Deana Ferreri, PhD

When it comes to product launches and approvals, Australia and the United States are roughly equal in terms of the maturity of their biosimilars markets. A recent study revealed another similarity: Despite a national initiative to make the Australian public more aware of biosimilars, Australian patients may have very low familiarity with biosimilar therapy.  

Investigators did a single-clinic study (N = 132) of patients with rheumatoid arthritis (RA) during the 2017 period when the etanercept biosimilar (SB4, Brenzys) became the first biosimilar medicine for RA in Australia.

“The proportion of our cohort who were familiar with biosimilar therapy was very low (6%); this result matched the 9% to 11% biosimilar awareness levels among patients with inflammatory conditions in the United States and Europe,” the investigators wrote.

However, the same study revealed that more than three-quarters of patients with RA were open to using biosimilars if recommended by their rheumatologist.

The authors noted that Australia’s national, single payer system spends approximately US $1.4 billion yearly on biologics and it has been estimated that widespread use of biosimilars could potentially reduce that by up to 24%. The Australian Department of Health launched a 

in 2015 to educate prescribers, pharmacists, and patients on the benefits of biosimilars. Australia is encouraging the use of biosimilars, aiming to expand patient access to biologics.

In May 2019, Australia's Generic Biosimilar Medicines Association furthered this effort by launching an educational 

 on biosimilars for prescribers, pharmacists, and patients.

The etanercept biosimilar became available for dispensing through community pharmacies in 

. The investigators conducted the study “prior to any significant prescribing of biosimilars” with the goal of understanding the perception of biosimilars by patients not yet familiar with these drugs. Patients with RA who visited a clinic in an Australian tertiary hospital between August 2017 and February 2018 were invited to participate.

Although there has been much investigation into physician awareness, knowledge, and attitudes regarding biosimilars, the authors say the patient perspective has been less studied, particularly in Australia. They noted patient acceptance is important for widespread adoption of biosimilars, citing inadequate patient acceptance as a leading factor inhibiting switching from originator to biosimilar in European rheumatology studies.

Each patient in the Australian study was asked about their awareness and potential acceptance of biosimilars before being shown a visual aid explaining the concept of biosimilars, after which biosimilar acceptance was assessed again.

Although just 6% of patients surveyed were familiar with biosimilars, prior to education, 77% reported they would accept a biosimilar if it were recommended by their rheumatologist.

Other international studies have shown high acceptance rates (Germany, 70%; France, 89%) when biosimilars were first introduced in those countries. Just 5% of patients in the Australian study said they would refuse a biosimilar. Another 18% were unsure, but 50% said they wanted to know more about biosimilars after seeing the visual aid.

The investigators also found that patients who routinely refuse generics were significantly more likely to refuse biosimilars.

Among those who said they would refuse a biosimilar, 57% were concerned about efficacy, and 14% were concerned about safety. Among those who would accept biosimilars, approximately 12% to 15% reported concerns about efficacy, safety, operating a new injection device or changing medicines.

Overall, only 25% of patients were concerned about pharmacy-level substitution without consulting the prescriber. In Australia, pharmacists are allowed to substitute a biosimilar for the reference biologic unless the prescriber explicitly 

 it. Some Canadian provinces have implemented automatic 

 of biosimilars for reference biologics. In the United States, many states have considered or implemented policies allowing pharmacists to switch to biosimilars unless the physician has indicated otherwise.  

The investigators said the low awareness in Australia “identifies a need to improve Australian patient awareness of biosimilars.”

However, “this study demonstrates a high baseline patient acceptance of biosimilar concept  despite being initially unfamiliar and highlights the impact of patients’ trust in their rheumatologist,” they concluded.

The investigators cautioned the study was conducted with the patients of a single clinic where the majority of patients were satisfied with their treatment. They concede the same level of patient trust might not be found in other settings.

Kovitwanichkanont T, Raghunath S, Wang D, et al. Who is afraid of biosimilars? Openness to biosimilars in an Australian cohort of patients with rheumatoid arthritis. 

. 2020;50(3):374—377. doi:10.1111/imj.14753.

Articles

Patients in an Australian clinic were generally open to using biosimilars but knew little about them, according to a recent study.
 

Patient Awareness of Biosimilars Is Poor in Australia, Study Says

Inflammatory bowel diseases (IBD), which include Crohn disease (CD) and ulcerative colitis (UC), are increasing in prevalence, and although biosimilars are available for treatment of these diseases and represent huge potential savings, there is lingering unwillingness to switch to these medications, 

“As the era of biosimilars is presently unavoidable, gaining a better understanding of biosimilars, especially for near future applications, is a crucial requirement in the field of therapeutics,” the authors said.

