Deana Ferreri, PhD

Trastuzumab biosimilars are available in intravenous (IV) but not subcutaneous (SC) form, and although the SC form of originator trastuzumab is often preferred, IV biosimilars may offer the better deal from the standpoints of cost and convenience, investigators concluded in a recent review of trastuzumab options.

“It is therefore important for health care providers to consider the potential benefits of IV trastuzumab biosimilars (eg, lack of need for additional injections) and whether they outweigh the benefits associated with SC administration, as well as to consider patient preferences,” the authors wrote. The review outlined the current options available for trastuzumab therapy to aid decision-making by health care providers.

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), is used to treat HER2-positive breast cancer and metastatic gastric cancer. According to the authors, combined with chemotherapy, biologics including trastuzumab “have emerged as paradigm-shifting treatments for patients with HER2-positive breast cancer, significantly improving patient outcomes and survival rates.”

The IV formulation of trastuzumab was approved by the FDA in 1998. An SC formulation was approved (for HER2-positive breast cancer only) by the European Medicines Agency in 2013 and FDA in 2019.

The reviewers noted a drawback of trastuzumab, as with other biologics, is its high cost. Since patent expirations in the European Union and United States, multiple trastuzumab biosimilars have been approved in these 2 regions, all formulated for IV use only. The patent on the SC formulation is set to expire in 2030 in the United States, precluding the availability of biosimilars using the SC route of administration for almost a decade.

Comparable pharmacological and clinical parameters

The authors noted that several studies have investigated the dose of SC trastuzumab required to produce similar pharmacokinetic parameters and serum trough concentrations to the IV formulation and that several studies have compared the efficacy and safety of IV vs SC trastuzumab. Collectively, according to the authors, these studies demonstrate that the IV and SC formulations have “generally comparable pharmacological and clinical profiles” in patients with HER2-positive breast cancer.

However, they acknowledged some questions do remain. The authors said the effect of body weight on the efficacy of each of the 2 formulations might “require additional evaluation.” Additionally, they noted that one study found twice as many patients taking the SC formulation compared with the IV form (6.8% vs 3.4%) developed antidrug antibodies. They also cited 2 trials that evaluated switching between the formulations. In one trial, adverse events (AEs) were similar in patients switched from SC to IV or IV to SC adjuvant therapy for HER2-positive early breast cancer. In a similar study of patients with metastatic breast cancer, there were more AEs in patients during the SC treatment compared with the IV treatment (67.6% vs 44.1%).

Each formulation may offer “unique advantages to patients depending on their individual needs,” the reviewers wrote. They noted the potential for pain at the injection site associated with the SC formulation, due to the large (5 mL) injection volume, and recommended health care providers discuss this with their patients.

The authors suggested that for patients receiving trastuzumab as monotherapy, SC administration could be a time-saving option in that it requires only 2 to 5 minutes vs 30 to 90 minutes for IV administration.

They concluded that as an adjuvant therapy, the SC formulation probably does not present an advantage in time or convenience to the patient, because trastuzumab would likely be combined with another IV therapy, and in many cases, the patient would have a central venous port in place. Therefore, IV administration could be more convenient for these patients, avoiding an additional injection. Contrary to this practicality, the patients in the 2 formulation-switching studies the authors cited overwhelmingly preferred SC administration (88.9% and 85.9%) over IV administration.

The authors cited 2 time-and-motion studies, 1 in the United Kingdom and 1 in Belgium. Both found higher costs associated with IV treatment compared with SC treatment. Based on the United Kingdom study, the authors estimated that over a full treatment course (18 cycles), SC trastuzumab would cost approximately $2826 less per patient. The authors noted limitations in both studies; in particular, they did not consider the cost of insertion, maintenance, and potential complications associated with IV catheters.

The authors argued that the discussion of cost savings associated with the SC administration route compared with the IV route “have predominantly overlooked the possible cost benefits of IV trastuzumab biosimilars.” However, patent expirations for the trastuzumab reference product were recent (European Union, 2014; United States, 2019), and therefore, they wrote, this limits “a comprehensive assessment of economic benefits.”

A budget impact analysis the authors cited estimated potential cost savings associated with trastuzumab biosimilars in 28 European countries, estimating cost savings between $1.1 billion and $2.74 billion during the first 5 years, and an additional 55,000 to 116,000 patients able to access trastuzumab therapy.

Trastuzumab biosimilars could improve access by giving physicians a lower-cost option to prescribe. According to the authors’ review of the literature, health care providers may be hesitant to prescribe biologics, despite their efficacy, because of their high cost. They cited a 2014 survey that found “nearly half of oncologists would increase the prescription of anti-HER2 biologics across multiple settings if a lower-cost biosimilar was available.”

The reviewers viewed IV trastuzumab biosimilars as having more potential for cost savings compared with the SC formulation of the reference product. “Given the general reduction in cost associated with the introduction of a biosimilar to the market, it is unlikely that the reduced administration costs associated with the SC formulation of trastuzumab will outweigh the lower cost of IV biosimilars,” they wrote.

Waller CF, Möbius J, Fuentes-Alburo A. Intravenous and subcutaneous formulations of trastuzumab, and trastuzumab biosimilars: implications for clinical practice. 

. Published online February 16, 2021. doi:10.1038/s41416-020-01255-z

Articles

In a review of trastuzumab treatment options, reviewers concluded subcutaneous (SC) vs intravenous (IV) options may be more costly and sometimes less practical. 

Study: Trastuzumab Biosimilar IV Offers Better Value Than Reference SC

Increased availability of biosimilars for treatment of rheumatoid arthritis (RA) is expected to result in greater access for patients and earlier treatment in the disease cycle, leading to increased risk of immunosuppression and an increased risk of infection. Therefore, the authors of a review of available evidence argue, it is important to better understand the management of RA to mitigate the risk of overtreatment with tumor necrosis factor (TNF) inhibitors and immunosuppression.

“While the contemporary clinical treatment goal is to achieve remission, the ideal immunological treatment goal is to achieve an immune homeostasis, such that the immune system can respond dynamically and appropriately to the environment,” the authors wrote.

