the entire health system,” said Murray Aitken, executive director of IQVIA.

The scorecard measures biosimilar penetration in each of the countries by using 3 basic measures: the amount of biosimilar competition, how far prices have fallen following the introduction of biosimilars, and the increase in overall use of the underlying drug (ie, infliximab), as opposed to reference drugs or biosimilars separately. Each country's evaluation includes a sustainability report that shows how well the biosimilar market is poised to grow and develop.

IQVIA has also produced a policy analysis for each of the 12 countries that presents a list of achievements, challenges, and measures that the countries could take to improve their biosimilar markets.

For example, the Netherlands has been one of the most successful countries at introducing biosimilars, according to the scorecard. For products spanning tumor necrosis factor inhibitors (anti-TNF), insulins, and drugs such as rituximab and trastuzumab, the country has high levels of competition between biosimilars and originator products.  

On sustainability measures, biosimilars in the Netherlands tend to reach the market very soon after European Medicines Agency (EMA) approval, and physicians are granted strong latitude in switching from reference products to biosimilars.

In its policy analysis for the Netherlands, IQVIA states that payers there recognize the value of biosimilars and incentivize hospitals to save money with biosimilars. Further, the market allows multiple biosimilar manufacturers to participate. The downside, IQVIA states, is that there are multiple biosimilar contracts, “with over 50 agreements in place being commonplace,” which leads to “fragmented” knowledge of these agents.

Poland, by contrast, has high levels of biosimilar competition. Prices have dropped by at least 50% for adalimumab and etanercept, and volume development, or additional access to the underlying drug, is greater than 25% in many cases, according to the IQVIA report.

On sustainability, Poland has done worse than the Netherlands. The average time to market following approval is 11 to 14 months, and literature and guidelines tend to discourage using biosimilars. Pharmacists are permitted to substitute biosimilars for reference products, but physicians may not switch patients from one biosimilar to another, according to the report.

Biosimilars have achieved widespread penetration in Poland, and there are healthy levels of competition, IQVIA said. On the negative side, there are reimbursement problems, and mandatory price cuts after patents expire make the Polish market unattractive for manufacturers of originator products.

The United Kingdom, according to the scorecard, has high levels of competition, prices have dropped significantly (30%-49%, mostly), and volume growth has sometimes exceeded 25%, although in some instances volume growth has been less than 5% (eg, insulin glargine, rituximab, trastuzumab).

Across multiple measures, the United Kingdom achieved very high marks for sustainability. Biosimilars reach market soon after EMA approval (0-5 months), guidelines and educational resources for physicians and patients are robust, and substitution policies are liberal. In addition, there are no mandatory price cuts imposed on originator products. IQVIA also noted that the market determines pricing rather than government-imposed reference price systems.

“A very clear policy with clear targets has been articulated by [the National Health Service] in favor of competition and encouraging use of best value biologic medicines,” IQVIA wrote about the UK system. However, IQVIA also wrote that uptake is variable depending on health trusts and region, and national targets for use of biosimilars “make it difficult for doctors to remain independent prescribers.”

Adrian van den Hoven, director general of Medicines for Europe, described the scorecard report as helpful for policy makers to develop sustainable markets for biologic medicines. “While the report shows that policy measures should be tailored to national contexts, it provides clear recommendations on how measures can be combined and adapted to deliver effective results,” he said.

Europe has many lessons about biosimilars for the United States; however, single-tender, or winner-take-all systems, which are common in Europe, tend to create an imbalance, according to a recent conference 

. The IQVIA report also mentions single-tender systems as being detrimental to a healthy, competitive market for biosimilars.

 A new scorecard system developed by IQVIA rates the health and sustainability of biosimilars markets across Europe.

IQVIA Rates European Countries on Biosimilar Market Health

Rituximab is a drug with efficacy for rheumatoid arthritis and other autoimmune diseases and its biosimilar form is catching on, thanks to a variety of factors, not the least of which is an effort by physicians to promote biosimilar use, Robert M. Rifkin, MD, a medical oncologist and hematologist with Rocky Mountain Cancer Centers in Denver, told The Center for Biosimilars

“We’re pushing hard, certainly in our network,” said Rifkin, whose practice is affiliated with The US Oncology Network, which includes 68 oncology practices across the United States. He is active in the development of biosimilars.

Biosimilars Put Downward Pressure on Prices

In the United States there are 2 rituximab biosimilars on the market. One is Truxima, which was launched in the United States late in 2019 and most recently won a prequalification 

 from the World Health Organization (WHO) for the treatment of diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and follicular lymphoma.

This raises the profile of the drug among physicians worldwide and encourages the use of this product. Truxima, which was developed by Celltrion Healthcare, became the second biosimilar after Ontruzant, a trastuzumab copy, to receive this WHO designation.

An additional rituximab biosimilar that adds to the downward pressure on prices and broadens treatment options for physicians is Pfizer’s Ruxience, which launched in January of this year. “It’s a competitive space, but clearly, what everybody is looking for is lower costs and increased access, which probably will be helped with the WHO’s recognition of Truxima,” Rifkin said.

On the physician side, when using biosimilars, it’s important to recognize that biosimilars may not have been FDA approved for all of the indications of the originator drug, so checking the label is important, Rifkin said. “The good news for Truxima is that they just got the rheumatoid arthritis indication.” This happened in early May. “So, that kind of levels the playing field.”

The US Oncology Network and group purchasing initiatives that Rifkin is involved with are helping to drive higher utilization of Truxima to achieve savings that can make a difference for patients. Patients may need to take this drug for long periods, particularly for treatment of rheumatoid arthritis, and knowing where to slot it in the treatment regimen is still a process of discovery, Rifkin said. “We’re putting it everywhere we can, up-front,” and the uptake numbers confirm that utilization is improving, he said.