The authors noted safety and efficacy studies and pharmacokinetic studies that have demonstrated equivalency of biosimilar infliximab CT-P13 (Inflectra, Remsima) to the originator, Remicade.

They said more studies are underway that could help to confirm the long-term efficacy and safety of biosimilars and help to “clarify ongoing debates regarding several unresolved or partially resolved extrapolations, switching, and the immunogenicity of biosimilars.”

Prospective studies assessing CT-P13 alone in patients with CD and UC have shown strongly positive outcomes. A study noted by the authors (N = 78) demonstrated clinical remission in 79% of patients with CD and 56% in patience with UC after 14 weeks.

In a separate study of the efficacy of CT-P13 induction therapy on mucosal healing in patients with UC (N  = 63), cumulative clinical response and steroid-free remission at week 14 were achieved in 82.5% and 47.4% of patients, respectively; mucosal healing was detected in 47.6% of patients, and complete mucosal healing was found in 27% of patients.

In the NOR-SWITCH study (N = 482) of switching from the originator to the biosimilar CT-P13, patients with CD, UC, ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis. Disease worsening across all indications was observed in 26% of patients on originator infliximab and 30% of patients in the CT-P13 group. The frequency of adverse events was 10% in the reference group and 9% in the CT-P13 group. These findings led investigators to conclude that switching from the originator drug to CT-P13 was not inferior to continued treatment with the originator.

Despite such findings, there was a divergence in international consensus. The European Crohn’s disease and Colitis Organization recommended the use of biosimilars and confirmed that switching from the originals to biosimilars is acceptable, but only after discussion with stakeholders, including patients, nurses and pharmacists. The American Gastroenterological Association recommended that prescribing physicians should avoid nonmedical switching from originals to biosimilars.

With respect to immunogenicity studies, the authors cited an in vitro study that demonstrated that the antibodies that developed against originator infliximab during previous exposure to the drug were cross-reactive with CT-P13. “This important finding suggests that similar immunogenicity and immunodominant epitopes are shared between these infliximab agents [originator and biosimilar],” the authors wrote.

Especially for IBD, biosimilars have the potential to reduce costs. In Norway, CT-P13 achieved savings of 51% to 65% compared with originator infliximab; in France, the discount is 45%, and in Japan, the current price of CTP13 is 67% lower than that of originator infliximab, the authors wrote. “Thus, the magnitude of price reduction may be important for switching prescriptions to biosimilars.”

Another survey suggested that 83% of physicians in the United States would prescribe biosimilars if they were 25% cheaper. It also found a bias against switching among US providers.  

Acceptance by physicians has increased as biosimilars are more widely used to treat IBD and more research has been published, according to the authors. They cite surveys of European physicians: In 2013, only 6% of physicians viewed biosimilars as interchangeable with their reference products. By 2015 that had increased to 44%. In 2013, 76% of physicians were opposed to extrapolation from other indications, which decreased to 33% in 2015.  In 2013, 63% had little or no little or no confidence in biosimilars, which decreased to 20% in 2015.

There remain areas that need further investigation. The authors note there is a lack of scientific and clinical evidence when it comes to 

, multiple switching, and cross-switching between biosimilars in patients with IBD.

The authors recommend long-term safety monitoring of biosimilars in IBD with post-marketing observational studies.

Looking to the future, the authors anticipate new evidence for IBD biosimilars. Besides CT-P13, additional infliximab biosimilars have been approved by FDA or EMA, and additional infliximab and adalimumab biosimilars are in preclinical testing and clinical trials. Cost reductions from biosimilars, the authors argue, will allow for the treatment of more patients with IBD and provide funds to educate patients and 

 on biosimilars, leading to increased adoption of biosimilars for further cost reductions. To achieve this, a better understanding of biosimilars from more research is necessary to address physician and patient concerns about extrapolations, switching, and immunogenicity concerns.

Park SH, Park JC, Lukas M, Kolar M, Loftus EV. Biosimilars: Concept, current status, and future perspectives in inflammatory bowel diseases. 

. 2020;18(1):34-44. doi: 10.5217/ir.2019.09147.

In inflammatory bowel diseases (IBD), biosimilars have been available for roughly 5 years, but more evidence may be necessary to persuade medical community to increase usage, according to a study.
 

