Deana Ferreri, PhD

Costs of administering reference (Neupogen) or biosimilar filgrastim (Zarxio) are predictably higher in the outpatient hospital setting than in the office setting, although savings were nonexistent when administering the biosimilar vs reference product in the outpatient hospital setting, 

Filgrastim is a granulocyte colony-stimulating factor drug used to prevent or treat chemotherapy induced neutropenia (lower-than-normal levels of white blood cells).

Investigators conducted a retrospective study of 65,372 episodes of filgrastim use from 2014 to 2019 among commercially covered women and men in health care settings across the United States. They sought to evaluate potential savings for use of Zarxio, tbo-filgrastim (Granix), and the reference product. Granix is approved in the European Union as a biosimilar, but in the United States it is considered a version of filgrastim because its approval did not come through the biosimilar pathway.

Median costs were higher in the outpatient hospital setting compared with the office setting for all 3 filgrastim products, the authors wrote in T

). Additionally, after results were adjusted for patient characteristics and geography, the investigators found cost savings associated with the biosimilar filgrastim “were limited to the office setting, with no savings in the outpatient hospital setting.”

The authors defined an episode as 1 or more filgrastim administrations and fewer than 7 days between administrations. Median costs were adjusted for patient characteristics and geographic differences. The cost of administration was defined as the “sum of out-of-pocket and health plan paid amounts for the drug per date of service.”

In the office setting, the median costs of the biosimilar filgrastim administration and tbo-filgrastim administration were $103.61 and $94.07 less than that of reference product administration, respectively, the investigators said.

There were no cost savings associated with use of the biosimilar in the outpatient hospital setting. The adjusted median cost of biosimilar administration was greater than reference product administration by $20.50 in this setting. In contrast, the cost of tbo-filgrastim administration in the outpatient hospital setting was $132.90 less than a reference product administration.

Although previous analyses have found lower costs for the biosimilar filgrastim than for reference filgrastim, the authors concluded their data suggest that “site of care can change this calculus, reducing savings.”

One possible contributing factor they suggested is the difference in payer payments for outpatient- vs office-based treatment.

"Although patients receive identical drug administrations in office or hospital outpatient settings, insurers generally reimburse higher payments to outpatient hospital settings to cover presumed greater overhead costs," they wrote.

The authors said that despite their findings being limited to commercially covered patients, the results suggest that “savings from biosimilar drugs are context specific,” although they said it is unknown whether the cost savings for other biosimilar drugs vary similarly by site of care.

“Biosimilars—drugs that are similar in quality, safety, and efficacy to reference biologic drugs—are intended to increase competition, reduce prices, and improve patient access to important treatments,” they said. They did not speculate on why in the outpatient hospital setting the cost of Zarxio administration was slightly higher, on average, than reference product administration.

They also did not speculate on why tbo-filgrastim was significantly less costly than reference filgrastim in both the outpatient and office settings, but not the biosimilar filgrastim. In addition to Neupogen, Zarxio, and Granix, another filgrastim product is available, the biosimilar Nivestym. This was approved and launched in late 2018, which was midway through the study period. Investigators did not review cost data for Nivestym.

Granix was approved in August 2012 and launched in November 2013, and Zarxio in March 2015 and September 2015, respectively.

Chang J, Karaca-Mandic P, Go RS, Schondelmeyer S, Weisdorf D, Jeffery MM. Site of care potentially limits cost savings from biosimilars. 

. 2021;27(8):e287-e289. doi:10.37765/ajmc.2021.88730

Articles

According to a multiyear, retrospective study, filgrastim biosimilar Zarxio cost $20.50 more on average per administration than reference Neupogen in the hospital outpatient setting. 

Study: Zarxio More Costly Than Neupogen in Outpatient Hospital Setting

The results of a meta-analysis of 3 phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) studies of the Sandoz 

 Ziextenzo support PK and PD similarity of the biosimilar to both US and EU reference versions of the originator (Neulasta).

Pegfilgrastim is a pegylated, long-acting form of filgrastim. Both are granulocyte colony-stimulating factor (

) drugs, which are used to stimulate neutrophil production in patients undergoing chemotherapy to reduce the risk of febrile neutropenia.

