Deana Ferreri, PhD

an adalimumab biosimilar (Idacio), an arthritis product, in Germany a year ago, has demonstrated that its proposed pegfilgrastim biosimilar (MSB11455) has similar safety and immunogenicity profiles to the reference product (Neulasta).

Pegfilgrastim is the long-acting form of filgrastim, a recombinant human granulocyte colony&#8208;stimulating factor (G&#8208;CSF). It is administered to patients undergoing myelosuppressive chemotherapy to reduce the risk of developing febrile neutropenia, a serious adverse effect of chemotherapy characterized by a high body temperature and low neutrophil count. Additionally, this condition can force patients to reduce the dose of chemotherapy or discontinue it entirely. 

G-CSF is a hematopoietic growth factor that stimulates proliferation, differentiation, and activation of neutrophils. The use of filgrastim or pegfilgrastim reduces the risk of febrile neutropenia, which improves the likelihood of patients completing chemotherapy.

Fresenius Kabi is headquartered in Germany and last year announced the 

 of its biosimilar activities in a new center in Eysins, Switzerland, where the company hopes to conduct biosimilar research in immunology and oncology. The company also has a tocilizumab biosimilar, for rheumatoid arthritis, in its development pipeline.

Biosimilars to pegfilgrastim have previously been approved and launched, such as Sandoz’s Ziextenzo in the 

. According to a recent conference abstract from Sandoz, the use of pegfilgrastim biosimilars has the potential to prevent more cases of febrile neutropenia by 

 to patients who are not generally treated (those at intermediate risk for febrile neutropenia) because of the high cost of the reference product.

There is potential for any biologic drug to provoke an immunogenic response, and immunogenicity is a major concern regarding biosimilars, because the “ability to stimulate antibody formation can differ between structurally closely related molecules, with even minor changes affecting immunogenicity,” as stated by the authors. The development of antidrug antibodies (ADAs) can negatively affect the therapeutic action of the drug or predispose the patient to adverse reactions.

Because pegfilgrastim is a recombinant human protein, immunogenicity is particularly concerning, because ADAs could cross-react with the endogenous human protein and interfere with the function of that protein in the body.

Analytical similarity and pharmacokinetic and pharmacodynamic 

 have previously been demonstrated for the proposed pegfilgrastim biosimilar, and the current study was designed to evaluate immunogenicity and safety in healthy volunteers compared with the reference product.

Safety and Immunogenicity of the Proposed Biosimilar 

The immunogenicity results demonstrated noninferiority of MSB11455 based on the prespecified margins. Treatment-induced ADA-positive rates were 8.9% in the MSB11455 group and 9.5% in the reference product group.

Most ADAs were specific to the polyethylene glycol (PEG) portion of pegfilgrastim rather than filgrastim. No filgrastim-specific neutralizing antibodies were reported, but 3 patients in the MSB11455 group and 1 in the reference product group had at least 1 sample with pegfilgrastim-neutralizing activity. The authors noted that “no relevant differences in ADA characteristics such as onset, titer, and specificity were found between the treatment groups.”

Safety and tolerability were similar between groups. Most patients (99.4%) in each group experienced some treatment-emergent adverse event (TEAE); the most common were headache and bone pain, which are known adverse effects of pegfilgrastim. Just 1 patient of the 168 in the MSB11455 group and 2 of 168 in the Neulasta group experienced a serious TEAE.

There were no significant differences in the pattern of TEAEs reported for ADA-positive subjects compared with ADA-negative patients, and similar TEAE frequency was found in anti-PEG positive patients between groups. The results provide support for the biosimilarity of the proposed biosimilar MSB11455 to pegfilgrastim, investigators concluded.

Articles

Fresenius Kabi’s pegfilgrastim biosimilar candidate has demonstrated a similar safety and immunogenicity profile to the reference product (Neulasta).