Report: Biosimilars Are Underutilized in IBD

Clinicians and investigators should be aware of how they can improve pharmacovigilance for biosimilars, according to a report by investigators in India who stress the complexity and temperature sensitivity of biosimilars.

“Biosimilars have a large size, complex structure, and complicated manufacturing process, and they are produced in a living organism,” which means they require specialized delivery devices and tighter temperature controls to prevent degradation, according to the authors.

Biosimilars require more extensive pharmacovigilance measures than generics and at least the same level of pharmacovigilance as their reference products, they add. They also recommend that pharmacovigilance studies and monitoring should continue for as long as a biosimilar is on the market, because the makeup of patient populations may change and drug consistency is liable to vary over time.

Proper Reporting and Risk Management Are Essential

“A good pharmacovigilance practice requires reporting to regulatory authorities all types of suspected reactions, suspected drug-to-drug or drug-to-food interactions, adverse drug reactions [ADRs] associated with drug withdrawal, medication errors or overdose, and lack of efficacy,” the authors wrote. Periodic safety update reports and risk management plans should also be part of a comprehensive pharmacovigilance program, they said.

Although biosimilar manufacturing may be efficient and safe, the passage from plant to clinic to patient involves variables that can affect quality of the agent. Patent issues also may affect the type of delivery devices that can be used.

Further, “As the active drug is delivered by the device and is in constant contact with the device, the device can play an important part in the delivered volume and quality of the drug it delivers. Hence, safety of the device delivery system is of utmost importance for biosimilars,” the authors wrote.

The most important environmental parameter is temperature, they said. “Pharmacovigilance should cover this area, which generally goes unnoticed until a problem, such as lack of efficacy or immunogenicity, is detected.” The authors recommend pharmacovigilance with respect to temperature should extend to transportation and storage conditions.

India Has a Longer Experience With Biosimilars

Biosimilars have a longer history in India compared with Europe, where the first biosimilar was marketed in 2000 for hepatitis B, and the United States, which approved its first biosimilar in 2015.

The multistep manufacturing process for biosimilars is prone to variations that affect the final drug, including immunogenicity, a major safety concern associated with biosimilars. “The manufacturing process of biosimilars is known to affect the level of process-related impurities and posttranslational modifications of the product.”

Biosimilars are administered via injection, rather than orally, as generics are, which raises issues of safety and adherence concerning the delivery device. The authors suggest tracking device manufacturing and evaluating factors such as ease of use, which could affect patient adherence.

The authors note that rare adverse events usually are seen when large numbers of patients are using a biosimilar. Therefore, biosimilars require postmarketing vigilance, and perhaps postapproval studies, to assist in the identification of previously unknown adverse drug reactions and to better assess the risks and benefits of a drug.  

Adequate pharmacovigilance requires specialized and experienced personnel (as for originator biologics) because of the complexity of safety data and difficulty detecting adverse events. The authors recommend these individuals also regularly search the literature for individual case reports that may be relevant.

How to Put Together a Pharmacovigilance Effort

India, Europe, and the United States each require periodic reports on the safety of biosimilars in the years following market authorization. The authors recommend connecting reported ADRs with specific batches of the biosimilar for comparison with the reference product and documenting patient history with the reference product when assessing immunogenicity or lack of efficacy.

The authors note that a thorough pharmacovigilance program for a biosimilar should include postauthorization safety and efficacy studies, and they said pharmaceutical companies are generally more willing to take these steps than to perform additional testing or larger pre-approval studies that could delay initial approval. Postapproval studies, they note, bolster confidence in prescribers.

“The actual hesitation is in conducting large and multiple preapproval studies, as they carry a nonapproval risk,” they wrote.

Furthermore, they hold that pharmacovigilance should continue as long as a product is on the market, as the risk-benefit ratio at the time of approval is likely to change due to use by a larger patient base with different characteristics than the clinical study population, longer exposure by patients, and potential structural changes to the molecule.

Additional recommendations included using a standard format for prescribing information and regularly updating the prescribing guidelines for the biosimilar, as new safety concerns can arise when the patient population is expanded. They said clinicians should be given latitude to collect blood samples from patients they suspect are having an immunogenic reaction or when there are other quality concerns with a biosimilar.

Oza B, Radhakrishna S, Pipalava P, Jose V. Pharmacovigilance of biosimilars - why is it different from generics and innovator biologics? 

. 2019;65(4):227-232. doi: 10.4103/jpgm.JPGM_109_19.

So many factors have the potential to affect the quality and performance of biosimilars that clinicians must be aware of the need for constant pharmacovigilance.