The investigators said that “since the designs of the 3 studies were different and the sensitivity of the bioanalytical assay varied slightly among the studies,” a meta-analysis could “provide a more precise estimate of biologics comparisons than the individual studies.” With this meta-analysis, they aimed to “address all aspects of residual uncertainty regarding the biosimilarity of Sandoz pegfilgrastim.”

The First PK/PD Study Failed to Demonstrate Biosimilarity

The first study, a 3-arm (biosimilar, US reference, EU reference) parallel-group study, in which participants receive separate drugs and regimens, failed to demonstrate biosimilarity, but “revealed an unexpected high intersubject variability” in PK parameters of pegfilgrastim, according to the authors. Plus, they said, a retrospective evaluation of study 1 found it was underpowered to demonstrate biosimilarity.

The authors noted that since the publication of this study, “the high degree of intersubject variability of the PK results has since been confirmed by others with the reference biologic.”

PD parameters, in contrast, were within the equivalence margins in this study, and there were “no meaningful differences” in safety, local tolerability, and immunogenicity between the biosimilar and reference groups.

The investigators said that study 1 demonstrated that a parallel design was not suitable, and “a crossover design is more appropriate for studies involving pegfilgrastim.” In a crossover study, each participant receives both the experimental drug (biosimilar, in this case) and the control (Neulasta).

Studies 2 and 3 Demonstrated Biosimilarity Using a Crossover Design

Study 2 was conducted to address the limitations of study 1. It compared the biosimilar with the EU reference product in 1 of 2 sequences. This study used a revised sample size estimation and tighter inclusion criteria for absolute neutrophil count and body mass index to address intra-individual variability and reduce the heterogeneity of the population, respectively. No meaningful differences in safety, local tolerability, or immunogenicity were detected in this study.

Study 3 used a 3-way, 6-sequence crossover design evaluating the biosimilar vs both US and EU reference products “to circumvent the interindividual variability and take into account intra-individual variability instead.” This study also demonstrated no meaningful differences in safety, local tolerability, and immunogenicity between the 3 pegfilgrastim products

The investigators considered biosimilarity to be demonstrated if all 90% confidence intervals (CIs) for the geometric mean ratios for treatment comparisons (comparison of biosimilar to US reference, etc) fell within the margins of 0.80 and 1.25.

They found that demographic and baseline characteristics were similar overall between the groups. They analyzed PK and PD parameters for 277 participants from study 1, 169 from study 2, and 496 from study 3. The 90% CIs of the geometric mean ratios for all 3 comparisons (biosimilar vs US reference, biosimilar vs EU reference, and biosimilar vs US reference and EU reference) were within the predefined equivalence margins, suggesting biosimilarity.

The investigators noted that their results suggest that area under the curve and maximum serum concentration were approximately 5% to 7% higher with the biosimilar compared with the 2 reference products. However, they said this “slightly higher exposure did not translate into any differences in PD effects in the present study,” adding that no clinically meaningful differences in efficacy or safety were observed in the phase 3 clinical studies.

Safety and Tolerability Found to Be Similar

The authors did not perform a meta-analysis on the safety data, but pooled data from all subjects who received at least 1 dose of the study drug in any of the 3 studies, including 781 subjects who received the biosimilar, 604 who received the US reference product, and 772 who received the EU reference product. They reported safety and tolerability were similar between the biosimilar, US reference, and EU reference in these healthy subjects.

Treatment-emergent adverse events (TEAEs) considered related to the study drug occurred in 85.8% of subjects in the biosimilar groups, 84.3% in the US reference groups, and 86.3% in the EU reference groups. The most common TEAEs included headache, back pain, bone pain, and myalgia.

There were no serious drug-related AEs in any group in any study. Six participants treated with the biosimilar and 5 treated with the EU reference product had a study drug-related TEAE leading to discontinuation of the study.

Although study 1 did not demonstrate PK biosimilarity, when combined with studies 2 and 3 in this meta-analysis, the authors said, the data support PK and PD biosimilarity as demonstrated in studies 2 and 3, with no clinically meaningful differences in safety or tolerability, adding to the totality of evidence for the Sandoz pegfilgrastim. They added, “with data from 1040 healthy subjects, this is the largest-known evaluation of PK/PD parameters and safety of a biosimilar of pegfilgrastim.”