Education on biosimilars helps. “I think our network is very well educated. We have a biosimilars toolkit that many of [The US Oncology Network] clinical staff members could look at if they wanted to and learn as much as they want about biosimilars.” Efforts are also made to ensure that all of the clinical data submitted for FDA approval are posted prominently for the health care workers and physicians so they can familiarize themselves with the evidence foundation for these products, Rifkin said.

With all of this work to support biosimilar adoption, uptake of these products is increasing slowly, but this pace is to be expected given that these are therapeutics rather than supportive-care products, Rifkin said.

That slow pace of acceptance and utilization is somewhat separate from the development pipeline. There are new biosimilar entrants in the pipeline for FDA and European regulatory approval, and growth like this is steadily increasing the number of biosimilars available to physicians or the medical community. There are already 5 trastuzumab biosimilars on the US market, 3 of which were launched in the first half of 2020, and Rifkin expects there to be more before the year closes out.

For physicians, this does complicate the process of choosing medications, he said, because contracts for use of these products are determined not at the provider level but higher up the supply chain and by payer organizations, and these are confusing to navigate.

“I think it’s going to be unrealistic to expect pharmacies, all of our big supply channels, and distributors to carry every single biosimilar. Certainly the originator [Herceptin] will remain there, and then I think various stakeholders will move toward the notion of a preferred biosimilar," he said.

“I really think you probably need to carry only a couple, because it’s going to get too confusing if I have 5 trastuzumabs on the shelf plus the originator. That’s a supply chain—stock issue, but more importantly, that increases the opportunity for mistakes,” he said.

As to whether payers are hearing the message that business-based restrictions on biosimilar use may complicate matters for physicians, Rifkin noted that it may be difficult to persuade a payer to grant flexibility in the use of one biosimilar over another if the preferred biosimilar is clearly a better financial deal. “A lot of the payers already have preplanned arrangements with manufacturers. We can remind them that we don’t want to carry 5 of the same biosimilars, but that may not have any effect,” he said.

The US Oncology Network is pushing to get more biosimilars into utilization, Robert M. Rifkin, MD, told The Center for Biosimilars® in an interview.
 

US Oncology's Rifkin Explains Rituximab Uptake

Celltrion Healthcare’s subcutaneous infliximab biosimilar (Remsima SC) has been recommended for approval for 5 new indications by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

Already indicated for rheumatoid arthritis in Europe (November 2019), Remsima SC has been recommended for marketing authorization for ankylosing spondylitis, Crohn disease, ulcerative colitis (UC), psoriatic arthritis, and psoriasis. The infliximab biosimilar is marketed as Inflectra in the United States.

Celltrion, based in Incheon, Republic of Korea, said the CHMP recommendations were supported by phase 1/3 studies that compared the pharmacokinetics, efficacy, and safety of the intravenous and SC formulations of Remsima in patients with Crohn disease and UC. CHMP has recommended a 120 mg dose of Remsima SC for the existing and additional 5 recommendations in adults regardless of body weight, based on the results.

Walter Reinisch, director of the Clinical IBD Study Group at Medical University of Vienna, Austria, said the SC formulation offers patients treatment flexibility during maintenance treatment with infliximab and “takes significantly less time than the current intravenous formulation, thereby reducing the time patients need to be in medical settings with infusion administrations.”

That observation takes on added significance against the backdrop of the coronavirus disease 2019 pandemic, he added, because patients “must take extra precautions and visit hospitals only when absolutely necessary.”  The SC formulation can be administered by patients without assistance from health care professionals.

The clinical studies that supported the CHMP recommendation involved randomization of patients to varied doses of the SC formulation or continued intravenous (IV) administration.

Following loading doses of IV 5 mg/kg received at weeks 0 and 2, patients were randomised at week 6 to receive either SC 120 mg (<80 kg) or 240 mg (≥80 kg) every 2 weeks in the SC arm, or they were continued on IV 5 mg/kg every 8 weeks in the IV arm. Starting from week 30, patients in the IV 5 mg/kg cohort were switched to SC 120 mg or 240 mg, according to body weight, Celltrion said in a 

The Crohn Disease Activity Index and partial Mayo scores for UC disease activity decreased over time in both arms until week 30. Comparable improvement was seen in the remaining IV patients switched to SC formulation starting at week 30 of the trial. Celltrion said rates of clinical response and remission at week 54 were maintained, and mucosal healing in Crohn disease and UC continued to improve. Serum concentrations were comparable and consistent up to week 54, and the overall safety profile was comparable between SC and IV arms.

Remsima has been on the market for 5 years and now is available in over 90 countries, the company said. “If approved by the EMA, Remsima will be the first infliximab to have both intravenous and subcutaneous formulations to treat patients with ankylosing spondylitis, Crohn disease, ulcerative colitis, psoriatic arthritis and psoriasis,” Hyoung-Ki Kim, vice chairman, said in the statement.

Through regulatory filings, Celltrion hopes to obtain patent protection for the SC formulation and dosage through 2037 and 2038, respectively, in the United States, Europe, and Asia.

Earlier this month, Celltrion announced that its infliximab product will be 

in the CATALYST trial for its potential in controling cytokine release syndrome, which occurs in patients with COVID-19.

Late last year, Celltrion reported that as of the third quarter of 2018 its infliximab biosimilar had achieved a 56% 

Based on clinical studies on dosing, efficacy, and pharmacokinetics, European authorities have recommended Celltrion's subcutaneous infliximab biosimilar (Remsima SC) for 5 new indications.