Based on their review of literature from the past 6 years, the authors concluded that it is important to consider comorbidities when making treatment decisions for patients with RA. Not just infection risk but also cardiovascular disease and cancer risks are increased in patients with RA. Both the immune dysfunction associated with RA and medications used to treat RA may affect risk of these conditions, they wrote.

The authorization of biologics targeting TNF more than 20 years ago dramatically improved treatment options, but the 

 limited access for many patients prior to the availability of less expensive biosimilars, the authors wrote. As treatment options expand, information on comorbidities could support the assessment of benefits and risks of each therapy.

The authors cited reports indicating the most common comorbidities in patients with RA are depression, asthma, cardiovascular events, solid-organ malignancies, and chronic obstructive pulmonary disease. They focused on cardiovascular disease (CVD), infections, and malignancies because these conditions “may lead to an increased risk of mortality” and “are also impacted by at least 1 of the therapeutic options currently available for the treatment of RA.”

The authors discussed studies that revealed elevated risks of heart failure, myocardial infarction, stroke, and coronary artery calcification and other conditions in patients with RA compared with control populations.

The elevated CVD risk associated with RA is thought to be due to a combination of traditional CVD risk factors, systemic inflammation associated with the RA disease process, and potentially adverse events from RA medications. The prevalence of CVD risk factors, such as smoking, hypertension, diabetes, hyperlipidemia, and obesity, is often higher among patients with RA compared with the general population, the authors noted, and current recommendations support CVD risk management as part of the overall clinical management of patients with RA.

According to the authors, the available evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) “should be used with caution” in patients with CVD or related risk factors, and the dose of glucocorticoids (GCs) should be minimized for prolonged use, as these treatments have been linked to increased risk of CVD in patients with RA.

On the other hand, they cited evidence suggesting inhibition of TNF offers risk reduction, as chronic inflammation can be a signal of the body’s attempt to control cardiovascular disease. Anti-TNF biologics used to treat RA include infliximab, adalimumab, and etanercept. Methotrexate also is associated with reduced risk of CVD in patients with RA.

Regarding newer drug classes, the interleukin-6 inhibitor tocilizumab has raised concerns over elevated lipid levels, although an increase in clinical risk has not been shown. The authors cited a small number of studies that have suggested tocilizumab or abatacept (which inhibits T-cell activation) may have cardiovascular advantages compared with anti-TNF biologics. This possible disconnect between lipids and cardiovascular risk “remains to be fully elucidated,” according to the authors.

Patients with RA are at increased risk of serious infections and infections overall. The authors discussed literature suggesting 3% to 8% of patients with RA experience infections, the most frequent being infections of the respiratory or urinary tracts, tuberculosis, and sepsis.

Like CVD, the increased infection risk in patients with RA is thought to be dependent on a number of factors, attributed to a combination of the immune dysregulation associated with RA, immunocompromising comorbidities, and immunosuppressive therapy. Additionally, they said, “there is evidence suggesting that the inflammatory processes underlying RA may also drive the development of infections,” as numerous studies have linked disease activity to risk of infection.

For GCs, the authors said, the “benefit-to-risk ratio of this treatment remains precarious,” as increasing susceptibility to serious infections and associated mortality associated with these drugs is “supported by numerous studies.”

For conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, the evidence suggests no increased risk for serious infection or serious infection-associated mortality, according to the authors.

Biologics overall are associated with an increased risk of infection compared with csDMARDs, and the association may be dose-dependent; however, the authors said, there is conflicting evidence. For example, the duration of biologic use in one study was associated with increased risk of serious infection, whereas another showed decreased risk of sepsis and lower mortality risk with biologics compared with csDMARDs.

Anti-TNF biologics in particular are associated with an increased risk of infection in patients with RA, the authors wrote, “although the magnitude of this risk is a topic of debate.” Whether any specific TNF inhibitor differs from another in serious infection risk remains unclear based on the authors’ review of the research. The authors said limited evidence suggests that patients treated with TNF inhibitors vs other biologics may have an increased risk of hospitalization due to infections compared with those treated with abatacept.

GC, csDMARD, and biologic therapies have been linked to reactivation of hepatitis B virus (HBV) infection. As such, there is a boxed warning regarding HBV reactivation in the prescribing information for rituximab, a monoclonal antibody targeting CD20 used to treat lymphoma and RA. The authors noted that medical organizations recommend screening for HBV prior to initiating immunosuppressive therapies or vaccinating patients with rheumatic diseases against HBV.

According to the authors’ review of literature, targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), including recently introduced Janus kinase (JAK) inhibitors, as of yet “have an unclear association with infection risk.” Existing data suggest a link between JAK inhibitor use and herpes zoster (HZ) infection and “support the HZ vaccination of patients with RA, particularly if patients are to receive JAK inhibitors,” they wrote.

There are limited data regarding any increased risk of 

 outcomes associated with RA therapies; however, the authors discussed early studies suggesting a lower risk of hospitalization associated with TNF inhibitors and a greater risk associated with GCs compared with other treatments.

Patients with RA have increased risk of developing lymphoma. Although the relationship is not fully clear, the authors wrote there is “strong evidence that the inflammatory processes underlying RA may also drive the development of lymphoma.”

The authors noted there is “no compelling evidence” suggesting an association between the csDMARD methotrexate and an increased risk of lymphoma in patients with RA.

They discussed the black box warning issued by the FDA in 2009 for the risk of non-Hodgkin lymphoma associated with TNF inhibitors. This warning, according to the authors, was based on limited data, and newer data have called these earlier observations into question, as “a recent overview of systematic reviews and meta-analyses of malignancy risk with TNF inhibitors noted no increase in lymphoma risk in patients with RA.”

Patients with RA also appear to be at greater risk of nonmelanoma skin cancer compared with the general population. Anti-TNF therapy is associated in particular with squamous cell carcinoma, and “further studies are required to explore the factors that underlie this increase.” The authors advised that “regular skin examination is desirable for patients with RA treated with TNF inhibitors.”