Gattu S, Wang J, Bellon A, Schelcher C, Nakov R, Arani R. Meta-analysis of pharmacokinetic/pharmacodynamic results of 3 phase 1 studies with biosimilar pegfilgrastim. 

. Published online August 4, 2021. doi:10.1002/cpdd.1005

A meta-analysis of pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of Sandoz pegfilgrastim biosimilar confirms biosimilarity. 

Meta-analysis of Sandoz Pegfilgrastim PK/PD Studies Supports Biosimilarity 

 of 348 children with Turner syndrome (TS) found that biosimilar recombinant human growth hormone (rhGH) therapy was safe and effective in real-life clinical practice.

The investigators reported on a subgroup of patients with TS from the PAtients TReated with Omnitrope (PATRO) Children study, a long-term, postmarketing surveillance study of children treated with biosimilar rhGH (Omnitrope; Sandoz).

TS is characterized by partial or complete loss of the second sex chromosome in females and is associated with comorbidities, including growth failure. TS has been treated with reference rhGH (Genotropin; Pfizer) since its approval in 1995. The biosimilar Omnitrope became available after approval by the European Medicines Agency and the FDA in 2006.

The investigators enrolled 348 patients being treated for TS at 130 centers across Europe. Their mean age was 9.0 (range, 0.7-18.5) years at baseline. Most (81.6%) were rhGH naïve, and 90.2% were prepubertal. The mean (SD) treatment duration in the study was 38.5 (26.8) months.

Safety was the primary end point of the study. The authors pointed out that rhGH is “generally well tolerated” in patients with TS; however, observational studies have reported greater risk for some adverse events (AEs) in patients with TS receiving rhGH. The AEs include intracranial hypertension, slipped capital femoral epiphyses, pancreatitis, and development or progression of scoliosis. The investigators wrote that their findings “do not support an increased risk of these events due to rhGH therapy.” However, noting the relatively short treatment duration in their study, they cautioned “longer-term follow-up would be required to verify these safety findings.”

Overall, approximately half of the patients (170; 48.9%) experienced AEs, most of which were mild or moderate. Twenty-five patients experienced treatment-related AEs, including headache, impaired glucose tolerance, increased insulin-like growth factor levels, and increased weight. One patient experienced scoliosis that was deemed treatment related.

Approximately half (172; 49.4%) of the patients discontinued the study. The most common reason (52 patients) for discontinuation was the attainment of adult height or bone age maturation. Six patients discontinued the study because of a lack of treatment response. Ten patients discontinued due to AEs, one of whom experienced a serious AE (intracranial hypertension) that was “possibly related to treatment.” The authors wrote that their safety findings “show no evidence of an increased risk of developing unexpected AEs or new malignancies during rhGH treatment.”

The investigators included 163 patients in their 3-year effectiveness cohort, 131 of whom were rhGH naïve prior to the study. Most patients (98.5% of the rhGH-naïve group and 90.6% of pretreated patients) were prepubertal.

Effectiveness was assessed by height velocity (HV), height standard deviation score (HSDS), and height velocity standard deviation score (HVSDS). The mean (SD) HV at 3 years was 5.2 (1.3) cm/year in prepubertal treatment-naïve patients and 4.7 (1.4) cm/year in prepubertal pretreated patients. From baseline to 3 years, gains in HSDS were 1.17 in prepubertal treatment-naïve patients and 0.04 in prepubertal pretreated patients. Mean increase in peak-centered HVSDS from baseline to 3 years was 3.94 in prepubertal rhGH-naïve patients and 0.47 in prepubertal pretreated patients.

Adult height was reached by 51 patients (31.1%), 35 of whom were rhGH naïve at baseline. In those 35 patients, the mean HSDS was –2.97 (1.03) at baseline, and at 3 years, the mean AHSDS was –2.02 (0.9). The AHSDS was similar in pretreated patients, at –2.10 (1.1).

These effectiveness findings “are broadly in line with those from other observational studies in TS patients,” according to the authors.

The authors concluded that treatment with biosimilar rhGH was well tolerated in patients with TS, and no unexpected safety signals were identified.