Why Pharmacovigilance Is Important for Biosimilars

Physicians and patients worldwide have been slow to use biosimilars, despite clinical trials demonstrating that approved biosimilars are as safe and effective as the reference versions. A recent literature review by Canadian investigators has concluded that, in many countries, a far more systematic effort is required to achieve widespread adoption of biosimilars in clinical practice.

“We [observed] a lack of systematic description of implementation design and evaluation and a paucity of in-depth and engaged research to understand stakeholders’ pragmatic considerations and the knowledge, messages, and meanings that shape clinician and patient decisions to choose biosimilars,” the authors write.

 is about to greatly expand, with 13 biologic drugs losing market exclusivity by 2022. In the Canadian province of British Columbia, a forced switching policy was adopted in 2019 that requires patients in the public health system to use biosimilars for rheumatology and diabetes instead of reference products. The Alberta and Ontario provincial governments both have decided to implement forced biosimilar switching policies.

The authors of the current study conclude that, wherever biosimilars are available, adoption rates may be poor without concurrent education and clear understanding of the clinical environments in which these agents would be prescribed.  

The reluctance of physicians and patients to choose biosimilars is widely documented. However, according to the authors, missing from the literature is “implementation science,” evidence on how to transition biosimilars to routine care. In the United States, for example, past investigation has demonstrated a significant need for evidence-based education on biosimilars in the areas of understanding bioequivalence and differentiating between biologics and biosimilars, the authors note.

Acceptance of an innovation into regular clinical practice requires stakeholders to change behaviors or adopt new technologies. Investigators used a diffusion-of-innovations model to examine factors and processes influencing the spread and sustained use of innovations in healthcare.

The authors note that adoption of biosimilars has improved in Scotland and the United Kingdom because of educational measures, but in Germany and Belgium, where biosimilars are available but there is no systematic educational effort, physicians generally prescribe reference products for first-line therapy.

The authors recommend encouraging use of biosimilars at the start of treatment, citing studies on the reluctance of patients to switch from an originator biologic once they are enjoying favorable results. In addition, “when the clinical stakes are high due to the debilitating nature of the illness being treated, there is more anxiety about change,” the authors write.

Regulatory agencies have taken steps to promote biosimilar use. The FDA’s Biosimilar Action Plan, for example, facilitated data sharing with regulatory agencies from other countries to accelerate the approval process for biosimilars already approved in Europe. Both the FDA and the European Medicines Agency (EMA) have provided resources for prescribers on the evidence supporting equivalence of biosimilars to address 

However, few physician organizations and patient advocacy groups, which are influential for prescribers, promote biosimilar use. The authors of the review cite this as a significant problem. Getting physicians to apply new knowledge into clinical practice requires them to receive persuasive information from many sources: practice guidelines from medical authorities, clinical studies, colleagues and opinion leaders, conferences and continuing education, marketing, experience, and patient preferences.

The advantages of biosimilars are clear when looking at their clinical equivalence to reference products and lower cost. “The advantages of biosimilars versus biologics are less clear when considering adopters’ beliefs and values surrounding care. In Germany and Belgium, where biosimilars are accessible, physicians choose a biologic over a biosimilar for first-line therapy and prioritize treatment efficacy over cost-effectiveness,” the authors write.

They note that the potential for experimentation with biosimilars without risk is limited and this could be a challenge for adoption.

 to biosimilars, which they warn does not change ingrained attitudes. Norway mandated automatic switching from infliximab to 1 of 2 biosimilars, with little effect on the market share of the biosimilars.

Subsequently, Norway launched a campaign involving stakeholders and providing education on biosimilars and adjustment of pricing, a more successful strategy that resulted in the 2 approved biosimilars reaching a majority market share.

Khan D, Luig T, Mosher D, Campbell-Scherer D. Lessons from international experience with biosimilar implementation: an application of the diffusion of innovations model. 

. 2020;15(3):16-27. doi: 10.12927/hcpol.2020.26133.

A gentle, persuasive effort to get patients and physicians to adopt biosimilars is likely to work better than a heavy-handed approach, say Canadian investigators, who recommend more study of how mindsets and prescribing practices are changed.

Investigators Recommend a More Systematic Effort to Get Biosimilars Adopted

The clinical equivalence of a biosimilar to its reference product may be demonstrated by a great deal of evidence, yet physicians, particularly oncologists, still may be hesitant to prescribe biosimilars. Authors of a review article in the 

 argue it is important for prescribers to understand how the biosimilars approval process differs from that of reference products—and why.