Optimizing Benefit-to-Risk Ratio of Treatments

The authors concluded that ”dysregulated systemic inflammatory responses” are associated with the development of comorbidities in RA. Responsibly managing RA, they said, requires weighing the potential contribution of each treatment option with comorbidities and risks.

With TNF inhibitors in particular, the authors argued, the risks of overtreatment must be weighed against the potential cardiovascular benefits. This is especially important because access to biosimilars is expected to rapidly lead to wider use of these agents. Conversely, the improved access and lower costs associated with biosimilars could also lead to earlier initiation of treatment, which the authors suggested could improve control of systemic inflammation, leading to prevention of cardiovascular complications in patients with RA.

To mitigate the risk associated with overtreatment and immunosuppression, the authors advised that “for those patients achieving prolonged and sustained disease remission, step-down approaches may be appropriate.” They added that “a shared decision-making approach will be critical” to responsibly managing RA.

Taylor PC, Atzeni F, Balsa A, Gossec L, Müller-Ladner U, Pope J. The key comorbidities in patients with rheumatoid arthritis: a narrative review. 

. 2021;10(3):509. doi:10.3390/jcm10030509

Biosimilar availability will expand treatment of rheumatoid arthritis (RA) to more patients and earlier disease settings, so it's important to understand the potential complications. 

Study: Increasing Biosimilar Use in RA Requires Greater Disease Management Knowledge

An 80-week observational study of 144 patients with inflammatory bowel disease (IBD) switched from the reference infliximab to biosimilar SB2 found no “medically meaningful” changes in indicators of effectiveness or safety.

Until the start of the study, the patients had been treated with the infliximab originator (Remicade), a monoclonal antibody to tumor necrosis factor alpha (TNF) used for over 20 years to treat IBD. It was the first biologic approved to treat IBD in the United States and Europe. The biosimilar SB2 (Renflexis, Flixabi) was approved by the European Medicines Agency (EMA) in 2016 and the FDA in 2017.

According to the researchers, data on SB2 in patients with IBD are scarce compared with those on CT-P13, the first infliximab biosimilar approved by the FDA in 2016. They found only 2 previous reports on 

, both from the same cohort of patients in Italy.

The observational study followed 94 patients with Crohn disease (CD) and 50 with ulcerative colitis (UC) at an outpatient IBD clinic in Germany. Each patient, following counseling with a physician, underwent a non-medical switch from the reference product to SB2. Outcome measures, including disease activity, C-reactive protein (CRP) levels, and adverse events, were recorded at 24, 48, and 72 weeks.

Disease activity, as measured by Harvey-Bradshaw Index (HBI) in CD and partial Mayo Score (pMS) in UC, remained consistent throughout the SB2 treatment period, the authors said. The mean change from baseline to 72 weeks was -0.4 (2.0) in HBI and 0.1 (1.3) in pMS.

At baseline 69% of patients were in clinical remission, and at week 80, 74% were in clinical remission. At baseline, 21% had mild activity and 10% had moderate activity, compared with 17% and 9% at week 80. No patients had severe activity at baseline or week 80.

Median CRP levels “remained within the normal threshold,” throughout the study period, according to the researchers. Median CRP levels were 2.2 mg/L (interquartile range[IQR], 0.9-5.6) at baseline, 2.3 (IQR, 0.9-7.2) at week 24, 2.3 (IQR, 1.0-7.1) at week 48, and 2.7 (IQR, 0.9-6.1) at week 72.

The authors wrote that “a consistent proportion of patients” were within the therapeutic range of infliximab trough level (TL) of 3-7 µg/ml throughout the study, with 28% in the therapeutic range at baseline, 35% at week 24, 32% at week 48, and 35% at week 72.

At baseline, anti-drug antibodies (ADAs) were detected in 11 patients (9.8%). According to the researchers, the rate of development of ADAs during SB2 treatment was “low and not outside the expected range.” After the switch to SB2, transient ADAs were detected in 3.6% of patients, and persistent ADAs were detected in 6.3% of patients. The authors wrote, “these findings are in line with published data that showed cross-reactivity of ADA to originator infliximab and the biosimilars CT-P13 and SB2 in IBD patients, suggesting full-interchangeability regarding immunogenicity.”

Overall, 27.8% of patients experienced adverse events (AEs), and 7.6% experienced serious AEs during SB2 treatment. The non-severe AEs included infections, abscesses, newly occurring fistulae, infusion reactions, and new-onset rheumatoid or dermatologic diseases. Among serious AEs, 4 malignancies were diagnosed, 4 patients with CD required surgery, 1 patient developed a liver abscess, and another was hospitalized for a severe bronchopulmonary infection.

The authors said the rate of discontinuation in their study (29.2%) was similar to that reported in the previous study they cited of SB2 in patients with IBD (26.1%). Discontinuation due to clinical secondary loss of response occurred in 13.9% of patients, which the authors said was “within the expected range.”Discontinuation due to serious AEs occurred in 6.3% of patients, persistent infusion reactions in 2.8%, and infectious complications in 3.5%. One patient paused treatment due to remission.

The authors concluded their data on effectiveness and safety of SB2 were “in line with the available results for switching procedures from originator infliximab to the biosimilar CT-P13” and called switching to SB2 “a feasible option” for patients with IBD.

They described their study as significant because it is “the first long-term data over an 18-month follow-up period” on effectiveness, safety, and immunogenicity of a switch from the reference product to SB2 in patients with IBD.

They acknowledged that, as an observational study in a real-life setting, there was no control group remaining on the reference product. Other limitations they noted were that endoscopic evaluation was not possible and fecal calprotectin could not be assessed.

Fischer S, Cohnen S, Klenske E, et al. Long-term effectiveness, safety and immunogenicity of the biosimilar SB2 in inflammatory bowel disease patients after switching from originator infliximab. 

l. Published online January 14, 2021. doi: 10.1177/1756284820982802.

A long-term observational study suggests a non-medical switch from infliximab to SB2 is “a feasible option” for patients with inflammatory bowel diseases (IBD).