“Several well-known AEs were observed, confirming the need for ongoing patient monitoring,” they wrote. Although safety was their primary end point, they wrote that their effectiveness data showed “substantial height gains were observed in prepubertal individuals over 3 years of treatment.”

Backeljauw P, Kanumakala S, Loche S, et al. Safety and effectiveness of recombinant human growth hormone in children with Turner syndrome: data from the PATRO children study. 

. 2021;94(3-4):133-143. doi:10.1159/000515875

A multicenter study of recombinant human growth hormone (rhGH) in children with Turner syndrome demonstrated safety and efficacy comparable to the reference product. 

Study: Biosimilar rhGH Well Tolerated and Effective in Turner Syndrome

Using data from a population-based cancer registry in the Netherlands, 

response and survival rates for patients with diffuse large B-cell lymphoma (DLBCL) who received either rituximab originator (Rituxan) or biosimilars. They found that 3-year overall survival (OS) was 73% in both the originator and biosimilar groups (

 = .855), and overall response rates (ORRs) were 85% in the originator group and 84% in the biosimilar group (

Rituximab, a monoclonal antibody to the B-cell surface antigen CD20, has been “the backbone of every treatment regimen in B-cell non-Hodgkin lymphomas” since its approval by the FDA in 1997 and European Medicines Agency (EMA) in 1998, the authors said. And in the Netherlands, rituximab biosimilars were rapidly incorporated into the treatment regiment for these cancers.

Two rituximab biosimilars, CT-P10 (Truxima; Celltrion) and GP2013 (Riximyo; Sandoz), were approved by the EMA in 2017. That year, the Dutch Association of Medical Specialists began to incorporate rituximab biosimilars into the standard of care. By 2018, the authors said, 91% of the rituximab purchased in the Netherlands was biosimilar product rather than originator, leading to a 43% reduction in annual expenditure on rituximab in 2019 compared with 2015.

The investigators noted that rituximab biosimilars were approved by the EMA based on studies in patients with rheumatoid arthritis and naïve follicular lymphoma. Until now, data on ORR and OS rates with rituximab biosimilars in DLBCL, they said, have been “limited to small postmarketing studies.”

Investigators identified 4429 patients from the Netherlands Cancer Registry with DLBCL who were 18 or older, received a diagnosis of DLBCL between 2014 and 2018, and received at least 1 cycle of R-CHOP (a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), which they noted is standard of care for patients with newly diagnosed DLBCL. There were 3553 patients treated with rituximab originator and 876 treated with a biosimilar. Of those treated with a biosimilar, 86% received CT-P10 and 14%, GP2013.

Complete response was achieved by 74% of patients in the reference cohort and 72% in the biosimilar group; 11% in each cohort achieved partial response (

Overall 3-year survival was 73% in each group. The risk of mortality was also similar between groups in a multivariate analysis that adjusted for age at diagnosis, sex, International Prognostic Index score, and number of cycles of R-CHOP in the biosimilar group (HR 0.89; 95% CI, 0.76-1.05; 

 = .182) compared with the originator group.

Because the study included patient data from several years prior to when rituximab biosimilars were routinely used in clinical practice, the median follow-up times were 62 months for the reference product and 32 months for the biosimilars. The authors used sensitivity analysis to account for this difference.

First, an analysis of 3-year overall survival was conducted excluding all patients treated with the reference product who were diagnosed prior to biosimilar approval. Analyzing just the 370 patients treated with the reference product and 876 patients treated with biosimilars who were diagnosed between April 2017 and December 2018, 3-year survival rates were similar, 74% and 73%, respectively (

In the second part of the sensitivity analysis, the researchers compared 3-year survival rates in patients receiving the originator before (n = 3183) and after (n = 370) biosimilar approval. They found 3-year survival rates of 73% for those diagnosed prior to April 2017 and 74% for those diagnosed afterward. “Overall, the results of the sensitivity analyses were similar to those of the primary analyses,” the authors wrote.