Oncologists may be unfamiliar with the regulatory process for biosimilars because the use of monoclonal antibody biosimilars for cancer treatment is relatively new. For example, the earliest approval of a trastuzumab biosimilar was in 2017 (Ogivri). Authors state that oncologists may be more comfortable using supportive care biosimilars.

A major point of confusion may be the role of the comparative clinical efficacy and safety study, the authors said. The aim of a comparative clinical study is to demonstrate there are no clinically meaningful differences between the biosimilar and the originator based on prespecified margins. An analysis of safety and immunogenicity is also central to this process. Rather than being the major piece of evidence demonstrating biosimilarity, the comparative clinical study plays a confirmatory role.

The comparative clinical efficacy and safety study in at least 1 relevant indication of the originator is typically the last step in the process of demonstrating equivalence of a biosimilar to its reference product. The authors describe the data from the comparative clinical study as just a fraction of the data needed by regulators for an approval application. Most data are derived from analytical testing, nonclinical in vivo studies (when required), and a pharmacokinetic and pharmacodynamic comparison study in healthy participants.

What may not be sufficiently recognized or understood, according to the authors, is that the analytical methods are generally more sensitive for detecting potential differences between a biosimilar and its reference product than a clinical study.

In fact, regulatory agencies do not require comparative clinical studies under all circumstances. The requirement for and scope of the clinical studies depends on the degree of uncertainty of biosimilarity based on analytical and other previous testing.

“For granulocyte colony-stimulating factor, for example, structure, physicochemical characteristics, and biologic activity can be well characterized, and clinically relevant PD parameters are available…. For many biosimilar mAbs; however, the absence of robust PD efficacy measures, as well as their importance to clinical outcome, means that comparative clinical trials will likely remain necessary,” the authors wrote.

Physicians may also be wary of extrapolating results of a clinical study in one indication to another. However, once biosimilarity has been demonstrated in 1 indication, conducting studies in other indications is often not warranted for scientific, cost, and ethical reasons, the authors said. 

Another question the review addresses is whether testing requirements for biosimilars are excessive. They note that no biosimilar that was found to be highly similar to the reference product via the use of analytical and pharmacokinetic in-human studies ever failed to gain approval because it failed an efficacy study for equivalence.

They discuss a number of factors that could influence the need for comparative clinical studies, including complexity of the reference product, differences in structure, and level of understanding of the mechanism of action.

However, the authors propose that for many biosimilar monoclonal antibodies, comparative clinical studies will remain necessary, due to the lack of robust measures of pharmacodynamic efficacy and the importance of these measures to clinical outcomes. They expect this will likely be especially true in oncology, where biosimilars could be used with “curative intent,” making the assessment of comparative clinical data a priority for prescribers.

Stebbing J, Mainwaring PN, Curigliano G, et al. Understanding the role of comparative clinical studies in the development of oncology biosimilars [published online February 14, 2020]. 

A review article contends that providers need to know more about the approval process for biosimilars and what data points are examined.

Biosimilar Reviews Assess Similarity, Not Benefit

A secondary analysis of a randomized controlled trial investigating low-dose methotrexate in patients at risk of cardiovascular events has provided estimates of risk for adverse events (AEs), some infrequent but serious, such as hepatic, pulmonary, hematologic toxicity, and skin cancer.

Low-dose methotrexate is a first-line therapy for 

 (RA) and is commonly used in other rheumatic diseases. The use of low-dose methotrexate in RA dates back more than 30 years, but despite these decades of clinical use, data on adverse effects has come mostly from observational studies rather than randomized controlled trials, the authors say. AEs identified by observational studies of patients with rheumatic diseases taking low-dose methotrexate include liver toxicity, gastrointestinal upset, pulmonary AEs, increased incidence of any cancer, melanoma, lung cancer, and non-Hodgkin lymphoma. However, these observational data have been limited by lack of a placebo group.

To address this knowledge gap, AEs of interest were monitored for and blindly adjudicated in the current trial (Cardiovascular Inflammation Reduction Trial; CIRT). Participants were randomized to low-dose methotrexate (maximum 20 mg/week; median dose 15 mg/week) or placebo, and both groups received 1 mg/day folic acid, 6 days/week.

Over the median follow-up period of 23 months, 87.0% of participants in the low-dose methotrexate group experienced any AE of interest, compared to 81.5% in the placebo group; the relative risk of AEs of interest in the methotrexate group was 17% higher than the placebo group.