Long-term Observational Study Supports Switch From Infliximab to SB2 in IBD

A retrospective, real-world study (N = 304) of the use of bevacizumab biosimilar (Mvasi, Amgen) in patients with metastatic colorectal cancer (mCRC) suggests physicians are comfortable prescribing the biosimilar in accord with historical use of the reference product (Avastin, Genentech), according to data presented at the 

ASCO Gastrointestinal Cancers Symposium 2021

Investigators based that conclusion on evidence that patients who received bevacizumab biosimilar in the first line of treatment for mCRC had demographic and clinical characteristics similar to those for patients treated with the reference product.

In addition, they said, among patients who had prior treatment with bevacizumab reference product (n = 162), most received the biosimilar in the first line of treatment within 28 days, which indicated the switch to biosimilar treatment occurred within the same line of therapy.

Bevacizumab is administered intravenously and works by starving tumors of nourishment by counteracting a protein (vascular endothelial growth factor) that enables tumors to develop blood vessels. Avastin was approved by the FDA in 2006 and European Medicines Agency (EMA) in 2009. 

 launched in July 2019 in the United States and was the first biosimilar to Avastin to gain FDA approval.

The biosimilar’s approval was based on a comparative clinical study in non-squamous non–small cell lung cancer, the researchers examined real-world use of bevacizumab biosimilar in mCRC, an approved indication they said is “lacking clinical trial data.”

They identified 304 eligible patients using a database of US electronic medical records from ConcertAI. The patients were adults with a diagnosis of mCRC who had been treated with bevacizumab biosimilar the first year after the product launch.

The respective divide between patients treated at community cancer centers as opposed to academic institutions was 86% vs 14%, respectively. Investigators said 57% of patients treated at community centers had prior bevacizumab compared with 31% of patients at academic centers.

Just over half (53%) of the entire patient cohort had previously received treatment with the reference product. The majority of patients received tumor-marking genetic tests and 53% of tumors had 

 mutations. The vast majority of tumors were negative for 

 mutations (92% and 86%, respectively). Microsatellite instability (MSI) and mismatch repair (MMR) testing indicated 93% of patients were MSI stable and 93% were MMR proficient.

Demographic characteristics and clinical characteristics, such as Eastern Cooperative Oncology Group performance status, tumor grade, comorbidities, and disease stage at diagnosis, were “comparable” between the 2 groups, according to the authors. Diabetes, chronic obstructive pulmonary disease, and renal disease were the most frequent comorbidities in both groups.

Investigators said 74% of patients who had prior bevacizumab treatment received bevacizumab biosimilar within 28 days of their last treatment with the reference product. Most (83%) experienced no disease progression between their last treatment with the reference product and starting treatment with bevacizumab biosimilar.

The study was conducted with Amgen funding.

DeClue RW, Rhodes W, Accortt NA, et al. Demographics and clinical characteristics of metastatic colorectal cancer patients treated with bevacizumab-awwb in real-world oncology clinics. Presented at: ASCO GI Cancers Symposium 2021; January 15-17, 2021. Accessed January 29, 2021. https://meetinglibrary.asco.org/record/194175/abstract

Investigators noted comparable use of bevacizumab biosimilar and reference products among patients treated for metastatic colorectal cancer (mCRC). 

Study: Bevacizumab Biosimilar Finds Acceptance in First-Line Treatment of mCRC

An attempt to understand whether regulatory and scientific sources are consistent with each other in their reporting of quality attributes (QAs) for biosimilars has demonstrated general conformance between these 2 sources of biosimilar information.

Reporting of biosimilar quality attributes (QAs) is “inconsistent but reasonably complementary” between regulatory and scientific publications, according to the study comparing European public assessment reports (EPARs) from the European Medicines Agency (EMA) with peer-reviewed scientific publications on biosimilars.

Investigators looked at the reporting of 2 general categories of biosimilar QAs: structural and functional. Structural qualities include amino acid sequence, which must be similar between biosimilars and their reference products. They also concern purity of the drugs and physicochemical properties. Functional QAs include immunochemical activity and biological activity, such as antibody binding to the target ligands necessary to achieve a clinical response.

QAs, therefore, “describe specific physical, chemical, biological or microbial properties” of a biosimilar, and although the aims of scientific and regulatory reporting differ, data on QAs should be consistent, according to the authors. Limited information about the consistency and complementarity of QA reporting made this study necessary, they wrote.

“Along with the surge of biosimilars introduced to the European market over the last decade, the need for comprehensive and reliable information among decision makers (eg, clinicians, pharmacists, payers, and regulators) about the justification of biosimilarity has become pertinent,” the authors wrote.

The authors focused exclusively on adalimumab biosimilars for their study because the monoclonal antibody (mAb) to tumor necrosis factor alpha (TNF) “has the largest number of approved mAb biosimilars and the broadest spectrum of therapeutic indications among TNF-α inhibitors.” They studied the reporting of 77 different QAs (53 structural and 24 functional) from reports on 6 adalimumab biosimilars.

The total number of individual QAs reported for adalimumab biosimilars in regulatory and scientific sources ranged from 47 to 60, and the number of QAs reported consistently by both source types varied by biosimilar, ranging from 28% to 75%. Overall, a greater number of QAs were reported in EPARs (range 36-57) compared with scientific publications (range 14-49).

In both EPARs and scientific publications, functional QAs were reported more frequently than structural QAs (96% vs 89%) and more consistently (88% vs 62%, respectively). The authors suggested the reason functional attributes were more frequently and more consistently reported could be that “they reflect the clinically relevant” mechanisms of action of the biologic drugs and are useful in predicting the outcomes of clinical studies.

For example, binding to and neutralizing TNF-ɑ are functional attributes relevant to adalimumab’s mechanism of action, and these QAs were reported consistently in both information source types for all 6 biosimilars.

Regulatory and scientific motives also may have much to do with the type and frequency of information that gets reported. “Regulators...may be more concerned with the consistency and accountability of decisions. Researchers, frequently affiliated with biosimilar companies, might be more focused on presenting positive news—that is, QAs with favorable results in terms of biosimilarity, such as highly similar attributes,” they wrote.