Fresenius Kabi Pegfilgrastim Shows Matching Safety, Immunogenicity

Choosing appropriate clinical end points and analysis procedures is essential to both establish clinical equivalence of biosimilars and convince physicians and patients that the agents are worthy of use. In a recent study, investigators use the HERITAGE study to argue for a more accurate system for measuring biosimilar equivalence.

There has been much discussion of moving away from hazard ratios (HRs), which measure risk of disease progression or death events between regimens or drugs, toward an analysis known as restricted mean survival time (RMST), which directly compares the number of these events over specified time intervals.

The authors of the study propose that RMST would provide more meaningful and interpretable information than HR.

The authors noted that studies of anticancer drugs typically use a time-to-event indicator, such as progression-free survival (PFS) or overall survival (OS), as the primary measure of efficacy. However, studies assessing clinical equivalence of biosimilars to those reference products instead use the overall response rate (ORR) at a specific time point, an HR-based measure.

The study details the authors’ analysis of reconstructed OS and PFS data from the HERITAGE trial using RMST.

 assessed equivalence of a trastuzumab biosimilar plus taxane compared with the reference product plus taxane in 458 patients with metastatic breast cancer. The primary end point was 24-week ORR, and disease events and deaths were recorded through 48 weeks. The authors reanalyzed the data on disease progression events and deaths as PFS and OS using RMST.

In the original study, there were nonsignificant differences in disease progression events and deaths between groups. However, the CIs, according to the authors of the new study, were quite wide, leading them to doubt that there were no true differences between groups. “For PFS, the hazard from the biosimilar group might be 28% higher than that from the reference product,” they wrote. “Consequently, even if the biosimilar product is approved by the regulatory agencies, clinicians and patients may not be convinced to adopt the biosimilar as an alternative to the reference product.”

Reanalyzing using RMST, the time to disease progression or death was 38.8 weeks in the biosimilar group compared with 37.5 weeks for the reference product, a difference of 1.3 (95% CI, −1.3 to 3.8) weeks. The RMST difference for OS between the biosimilar and reference product was 0.7&thinsp;(95% CI, −0.7 to 2.1) weeks. For the biosimilar, these findings demonstrate maximum differences in PFS and OS of just 10.1% and 5%, respectively, both reasonably-sized CIs, according to the authors.

“Unlike the results from the hazard ratio, these time-scaled small differences in OS and PFS…provide a clinically meaningful way to evaluate whether the biosimilar is clinically equivalent to trastuzumab over a 48-week time window,” the authors wrote.

The authors asserted that expressing the results as the number of weeks before a progression event in each group is more easily interpretable than describing the percent difference in events as a function of time using HR.

The authors explained that the use of HR requires an assumption that each group being compared has a constant rate of events over time.

However, in oncology biosimilar equivalence trials, the rate is not necessarily constant; the number of disease progression events or deaths during the study period is often limited. RMST, on the other hand, requires no assumption of a constant rate.

Furthermore, the precision of HRs, the authors said, depends on the number of events rather than the duration of the study, meaning that sufficiently precise HRs to determine clinical equivalence in many cases will require an unreasonably large sample size, and a longer study does not necessarily mean more precision.

RMST requires no assumption of proportional hazards (constant rates of events). With a time-to-event measure such as RMST, a change in the rate of events over time will not violate the underlying assumptions of the model.

The authors concluded that RMST-based methods “provide a clinically interpretable between-group difference with feasible study size and study duration compared with the HR-based approach.”

Finally, they suggest the use of RMST-based methods for postmarket surveillance, because “for most current biosimilar trials, one may argue that the patients’ exposure times might be too short to assess PFS and OS and long-term safety.”

Uno H, Schrag D, Kim DH, et al. Assessing clinical equivalence in oncology biosimilar trials with time-to-event outcomes. 

. 2019;3(4):pkz058. doi:10.1093/jncics/pkz058

Investigators use the HERITAGE trial findings to argue for a more precise way of measuring clinical equivalence for biosimilars.

Investigators Propose Different Measures for Biosimilar Equivalence

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.

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.
 

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.