Although the rate of renal AEs was lower by 15% in the methotrexate group, other AEs were higher. Skin cancer doubled and gastrointestinal AEs rose 23%. Infectious AEs rose 15%, pulmonary AEs rose 42%, and hematologic AEs rose 22%.

In an accompanying editorial, Vivian P. Bykerk, MD, of the Hospital for Special Surgery and Weill Cornell Medical College, states that the authors of this safety analysis should be commended for establishing these estimates of AE risk, which can be used to improve monitoring of patients using methotrexate.

Both the author of the editorial and those of the trial acknowledge the question of whether these data are generalizable to patients with RA. However, in the editorial Bykerk notes the rates of AEs were similar to previous estimates based on observational studies.

Over the decades of low-dose methotrexate use for RA, new and advanced therapies have been developed for RA and other forms of inflammatory arthritis. Today, patients with intolerable or potentially serious side effects are able to discontinue treatment with methotrexate and switch to another therapy; in fact, as stated in the editorial, approximately 30% of these patients use biologics without methotrexate, according to registry data.

According to Bykerk, this is the first well-powered, placebo-controlled trial of low-dose methotrexate designed to provide accurate estimates of serious AEs, providing valuable information that can improve monitoring of patients on methotrexate going forward.

Solomon DH, Glynn RJ, Karlson EW, et al. Adverse effects of low-dose methotrexate: a randomized trial [published online February 18, 2020]. 

Bykerk VP. A call to systematically monitor for adverse events in users of low-dose methotrexate therapy [published online February 18, 2020]. 

The use of low-dose methotrexate in rheumatoid arthritis dates back more than 30 years, but despite these decades of clinical use, data on adverse effects have come mostly from observational studies rather than randomized controlled trials (RCTs), the authors say.

Editorial Calls for Monitoring of Low-Dose Methotrexate Users for Adverse Events in Light of New RCT Data 

The year 2019 brought new evidence supporting nonmedical switching from infliximab (Remicade) and etanercept (Enbrel) to biosimilars (CT-P13 and SB4, respectively) for inflammatory arthritis, plus research suggesting using positive messages with patients improves willingness to switch to biosimilars.

In a year-in-review article published in 

 author Jonathan Kay of UMass Memorial Medical Center and the University of Massachusetts Medical School outlines studies published in last year on nonmedical switching from originator biologics to biosimilars in rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis.

In 2019, results were published from the 26-week open-label extension of the 

 which had previously established similar efficacy and safety upon nonmedical switching from infliximab to biosimilar CT-P13 in 2017. In the extension of the trial, patients from the infliximab group were switched to CT-P13, and patients who had switched to CT-P13 remained on the biosimilar. Similar proportions of patients in the 2 groups experienced disease activity worsening. Rates of adverse events, infusion reactions, and antidrug antibodies were also similar, providing additional evidence supporting nonmedical switching from infliximab to its biosimilar CT-P13.

Real-world evidence for etanercept biosimilar SB4

In 2016, Denmark mandated etanercept be replaced with its lower-cost biosimilar SB4 in most patients with rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis. An observational cohort study published in 2019 revealed the real-world effects of this 

  There were no differences in disease activity comparing the 3 months before and after the switch, a smaller proportion of switched patients withdrew from treatment compared to those who remained on etanercept, and 1-year adjusted retention rates were similar. Reasons for switching back to etanercept were mainly subjective, and according to Kay, some switches back to the originator were likely due to the nocebo effect.

Communicating with patients about biosimilars

Also published in 2019 was a randomized controlled trial in New Zealand in which patients being treated with originator biologics received 1 of 4 video explanations on biosimilars, 2 with positive messaging and 2 negative. Those participants who saw a positively framed message were more than twice as willing to switch to a biosimilar and thought the biosimilar would be more effective compared to those who saw negative messages.

Kay also notes the previously published BIO-SPAN study, in which staff were instructed to inform patients of cost savings and lower rate of injection site reactions associated with SB4; they were also trained to discuss the nocebo effect with patients. In that study, 99% of patients who were asked to switch to SB4 were willing to switch.

 from healthcare providers shape their expectations, emphasizing the potential benefits of biosimilars may increase willingness to switch, reduce failure due to the nocebo effect, and improve medication persistence.

Kay J. Overcoming barriers to biosimilars in inflammatory arthritis. 

. 2020;16(2):65—66. doi:10.1038/s41584-019-0359-7

Goll GL, Jørgensen KK, Sexton J, et al. Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: open-label extension of the NOR-SWITCH trial. 