The authors analyzed whether publications included test results, biosimilarity interpretation, or both for each QA. EPARs more commonly included a biosimilarity interpretation without test results compared with scientific publications. The 2 sources agreed, on average, on 90% (range 78%-100%) of QAs in their interpretations of biosimilarity.

The authors noted the QAs with agreement on biosimilarity interpretation “were frequently related to biological and immunochemical activity [functional QAs],” whereas, “the types of QAs with different biosimilarity interpretations in both sources were frequently related to [post-translational] modifications and biological activity.”

The authors advised consulting both sources of information to obtain a “more complete reporting of the biosimilarity assessment” and “an improved understanding of how biosimilarity was established at the molecular level.”

According to the authors, there have been few previous assessments of “whether and how data presented in these 2 publicly available information sources overlap.” However, studies assessing the reporting of safety and efficacy data “have found substantial discord between regulatory reports and scientific publications.” Their study, they said, was probably the first to examine whether the reporting of QAs is consistent or complementary between regulatory and scientific sources.

The authors argued bringing greater consistency to reporting of QAs between sources could ultimately contribute to increased acceptance and use of biosimilars by clinicians. “A comprehensive and consistently reported set of QAs is needed to understand the science behind regulatory approval and increase confidence in biosimilars in clinical practice,” they wrote.

Alsamil AM, Giezen TJ, Egberts TC, Leufkens HG, Gardarsdottir H. Comparison of consistency and complementarity of reporting biosimilar quality attributes between regulatory and scientific communities: an adalimumab case study. 

. 2021;S1045-1056(20)30142-1. doi:10.1016/j.biologicals.2020.12.003

Consistency of reporting quality attributes for biosimilars may differ, complicating the job of getting a full picture of biosimilarity. 

Investigators Weigh Differences in Biosimilar Quality Reporting

Switching patients with inflammatory bowel disease (IBD) from the CT-P13 infliximab biosimilar to the SB2 infliximab biosimilar appears to be safe and effective whether 1 or more switches between biosimilars and the originator product were involved, investigators concluded in a retrospective 

In seeking to elucidate the safety and efficacy of switching, the investigators noted little clinical evidence is yet available on switching patients with IBD between infliximab products. Further, they cited a lack of evidence for SB2 

, saying most of the available evidence “derives from the rheumatologic field.”

They enrolled patients who had originally been treated with CT-P13 or the originator product, but all patients had been treated with CT-P13 before switching to SB2. Clinical activity and adverse events were evaluated; the investigators also compared loss of response (LOR) between the biosimilars.

Originator infliximab (Remicade), a monoclonal antibody to tumor necrosis factor alpha, has been used to treat IBD for over 20 years. CT-P13 (Inflectra, Remsima; Celltrion) was the first approved infliximab biosimilar for IBD—Europe in 2013 and the United States in 2016)—and SB2 (Renflexis; Samsung Bioepis) was approved in Europe in 2016 and in the United States in 2017.

Multiple switches, from the reference product to CT-P13 and then to SB2 are likely to occur, the authors said, because of the lower cost of SB2 vs CT-P13. However, European guidelines do not advocate multiple switches because of a lack of clinical evidence.

Thirty-six patients, 14 with Crohn disease and 22 with ulcerative colitis, were followed for 6 months following a switch from CT-P13 to SB2. Twelve had previously switched from the infliximab reference product to CT-P13, and the rest were naïve to infliximab before treatment with CT-P13. Thirteen patients were treated with adalimumab or golimumab immunosuppressants prior to using an infliximab product.

Clinical activity was assessed 6 months before and 3 months after switching to SB2. The proportion of patients in clinical remission was 58.3% both before and after the switch, and rates of mild clinical activity were not significantly different before and after (27.8% vs 33.3%, respectively; 

 = 0.68). The percentages of patients with normal C-reactive protein levels were not significantly different 6 months before and 3 months after switching (94.4% vs 91.7%, respectively; 

The authors said SB2 treatment for 2 patients was suspended after they achieved clinical and endoscopic remission,” and 2 patients (5.5%) receiving SB2 experienced an adverse event (AE).

After switching from CT-P13 to SB2, 25 patients (69.4%) maintained clinical remission and 11 (30.5%) experienced LOR.

Comparing patients who experienced LOR with those who didn’t, the investigators found that 40% of those without LOR (n = 25) had undergone ≥2 switches (reference product to CT-P13 to SB2) compared with just 9.1% of patients who did experience LOR (n = 11), although the difference did not reach significance. Previous AEs during treatment with CT-P13 were more common among patients who experienced LOR on SB2 (27.3%) compared with those who did not (4%), although these findings also did not reach significance.

In univariate and multivariate analyses, the investigators evaluated the number of switches, AEs during CT-P13 treatment, previous LOR to CT-P13, endoscopic activity, clinical activity, clinical variables, and demographic variables, and did not find significant associations with LOR on SB2.

The authors recommended these factors be studied in a larger population to determine their potential influence on LOR, saying, “The low number of enrolled patients could explain why, at univariate, no significant variable was predictive.”

The nvestigators said it would have been “helpful to evaluate the value of infliximab trough levels and the detection of anti-infliximab antibodies,” to more precisely evaluate the potential association between previous AEs to CT-P13 and LOR to SB2. However, they were unable to perform this analysis due to the retrospective nature of the study and recommended future investigation into this potential predictive factor.

They concluded that switching from CT-P13 to SB2 is safe and effective in patients with a single switch or multiple switches among infliximab treatments. The authors described their efforts as “one of the initial studies investigating the efficacy and safety of the SB2 administration to IBD patients in a real-life setting.”

Lovero R, Losurdo G, La Fortezza RF, et al. Safety and efficacy of switching from infliximab biosimilar CT-P13 to infliximab biosimilar SB2 in patients with inflammatory bowel disease. 

. 2021;32(2):201-207. doi:10.1097/MEG.0000000000001988

A need for clinical evidence on the efficacy and safety of infliximab switching led the authors to pursue this investigation.

