Deana Ferreri

Gastroenterologists generally are accepting of biosimilars for initiating therapy in patients who are biologics-naïve. However, they remain skeptical of switching patients to biosimilars if their disease is successfully managed with an originator biologic.This practice is called nonmedical switching, and it may be done to get patients on a less expensive form of the same therapy.

 of nonmedical-switching studies of patients with inflammatory bowel disease (IBD) has detailed the knowledge gaps and study limitations responsible for this hesitation by gastroenterologists.

The majority of studies thus far have suggested nonmedical switching from infliximab to its biosimilar CT-P13 (Inflectra; Remsima) is safe. Previous reviews have 

The systematic review identified 44 studies on switching patients from infliximab (Remicade), the first biologic marketed for use in IBD, to the biosimilar CT-P13; however, only 3 were randomized controlled trials (RCTs), only 1 of which has been published. Approximately half of the studies reviewed by the authors, most of which were observational and not intended to change treatment patterns, were not yet published.

The authors of the current review concede that “safety and efficacy of biosimilar use in infliximab-naïve patients is generally accepted,” but they advise caution on nonmedical switching because of study limitations that include the small number of RCTs compared with observational studies, lack of controls in observational studies, lack of long-term data, and a reliance on studies published at conferences for which key study design details are missing.

 by Frank I. Scott of the Crohn’s and Colitis Center at the University of Colorado Anschutz Medical Campus agrees that more research is needed before nonmedical switching can be widely adopted.

The review authors found shortcomings with the single published RCT, the 

, which studied a switch from originator infliximab to the biosimilar in 6 inflammatory diseases, including IBD. The study included the use of a composite measure of disease worsening across the same 6 heterogeneous inflammatory diseases, with different dosing regimens and concomitant therapies.

The authors also criticized the inclusion criteria for the trial as having “ill-defined disease-specific criteria,” which they said “introduces the potential for bias and limits the inferences that can be extrapolated to IBD.” Furthermore, they criticized the noninferiority margin, which they say could have demonstrated noninferiority even if up to 50% of the patients switched to CT-P13 experienced disease worsening, based on enrollment numbers.

Although the NOR-SWITCH trial demonstrated noninferiority and included patients with IBD, the data presented on ulcerative colitis and Crohn disease (CD) “did not allay” the concerns of gastroenterologists regarding switching their patients on infliximab to a biosimilar, according to the editorial. The review authors noted “the trend toward increased disease worsening in CD patients has caused some concern in the gastrointestinal community and a desire for more robust data in IBD patients.”

In an IBD subgroup open-label extension of NOR-SWITCH, stable switched patients stayed on CT-P13, and stable patients on infliximab switched to CT-P13. Efficacy, safety, and immunogenicity were similar between the groups; however, the authors of the systematic review said that “low enrollment numbers precluded conclusive implications to be drawn.”

The other 2 RCTs on nonmedical switching were conducted wholly on patients with IBD. In these trials, similar efficacy, safety, and immunogenicity were reported between groups. However, the authors of the systematic review caution that our understanding of the details of these studies is incomplete because they were presented at conferences and have yet to be published, a concern Scott echoes in his editorial.

The authors of the review acknowledge that, overall, the 21 published observational studies suggest that nonmedical switching from the infliximab originator to the biosimilar is safe, but they also note that study designs were heterogeneous and many lacked a control group. Loss of response and discontinuation rates also varied widely between studies. This variability in observational study design and results make it “difficult for broad generalizations regarding the safety and effectiveness of nonmedical [switching] to be made,” the authors noted, adding that observational studies have not had robust assessments for antidrug antibodies, leading to knowledge gaps regarding immunogenicity.

Mandatory switching to biosimilars to reduce health care costs and expand access to biologic therapies has been criticized by gastroenterologists, “who cite a lack of high-quality controlled trials to support such decisions in stable patients,” according to the review article. Several countries have instituted some measure of mandated switching to biosimilars, such as 

, and these policies have drawn criticism from 

. According to the editorial, “While nonmedical switching policies have been enacted, there has been incomplete pharmacovigilance reporting.”

Both the systematic review and accompanying editorial stress the need to ensure patient safety before cost reduction, as well as that future studies should address the knowledge gaps regarding long-term effectiveness and immunogenicity. They also recommend a greater reliance on published RCTs as opposed to those only available as conference abstracts.

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Although the totality of the evidence is reassuring, the jury is still out on nonmedical switching to biosimilars, according to new study results.
 

Gastroenterologists Want More Evidence on Nonmedical Switching

The main hurdle preventing biosimilars from coming to market is the primary patent on the originator product, not supplementary patents, according to a European 

. Investigators also found that product exclusivity extensions, which are customary in Europe, delay the market entry of competitor products.