. 2019;285(6):653—669. doi:10.1111/joim.12880

Glintborg B, Loft AG, Omerovic E, et al. To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry. 

. 2019;78(2):192—200. doi:10.1136/annrheumdis-2018-213474

Gasteiger C, Jones ASK, Kleinstäuber M, et al. The effects of message framing on patients' perceptions and willingness to change to a biosimilar in a hypothetical drug switch [published online ahead of print, 2019 Jun 24]. 

. 2019;10.1002/acr.24012. doi:10.1002/acr.24012

Tweehuysen L, Huiskes VJB, van den Bemt BJF, et al. Open-Label, Non-Mandatory Transitioning From Originator Etanercept to Biosimilar SB4: Six-Month Results From a Controlled Cohort Study. 

. 2018;70(9):1408—1418. doi:10.1002/art.4051

A recent year-in-review article outlines studies published in 2019 about nonmedical switching from originator biologics to biosimilars in rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis.

2019 Saw Mounting Evidence to Support Nonmedical Switching, Review Article Says

 discusses the data relevant to inflammatory bowel disease on biosimilars for anti-tumor necrosis factor (anti-TNF) inhibitors and urges physicians to consider anti-TNF biosimilars for patients with IBD.

The use of originator infliximab (Remicade), the first anti-TNF biologic approved in 1998, and additional anti-TNF drugs was found to improve outcomes and reduce the requirement for surgical interventions in patients with IBD compared to previous therapies. As a result, anti-TNF drugs are now the major drugs utilized for moderate to severe cases of ulcerative colitis (UC) and Crohn disease (CD), collectively known as IBD. These chronic, relapsing inflammatory conditions of the gastrointestinal tract compromise quality of life in patients and account for substantial healthcare expenditures. The proportion of patients with IBD is projected to increase, leading to increased costs.

Because of the high cost of biologics, the authors recognized a need to provide access to evidence-based information on biosimilars for healthcare providers working with patients with IBD.

The most widely studied biosimilar in IBD is the infliximab biosimilar CT-P13 (Remsima), approved in 2013 in Europe and 2016 in the United States. The authors note the strengths of the evidence demonstrating equivalence, in particular a 

 on patients with CD that used a stricter equivalence margin than that required by regulatory agencies.

The authors acknowledge that in one switch study, the evidence on CD slightly favored remaining on the originator; furthermore, in a non-inferiority trial differences in effectiveness and immunogenicity between groups did not reach statistical significance but could potentially be clinically significant. However, they contend the evidence overall from 

 supports the safety and effectiveness of a 

Extrapolation of evidence from other indications

European Union patents on adalimumab expired in October 2018, and thus far, according to the authors, there have been no studies published on adalimumab biosimilars in patients with IBD.

They acknowledge physicians and patients may have concerns about biosimilars that have been investigated only in conditions other than IBD. They note that regulatory agencies encourage extrapolation to other conditions; regardless of the particular illness, the drug has the same mechanism of binding TNF-alpha, and therefore, the authors say, extrapolation is reasonable.

Physician and patient acceptance of biosimilars

The authors’ suggest physicians take an evidence-based approach to biosimilars, taking into account the cost savings, the regulatory process, the amount of evidence required for a biosimilar to gain approval, and the published evidence on effectiveness and safety of the biosimilar before preferentially prescribing the reference product.

Finally, the authors recognize that strategies to address patient concerns and prevent failures due to the 

 are needed. Initial management of the patient’s expectations by physicians, nurses, pharmacists, and other providers, is essential to minimize the nocebo effect.

Al Sulais E, AlAmeel T. Biosimilars to antitumor necrosis factor agents in inflammatory bowel disease [published online January 10, 2020]. 

Because of the high cost of biologics, the authors recognized a need to provide access to evidence-based information on biosimilars for healthcare providers working with patients with inflammatory bowel disease. 

Evidence Supports the Use of Anti-TNF Biosimilars for IBD, Review Says

A crossover study comparing autoinjector and pre-filled syringe delivery methods of etanercept biosimilar SB4 showed bioequivalent pharmacokinetic parameters and similar safety profiles following a single administration in healthy men.

SB4, the etanercept biosimilar from Samsung Bioepis, which is sold as Benepali in European countries, was 

 for all indications of its originator (Enbrel). Switch studies have suggested that SB4 is similar in safety and effectiveness in patients 

According to the authors, previous studies demonstrating equivalence of SB4 to etanercept in pharmacokinetics and safety have used pre-filled syringes. However, these devices may be difficult for some patients to use if they have reduced hand dexterity due to the challenges of living with rheumatoid arthritis.