Infliximab Biosimilar Switching Study Yields Evidence of Safety, Efficacy

Could machine learning (artificial intelligence) be used to help predict outcomes for specific patients treated with biosimilars? Authors of a 

of studies on machine learning speculated on that potentiality and noted many other ways in which an adaptive computerized study of biosimilar use in the real world might be used to elucidate the value and qualities of individual biosimilars and inform providers to improve practice.

Because of the complex nature of biosimilars, they wrote, there are minute differences between them and their reference products that need to be more fully understood to build a practical understanding of these agents and their effects on patients. For example, patients might have immediate reactions to specific biosimilars or experience adverse events only after repeated treatments. Machine learning could track and interpret this information, although they said this relies on being able to “teach” computerized systems to interpret data collected across diverse health care systems with different protocols for recording patient data. 

“Unwanted immune reactions may be induced for numerous reasons, including product variations. However, it is challenging to assess these unwanted immune reactions because of the multiplicity of causes and potential delays before any reaction,” the authors wrote.

It has long been accepted that the analysis of drugs should not end with the clinical assessments done to achieve FDA approval for commercialization. Follow-up should continue long afterward, especially with biosimilars, regulators and patient advocates have said. Due to their complex manufacturing and derivation from living organisms, biologic drugs are mutable and batches of drug will vary over time.

the use of artificial intelligence technologies, which it says ”have the potential to transform health care by deriving new and important insights from the vast amount of data generated during the delivery of health care every day.”

Authors of the review said they hope to spur a broader discussion about machine learning with respect to biosimilars and include insight into maintaining patient safety amid the economic incentives that play a large role in which biosimilars get used. Biosimilars may offer discounts from originator products as deep as 30%; however, “economic incentives to use biosimilars and questions from the clinical community regarding unwanted immunogenicity can be incompatible,” the authors wrote.

“Machine learning, which is one type of artificial intelligence method, refers to programs that can adapt the instructions being used to produce the outcome. Here, the human aspect is its ability to learn and adapt the program’s code to experience,” the authors wrote. In particular, they suggested machine learning be used to identify risk factors for immune reactions, which they said could ensure safe biosimilar use while supporting their associated cost savings.

Machine learning, the authors explained, has the potential to detect important patterns or predict outcomes, but machine learning models require a learning process, just as humans do, to employ data in a way that enhances the accuracy of their predictions. The authors identified recent articles discussing machine learning applications in health care, but they noted that none have applied to biosimilar safety. Machine learning algorithms are a better fit for assessing immunogenicity than traditional statistical models, the authors suggested, because of the complexity and volume of the data involved. Immunogenicity assessments involve the characterization of human immune responses between biosimilars and reference products, in order to understand how patients might react to these agents.

The authors advocated for the use of real-world data to supplement clinical trial data on safety and immunogenicity. Although clinical trials measure safety metrics and antidrug antibodies, which may impair biosimilar performance, they “cannot provide a full picture of the safety profile,” the authors wrote, “because they are performed on a standardized population during a limited period.”

For purposes of informing and programming artificial intelligence systems, real-world data on biologic and biosimilar use and patient outcomes would be drawn from multiple sources, such as hospital systems and payers. Machine learning systems are best equipped to manage such a flood of data and help to make accurate and useful interpretations, the authors said. They suggested that “neural networks” would be capable of such functionality. 

Using immune reactions as an example, the authors outlined a hypothetical neural network model for identifying risk factors for developing an immune reaction after a switch from a biologic reference product to a biosimilar. For a patient treated with reference biologic and then switched to a biosimilar, the model would consider the spectrum of medications the patient has received, the biosimilar prescribed, the reference biologic previously prescribed, drug batch information, and other data. The neural model would classify patients according to predefined categories of immune reactions and hone its power to predict an immune response for an individual hypothetical patient. 

Proper handling of patient information is also a challenge of making a system like this work, the authors wrote: “Any machine learning application needs to comply with the ethical guidelines laid down by national ethics committees.” Complying with data privacy regulations in each country could be challenging, they said, but using aggregated and anonymized data would reduce the risk of violating those regulations.

One problem with neural networks, the authors wrote, is a lack of transparency, which may raise questions about how the machine learning systems arrived at their conclusions during the sifting of patient data. Neural networks use protocols that are layered one on top of another, and each of these folds involves a leap to a new level of interpretation whose workings may be hidden from clinicians trying to understand the reasoning process. “As a result, the black box might create conflict between processing by the neural network model and human interpretation,” the authors wrote. 

In addition to immunogenicity studies, machine learning models could be used to automate pharmacovigilance processes, detect safety signals, make risk assessments to facilitate decision-making on dose regimens or switching, and compare switching initiated by a clinician vs substitution at the pharmacy, which could inform policy on substitution, the authors suggested. They concluded that machine learning technology “should be seen as a tool to learn more about biologic drugs after clinical trials and the medical practices during their uses.”

Perpoil A, Grimandi G, Birklé S, et al. Public health impact of using biosimilars, is automated follow up relevant? 

. 2020;18(1):E186. doi:10.3390/ijerph18010186

Authors of a new study conclude that artificial intelligence could improve the selection of biosimilars for therapy. 

Study: Machine Learning Could Optimize Biosimilar Therapy

the “totality of evidence” for the bevacizumab biosimilar Mvasi (ABP 215) found “no clinically meaningful differences” between the biosimilar and its reference product, and they also concluded “robust data” from multiple trials support extrapolation to all indications of the reference product.

Mvasi is approved in the United States and European Union for several oncology indications, including metastatic colorectal cancer, metastatic cervical cancer, and metastatic nonsquamous non–small cell lung cancer (NSCLC). The authors stated they had no role in any of the human or animal studies included in their review.

Mvasi, an Amgen product, is a monoclonal antibody that binds with vascular endothelial growth factor A (VEGF-A) to retard blood vessel growth that contributes to tumor development. Mvasi was the first bevacizumab biosimilar approved in the United States (2017) and European Union (2018). In the United States, the biosimilar was launched in July 2019.