A patent protects the intellectual property of pharmaceutical manufacturers, guaranteeing them market exclusivity for a set number of years to recoup their drug development costs. Pharmaceutical corporations routinely get secondary patents for tweaks to those drugs to extend their exclusivity, but the study of biosimilar litigation in Europe found that secondary patents were not sufficient to delay the market entry of biosimilars for 9 top-selling monoclonal antibodies.

“Except for 1 patent on trastuzumab where the decision to reject the patent was overturned in appeal, biosimilar developers have won all identified opposition and national patent litigation cases. This indicates that some patents on trastuzumab were seen as a real hurdle for biosimilar entry, but that biosimilar developers can challenge these patents and win,” the authors wrote.

In the United States, patents are often considered 

 barriers to biosimilar market entry, and the multiple patent filings over individual products are known as patent thickets. 

 on patent litigation have been sought to improve access to these lower-cost medicines. In Europe, the authors of this new study suggest, some patent barriers may be more illusory than real.

The drugs in the study received the standard 20-year European patent protection, and much of that time elapsed before development and approval stages were complete and the products could be brought to market. Many of the drugs received 5-year exclusivity extensions through the award of a supplementary protection certificate (SPC); in some cases, extensions were awarded to encourage the development of pediatric medicine.

In total, the drugs studied had market exclusivity for between 10 and 17 years, which the study authors described as “rather large” but consistent with European guidance that innovators “should be able to enjoy an overall maximum of 15 years of exclusivity” after marketing authorization is received.

Innovators sought to extend that exclusivity by patenting variations on the formulation, new dosage regimens, routes of administration, and combination therapies. They also sought to protect their markets by developing next-generation products related to the patented antibody.

The study authors analyzed patent filings and legal challenges from biosimilar developers to determine how basic patents, patent extensions, and secondary patents affected market entry for biosimilars. They provided detailed case studies of 3 monoclonal antibodies used for to treat cancer: trastuzumab (Herceptin), bevacizumab (Avastin), and cetuximab (Erbitux).

They found that the developers of each reference product filed for multiple patents after receipt of their original product patent; however, in most cases, the secondary patents were either not upheld by the European Patent Office or successfully challenged by competitors in court.

The European Medicines Agency has approved more than 50 biosimilars since 2005, with the first monoclonal antibody biosimilars approved in 2013. The study authors noted biosimilar developers face “substantial hurdles arising from patents taken after the basic patent,” but they said those hurdles are “surmountable, given that many cases were observed to have been won by biosimilar developers and agreements were made to settle ongoing cases.” In some cases, rather than litigate, the biosimilar developers were able to “invent around” a patent.

The authors also found patents on new formulations were not an effective protection strategy; they noted that these secondary patents often are ruled invalid because they are not “inventive.” They noted that AbbVie filed a patent for a formulation of Humira with less injection pain but that this patent was later revoked.

Patenting of a new administration route is a desirable strategy for an innovator seeking to retain market share, they wrote. For example, an agent becomes more convenient for patients if a subcutaneous route for a previously intravenously delivered drug becomes available. The authors add that this path is also open to developers of biosimilars. Celltrion received European market authorization for a subcutaneous formulation of its infliximab biosimilar (Remsima) in 2019. Biosimilars developers may also take advantage of new techniques for production of the antibody, which may be patentable.

A new dosage regimen may be patentable if it provides “unexpected advantages” over previous regimens. Biosimilar developers may have the option to leave the patented dosage regimen out of the label of the biosimilar, but they prefer to use a dosage regimen consistent with that of the reference product, according to the authors. At the basic patent expiration of adalimumab (Humira) in 2017, there were still 2 dose regimen patents active. However, biosimilar developers eventually gained market entry in 2018 following litigation.

The authors concluded that in Europe, secondary patents have not been the major barrier for biosimilars; instead, “the key protection instruments are the basic patent and the additional protection provided by the award of an SPC with possible pediatric extension, which provide for an average effective market protection of the innovator product of 15 years.”

Additionally, in cases where biosimilars were not available until several years after patent expiration, the authors attributed some of this delay to the complexity of development and manufacturing, not the patent strategies of the developers of the originator biologics.

Moorkens E, Vulto AG, Huys I. An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry? 

. 2020;12(1):1743517. doi: 10.1080/19420862.2020.1743517.

European investigators say their analysis of court cases involving innovator monoclonal antibodies suggests secondary patents have generally failed to stop biosimilar competition.

In Europe, Secondary Patents Can't Stop Biosimilars, Study Says

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.

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

Deana Ferreri

Gastroenterologists Want More Evidence on Nonmedical Switching

In Europe, Secondary Patents Can't Stop Biosimilars, Study Says

Patient Awareness of Biosimilars Is Poor in Australia, Study Says