Autoinjector pens can provide an improved injection experience for these patients, resulting in better medication adherence. The authors also note that SB4 autoinjectors have demonstrated ease of use compared to originator etanercept in previous surveys of patients, nurses, and rheumatologists.   

This phase 1, open-label, single-dose crossover study measured pharmacokinetics following a single dose of SB4 in 44 healthy men in The Netherlands. Participants were assigned to 1 of 2 sequences, in which they received a single 50 mg dose of SB4 via autoinjector or pre-filled syringe, followed by a 14-day washout period, and then a single dose via the other delivery method.

Mean values of the primary pharmacokinetic endpoints (area under the concentration-time curve from time zero to infinity (AUCinf), time zero to the last quantifiable concentration (AUClast), and maximum serum concentration (Cmax)) were similar between delivery methods. The ratios of autoinjector to pre-filled syringe methods for these pharmacokinetic factors for all fell within the pre-defined equivalence range of 80-125%. Comparing pharmacokinetic parameters in subgroups by body weight, the effect of body weight on pharmacokinetics also appeared similar between both delivery methods.

Autoinjector delivery was well tolerated, although treatment-associated adverse events were somewhat (64.0% of participants compared to 46.7% in the pre-filled syringe group). The most common adverse events overall were headache, oropharyngeal pain, pruritus, neutropenia, and rhinitis, and no serious adverse events occurred. Additionally, there were no severe injection site reactions for either delivery method.

Shin D, Kim Y, Go A, Velinova M. Comparison of the pharmacokinetics, safety, and tolerability of the autoinjector (AI) and pre-filled syringe (PFS) of SB4 in healthy subjects [published online January 8, 2020]. 

Previous studies demonstrating equivalence of SB4 to etanercept in pharmacokinetics and safety have used pre-filled syringes, but these devices may be difficult for some patients to use if they have reduced hand dexterity due to the challenges of living with rheumatoid arthritis.

Study Finds Similar Pharmacokinetics, Safety of SB4 in 2 Self-Delivery Methods

Biologics currently make up half of the pharmacological market for oncology, but the steep cost of these drugs is a barrier to access. By 2023, patents on nearly 20 oncology biologics will expire, which could lead to more biosimilars in cancer care and therefore reduced costs, according to a review article.

Data supporting the effectiveness and safety of biosimilars has accumulated since 2003, when the European Medicines Agency (EMA) launched its biosimilar regulatory and approval process. The FDA began regulating biosimilars in 2009. Both EMA and FDA approve biosimilars demonstrated to have no clinically meaningful differences in purity, safety, and efficacy compared to their respective reference products.

Nonetheless, biosimilars are not identical to their reference products, which has slowed acceptance by physicians and patients. The authors cite previous research suggesting a lack of understanding of and familiarity with biosimilars among oncologists. The authors also note no biosimilar has been approved by the FDA as 

Immunogenicity is a major concern of physicians familiar with biosimilars. The authors acknowledge small changes in the structure of the biologic or a different route of administration could increase the risk of adverse events. They stress the importance of pharmacovigilance and collection of long-term safety data of approved biosimilars to improve physician confidence in biosimilars.

The authors discuss the biologics for which biosimilars are currently approved as treatment or supportive care of cancer in Europe and/or the United States. As of the date 

first published last fall, the authors said:

A rituximab biosimilar was the first oncology biosimilar approved in Europe. There are now 6 approved in Europe and 2 in the United States.

The patent on trastuzumab (Herceptin) expired in Europe in 2014. The EMA approved the first trastuzumab biosimilar in 2017 and 4 more in 2018.

FDA approved biosimilars to bevacizumab in 2017, as did EMA in 2018. The US patent on bevacizumab (Avastin) expired in 2019.

Nine filgrastim biosimilars have been approved in Europe since 2008 and 2 in the United States.

There are 5 pefgilgrastrim biosimilars approved In Europe and 2 in the United States.

Five epoetin biosimilars have been approved in Europe and 1 in the United States.

The authors stress the need to educate physicians and patients about the safety and efficacy of biosimilars and collect long-term safety data to improve their acceptance and promote their use in routine cancer treatment.

Konstantinidou S, Papaspiliou A, Kokkotou E. Current and future roles of biosimilars in oncology practice. 

. 2020;19(1):45—51. doi:10.3892/ol.2019.11105.

By 2023, patents on nearly 20 oncology biologics will expire, which could lead to more biosimilars in cancer care and therefore reduced costs, according to a review article.