According to the authors, analytical tests that compared Mvasi with reference product samples from the United States and European Union showed biosimilarity in physicochemical properties, including primary structure, secondary structure, and thermal stability.

Functional properties also were similar. The authors outlined studies that demonstrated Mvasi’s comparable binding affinity to VEGF, inhibition of VEGF binding to its receptor, and inhibition of proliferation of endothelial cells in vitro. “These findings indicate that [Mvasi] and the [reference product] have the same mechanism of action (MOA),” the authors wrote.

The authors cited 2 studies in healthy individuals that indicated comparable pharmacokinetic properties between Mvasi and its reference product. Safety and tolerability in these studies also were similar. None of the enrollees developed binding or neutralizing antidrug antibodies, investigators said.

A comparative clinical trial (MAPLE) involving 642 patients with stage IV or recurrent nonsquamous NSCLC who also received carboplatin and paclitaxel also demonstrated biosimilarity. The primary efficacy end point was the risk ratio of objective response rate (ORR, defined as best overall response). Objective responses were observed in 39.0% and 41.7% of patients receiving Mvasi and reference product, respectively, and the 2-sided confidence interval for ORR fell within the prespecified margin, indicating similar clinical efficacy.

Safety and immunogenicity indicators were also similar between groups. Among patients receiving Mvasi, 26.2% experienced a serious adverse event (AE), vs 23.0% for the reference product cohort; 18.8% and 17.2% of patients on Mvasi and the reference product, respectively, experienced an AE leading to discontinuation.

Anti-VEGF toxicities, such as hypertension, gastrointestinal perforation, or wound healing complications were similar between groups. Immunogenicity was low in both treatment groups, with 1.4% in the Mvasi group and 2.5% in the reference product group developing antidrug antibodies, which were transient in 1.0% and 1.1% of subjects, respectively. No patients tested positive for neutralizing antibodies.

The authors concluded the totality of evidence supports the extrapolation of Mvasi to all approved indications of the reference product, as “no clinically meaningful differences were found in function, purity, potency, PK, clinical efficacy, safety, or immunogenicity.”

They said these studies “should provide oncologists with assurance about using [Mvasi] in treating all approved indications per the prescribing information in their country or region.”

Providers should feel confident using Mvasi, a bevacizumab biosimilar, for all indications of the reference product (Avastin), reviewers stated. 

Reviewers Consider "Totality of Evidence" for Mvasi

, authors call for stronger regulatory action to frustrate tactics used to delay the market entry of biosimilar products in the United States. They call for policy improvements on substitution of biosimilars for reference products, and they argue the case for greater extrapolation of indications for biosimilars so that they automatically cover orphan drug designations of the originator brands.

The review was conducted by members of the Southern Network on Adverse Drug Reactions, an international collaboration of physicians, surgeons, lawyers, scientists, and pharmacists, who who examined various aspects of the biosimilar landscape in the United States, European Union, and Japan—3 of the world’s largest biologics marketplaces.

The authors noted that 27% of new cancer drug approvals in the European Union, United States, and Japan are for biologics. Biosimilars have become available as 

 for the trastuzumab, bevacizumab, and rituximab originator products.

The first therapeutic oncology biosimilar candidates were submitted for European Medicines Agency (EMA) and FDA approval in 2016 and to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) in 2017. These regions “account for the majority of biological pharmacotherapy use worldwide” and invest the most in research and development for biologics, according to the authors.

The EU, which has the longest history with biosimilars, accounts for 90% of global biosimilar sales. In total, 33 biosimilars for oncology have been approved by the EMA, 16 by the FDA, and 10 by Japan’s PMDA. Between 2017 and 2019 the European Union approved 13 biosimilars to bevacizumab, rituximab, and trastuzumab; the United States approved 9; and Japan approved 7. The EMA and FDA have also approved supportive care oncology biosimilars to filgrastim, pegfilgrastim, and epoetin alfa.

The policy review examined variations in approval policies, interchangeability, pricing, and barriers to competition among the 3 regions. The potential cost savings for oncology biosimilars are immense, according to the authors. “Medical spending savings of more than $110 billion by 2029 are projected among the European Union, the United States, and Japan, with the use of oncology biosimilars in place of reference biologics accounting for most of these savings.”

Extrapolation, Interchangeability, and Substitution

The authors noted that the United States approaches extrapolation distinctly differently from how the European Union and Japan regard it. EU and Japanese regulators allow biosimilar manufacturers to “ask for oncology biosimilar approvals to be extrapolated to indications that in the USA had been designated as an orphan drug setting.”

The authors recommended the United States adopt “full extrapolation for each clinical indication approved for the reference biologic” to encourage a competitive market for therapeutic oncology biosimilars.

Regulatory approaches to interchangeability also differ among the 3 regions. In the European Union, interchangeability and substitution policies are decided by individual countries, many of which allow substitution of a reference biologic with a biosimilar at the pharmacy. Biosimilar substitution is not permitted in Japan. In the United States, substitution is not permitted unless the biosimilar has met the requirements to be designated as interchangeable, which no biosimilar has yet.

The authors recommended the PMDA “consider liberalizing its policies on substitution.” In the United States, they recommended the FDA modify its requirements on interchangeability “to help achieve this designation for an increasing number of therapeutic oncology biosimilars.” They also called for US states to reconsider prohibitions on biosimilar substitution, “as it creates an undue burden on providers and raises patient concerns with little safety benefit.”

In the European Union, biosimilar price discounts average 30%, and in Japan, discounts are 30% or, if the biosimilar has at least 10 approved indications, 40%. In the United States, discounts range from 10% to 33%; however, rebates and “preferred positions on formularies often result in reference biologics being the least expensive option.”

The authors said pay-for-delay agreements, in which the biosimilar manufacturer is paid by the reference biologic manufacturer to delay entry of the biosimilar to the market, are common in the United States and Europe. In the United States, they noted, pay-for-delay agreements were entered into by manufacturers of 4 FDA-approved trastuzumab biosimilars. They commented that this practice delays patient access to more affordable treatment.