According to the authors, theirs is the first population-based study following EMA approval of the first rituximab biosimilar to investigate survival in patients with newly diagnosed DLBCL treated with the rituximab originator or biosimilar. They wrote that their data suggest that patients with DLBCL “benefit equally” from rituximab originator or biosimilars combined with CHOP treatment. They acknowledged “the lack of detailed information on dosage per cycle at the patient level and treatment-related toxicities, including infusion-related reactions,” as limitations of their study.

Brink M, Kahle XU, Vermaat JSP, et al. Impact of rituximab biosimilars on overall survival in diffuse large B-cell lymphoma: a Dutch population-based study. 

. 2021;5(15):2958-2964. doi:10.1182/bloodadvances.2021004295

A retrospective study of rituximab biosimilars Truxima and Riximyo demonstrated comparable response and survival for patients with diffuse large B-cell lymphoma (DLBCL).

Dutch Study Confirms Response, Survival for Rituximab Biosimilars in DLBCL

 examined pricing changes in the insulin glargine market following the FDA approval and entry of Basaglar (insulin glargine injection; Eli Lilly) into the market.

The authors said their data suggest the approval was followed by a “substantial change in the trajectory of net prices” for insulin glargine products. After a steady increase in prices for Lantus, the only insulin glargine on the market from 2010 to 2014—the FDA approved Biocon Biologics’ Semglee insulin glargine 

—the average net price of all insulin glargine products decreased from 2015 to 2020.1

Basaglar, although it has the identical amino acid sequence to Biocon Biologics and is referred to as a biosimilar in the publication, was approved as a new drug, not a biosimilar. Until 2020, new versions of insulin products were approved in the United States via the Food, Drug, and Cosmetic Act section 505(b)(2) new drug application pathway. 

, biosimilar insulin products could be approved instead via the Public Health Service Act section 351(k) biologics license application pathway.2

Insulin glargine, a long-acting form of insulin, has been sold under the name Lantus by Sanofi since 2000. However, the patent on insulin glargine expired in February 2015, opening an opportunity for new insulin glargine products. Basaglar was approved by the FDA in December 2015 after a tentative approval in 2014, and it entered the market in December 2016.

The researchers noted that patent litigation delayed Basaglar’s market entry following its approval. Prior to the launch of Basaglar, Sanofi launched Toujeo, a higher-concentration insulin glargine product “that would not directly compete with Basaglar,” which the researchers reasoned was “a possible strategic move to maintain market share.”

The researchers studied 10 years of net price estimates and sales data from the SSR Health Drug Database, from Q1 of 2010 to the Q2 of 2020, for all 3 insulin glargine products.

Prior to 2015, Lantus was the only insulin glargine product on the market. According to the authors, its list price rose from $9.23 per 100 IU in Q1 of 2010 to $22.21 in Q3 of 2014, a 4.9% increase per quarter. They noted net prices were lower than list prices ($6.94 and $12.79, respectively) and rose more slowly (3.8% quarterly).

From 2015 to 2020, list prices “remained steady”; however, net prices of Lantus and the weighted average of all insulin glargine products declined. The price of Lantus declined by 5.2% per 100 IU per quarter compared with the average net price decline of 3.4% per quarter.

The researchers found that Lantus maintained the highest net sales of the 3 products throughout the 10-year period. However, by Q2 of 2020, Basaglar accounted for up 42.2% of sales compared with 46.2% for Lantus. Sanofi’s Toujeo, sold after Lantus lost exclusivity, “never gained greater than 15% market share,” according to the authors.

The researchers also conducted a single-group interrupted time series analysis to evaluate the trends in the weighted average net price of insulin glargine before and after Q4 of 2014, the approximate time of tentative approval of Basaglar. Their model estimated that prior to Basaglar’s approval, the net price of 100 IU of insulin glargine increased an average $0.36 per quarter, followed by a downward trend after approval of approximately $0.67 per quarter.

The investigators identified their focus on net prices rather than list prices, evaluating total sales, and the 10-year span of the data as strengths of their research. They said these factors allowed them to avoid methodological challenges frequently encountered in studies on the entry of a biosimilar into a biologic market, such as “failing to account for manufacturer-provided rebates, examining only a segment of US payers, and focusing on short-term changes.”

Future research, they said, could examine the association of market entry of new insulin biosimilars on the prices of both direct and nondirect competitors, and “the outcomes of decreasing net prices on patient out-of-pocket costs should be further investigated.”

1. Levy J, Chowdhury ZM, Socal MP, Trujillo AJ. Changes associated with the entry of a biosimilar in the insulin glargine market. 

. Published online June 28, 2021. doi:10.1001/jamainternmed.2021.2769

2. Kim AP, Bindler RJ. The future of biosimilar insulins. 

. 2016;29(3):161-166. doi:10.2337/diaspect.29.3.161

The average net price of all insulin glargine products decreased between 2015 and 2020 following the steady price increase seen for Lantus from 2010 to 2014.

Average Net Price for Insulin Glargine Declined After Basaglar Won FDA Approval

in Italy demonstrated equivalent safety, efficacy, and tolerability for patients with inflammatory bowel disease (IBD) who switched from reference infliximab (Remicade) to the biosimilar Renflexis (SB2, Flixabi), investigators concluded.

They said this was the largest study (N = 85) to date investigating crossover from Remicade to SB2.

Our primary aim was to prospectively verify the ability of SB2 to maintain the clinical and biochemical response induced by IFX originator after switching.

“Our patients maintained clinical response to therapy after switching and did not develop serious adverse events (AEs). In addition, we did not find differences in immunogenicity between infliximab originator and SB2,” investigators said.

IBD includes ulcerative colitis (UC) and Crohn disease (CD), relapsing and remitting inflammatory diseases of the intestinal tract, for which anti–tumor necrosis factor (TNF) biologics including infliximab may be prescribed. TNF inhibitors have “greatly improved” outcomes for patients with refractory IBD and those who are intolerant to standard treatments, according to the researchers.

The authors explained that, in the context of IBD, there is “substantial and robust literature” on the biosimilar CT-P13 (Inflectra, Remsima) and only a “paucity of data” on 

. CT-P13 was approved by the European Medicines Agency in 2013 and FDA in 2016, and SB2 was approved in 2016 by the EMA and 2017 by the FDA.

This study was conducted between 2018 and 2020 at 3 IBD treatment centers in Italy. The patient population included 28 (32.9%) with UC and 57 (67.1%) with CD. This was the first switch between infliximab products for this patient cohort. Data were collected at the time of switch and then at the first 2 follow-up visits to the IBD clinic, on average 135 days and 329 days later.

The proportion of patients in clinical remission was 82% at baseline and 69% at the second visit

At baseline, 70 (82.3%) patients were in remission, 12 (14.1%) had mild disease activity, 3 (3.5%) had moderate disease activity, and none of the patients had severe disease activity. At the first visit, 60 (70.6%) were in remission, 17 (20%) had mild disease, 8 (9.4%) had moderate disease, and none had severe disease.

Data for the second visit was available for 76 of the original 85 participants. By the second visit, 59 (69.4%) patients were in remission, 15 (17.6%) had mild disease, and 2 (2.4%) had severe disease. The authors noted there was a statistically significant difference in these proportions from baseline to visit one, but not from baseline to the second visit.

The authors said that over the duration of the study, 52 of the 70 patients in remission at baseline stayed in remission, and 11 developed mild disease. Five of the 12 patients with mild disease at baseline maintained mild disease, and 2 developed severe disease. One patient with moderate disease at baseline had mild disease at the second visit, and another was in remission.

Neither median fecal calprotectin, an indicator of inflammation in the gastrointestinal tract, nor the systemic inflammation indicator C-reactive protein (CRP) showed significant differences between baseline and the second visit.

The clinics used therapeutic drug monitoring to optimize drug administration rates. The researchers identified a significant increase in the need for therapeutic drug optimization; at baseline, 29 patients required treatment optimization compared with 37 patients at the first visit.

The recent development and authorization of various infliximab biosimilars for the treatment of IBD largely changed our daily clinical practice, opening new possibilities, even though with some concerns about their use. Indeed, currently data to properly support their use in the IBD setting is still lacking.

Four adverse events (AE) were recorded at the first visit and 5 at the second visit; no serious adverse events were reported. Overall, 16 patients (18.8%) discontinued treatment, 4 by visit 1 and 12 by visit 2: 5 patients due to adverse reactions, 8 due to lack of efficacy, 2 due to remission, and 1 due to pregnancy. One patient who discontinued treatment after the first visit due to lack of efficacy resumed therapy with the reference product and regained remission.