The reviewers recommended the US Federal Trade Commission (FTC) review nontransparent rebates and pay-for-delay agreements “for their potentially anticompetitive nature,” noting that there are “similar concerns” in the United Kingdom.

Patent Challenges and Anticompetitive Practices

The authors reported that oncology biosimilar launches in the United States have been more adversely affected by patent challenges than in the European Union and Japan. Patent challenges, they wrote, are rare in the European Union and are made only occasionally in Japan, whereas patent challenges have occurred for 56% of approved oncology biosimilars in the United States, and “many” therapeutic and supportive oncology biosimilars were not launched after winning FDA approval, “because patent litigations or administrative patent challenges were ongoing.”

In addition to patent litigation, the authors discussed delays due to inter partes reviews (patent legitimacy reviews), which they described as “narrower in scope and less expensive than litigation,” but still able to delay market launches for years, “thereby negatively affecting patient access to health care products.”

The reviewers recommended sweeping changes in the United States to preclude makers of reference biologics from delaying the introduction of biosimilars. In the United States, they wrote, “large changes [are] needed to the so-called 

 and to the frequent filing of administrative challenges (inter partes reviews).”

The reviewers did note that the FDA and FTC have recently agreed to strengthen their efforts to reduce and discourage anticompetitive behavior. “This agreement is key to facilitating robust competition within the biologics marketplace by decreasing health care costs of oncology biologics,” they wrote.

Overall, the authors advocated encouraging competition by minimizing pay-for-delay agreements and patent challenges, while supporting physician and patient education on biosimilars. They also cited a need for long-term pharmacovigilance, “particularly with respect to immunogenicity.”

The authors closed by arguing that addressing their identified barriers to oncology biosimilar launch, “would improve the regulatory approval process, improve access to therapeutic biologics and biosimilars, and potentially lead to cost savings that have been anticipated since 2015.”

Bennett CL, Schoen MW, Hoque S, et al. Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated policy review from the Southern Network on Adverse Reactions. 

. 2020;21(12):575-588. doi:10.1016/S1470-2045(20)30485-X

An international group of physicians, surgeons, lawyers, scientists, and pharmacists weighs in on biosimilar policy differences and deficiencies in the United States, Europe, and Japan.  

Policy Review Cites Need for Regulatory Clampdown on Pay-for-Delay Tactics

In 2009, the World Health Organization (WHO) Expert Committee on Biological Standardization created a set of recommendations and guidelines to help its member states implement regulation of biologics and biosimilars. However, member states still face regulatory challenges, based on a 2019-2020 WHO survey of participants in 20 countries. The WHO report on this recommends steps to overcome these challenges.

Progress has been made since an earlier, 2010 survey, the authors said. The challenges identified in the 2010 survey have largely been resolved, but the 2019-2020 survey identified 4 remaining challenges: unavailability or insufficient reference products in particular countries; lack of resources; problems with the quality of some biosimilars; and difficulties with interchangeability and naming of biosimilars.

The authors recommended potential solutions, noting that resolving these challenges will require cooperation between regulatory authorities in different countries. Their proposed solutions included exchanging information on biologics with other regulatory authorities, avoiding unnecessary duplication of studies by accepting foreign-licensed and -sourced reference products, relying on approvals from other regulatory authorities or using joint review to facilitate approval of biosimilars, reassessing products approved before the biosimilar regulatory framework was in place, and establishing regulatory oversight for good pharmacovigilance.

Challenges Associated With Reference Products

The authors noted that many of the challenges identified by the 20 surveyed countries were related to reference biologics, including limited access to information on the reference biologic, financial constraints due to the price of the reference biologic, and difficulty of obtaining reference biologic samples to assess comparability.

The authors noted some countries accept reference biologics that are foreign-licensed and -sourced, whereas others require a domestically licensed reference product or bridge studies for a foreign-sourced reference product. The authors commented that bridge studies are costly and often result in unnecessary duplication of studies.

To address these challenges, the authors recommended exchanging information with other national regulatory authorities, accepting foreign-sourced reference products, and avoiding unnecessary bridge studies. They said, “if data and information are available in the public domain and are sufficient to establish this bridge, the additional study might be waived and would result in reducing the cost of biosimilar development.” They noted that some countries have already implemented information-sharing processes with other national regulatory authorities.

Insufficient resources for national regulatory authorities were a commonly cited challenge. The authors commented that building capacity and expertise in a national regulatory authority is “a lengthy process,” and shorter-term measures are needed, such as reliance on information from other regulatory authorities or a joint review process. Some countries have already implemented these strategies to facilitate the biosimilar approval process. Ghana, India, Iran, Jordan, Malaysia, Peru, and Zambia rely on the expertise of other countries which have previously approved reference biologics and biosimilars. Joint review to share the work between regulatory authorities has been implemented in Africa. The authors recommend using these short-term measures to improve efficiency of biosimilar approvals.

In some countries, there are biosimilar products on the market that were approved prior to the establishment of a regulatory framework for approving biosimilars. This has led to problems distinguishing between “real” biosimilars and what the authors called “nonbiosimilar, noninnovator products.” The authors recommended reassessment of these products with regard to the established biosimilar approval process. They noted that several countries have already begun reevaluating nonbiosimilar, noninnovator products.

According to the authors, “the hottest topic in biosimilars has moved on from establishing a suitable regulatory framework to the practice of interchangeability.” They noted that the FDA’s requirements for interchangeability “are very challenging and no such products have been approved by the FDA to date.” They report each regulatory authority has its own approach, but no other national regulatory authority has adopted the FDA approach. Only Iran and Japan establish interchangeability immediately upon approval of the biosimilar, with most other countries either relying on the decision of prescribers or basing the decision on clinical evidence provided by the manufacturer.

The authors cited interchangeability as a difficult issue, especially for health care professionals. They argued interchangeability is “more of an issue to be considered and decided by physicians and patients rather than a regulatory issue,” and that “the role of regulatory authorities in this is to inform physicians and patients about the regulatory assessment and decision as a prerequisite for switching products on the market.”

A survey of 20 countries highlights the remaining regulatory challenges facing biosimilar adoption.