The authors noted that a loss of response to anti-TNF therapy may occur due to low serum drug levels or high levels of anti-drug antibodies (ADAs), and that 10% to 50% of patients treated with TNF inhibitors experience a loss of response.

They measured serum trough levels (TLs) and ADAs in a subgroup of 55 patients at baseline and the first visit. At baseline, 20 patients (36.3%) demonstrated subtherapeutic TLs; 5 returned to therapeutic TLs, and 5 lost therapeutic TLs at the first visit. At both visits the same 2 patients (3.7%) showed ADAs; no new ADAs were identified after the switch to SB2. The authors said these data on TLs and ADAs suggest “no significant implication of these pharmacological features in therapeutic failure.”

The authors concluded, “overall, our data show that most of the patients switching from infliximab originator to SB2 maintain the clinical and biochemical remission for at least 1 year,” further noting they detected no serious AEs and no evidence of differences in immunogenicity between the originator and the biosimilar. However, they also acknowledged that 2 patients with mild disease developed severe disease, 8 patients required drug optimization, 16 patients discontinued therapy, and 10 patients required the addition of steroid therapy during the study.

They recommended more real-world, multi-center studies with larger sample sizes and longer follow-up times “to obtain more consistent data and further support the use of biosimilar drugs in clinical practice.”

Massimi D, Barberio B, Bertani L, et al. Switching from infliximab originator to SB2 biosimilar in inflammatory bowel diseases: a multicentric prospective real-life study. 

. Published online June 27, 2021. doi:10.1177/17562848211023384

Real-world study in Italy finds most patients with inflammatory bowel disease (IBD) maintain clinical and biochemical response after switching from infliximab reference product to SB2.

Study Supports Switch From Remicade to SB2 in IBD

Is there a double standard when it comes to regulatory requirements for data on originator biologics vs biosimilars?

 argue that biosimilar developers are often required to perform comparability testing that is not expected of originator biologics developers. They suggest that via a “reliance” approach, regulators worldwide could share data and standards on biosimilar acceptance, leading to faster approvals, rather than expending resources conducting separate reviews and requiring study data that may be redundant.

Reliance is a precedented solution that offers important advantages for regulators and is a particularly rational approach for biosimilars.

The authors hinge their argument partly on advances in comparability assessments, which help determine whether a reference biologic produced by a new manufacturing process or a biosimilar has clinically meaningful differences from the previously approved originator product.

They note that originator companies often implement manufacturing process changes or extend biologics manufacturing to different locations and may not be required to do more than analytical testing to confirm consistency of product. Biosimilar development relies on conformity with the reference product; therefore, the regulatory requirements for acceptance should not be different, the authors argue

The authors contend that a consistent application of the science of comparability to all biologics would improve the efficiency of biosimilar development and review, stimulate market competition, and expand patient access.

Modern analytical tools allow for more sensitive and reliable data on comparability that is “often sufficient to confirm comparability without the use of other methods,” they wrote. They outlined technological advances in 4 key areas that have driven the evolution of comparability assessments:

Clear and convergent guidelines from regulators

Use of risk-based methods for weighting analytical data

Progressive improvements and innovation in analytical techniques

Improved understanding of glycosylation and other post-translational modifications

The authors noted that following a change to the manufacturing process of an originator biologic, analytical data “are almost invariably considered to be sufficient by all major regulators” to demonstrate that the change has not altered the approved version of the originator biologic. Incongruously, clinical studies may be required for a biosimilar to demonstrate similarity, they said.

However, following establishment of analytical and pharmacokinetic similarity, clinical equivalence studies “generally do not provide new information as regards biosimilarity,” the authors wrote, citing research on the approvals of approximately 100 biosimilars. This echoed concerns the same group expressed in a previous 

 published in 2019, where they called the “totality of evidence” biosimilars development paradigm “unnecessarily burdensome and inefficient.”

Reliance upon a technical assessment conducted in another jurisdiction would not subsequently commit regulators to the same, or indeed any, regulatory action, and they would retain their statutory independence and responsibilities for regulation at all times.

They noted that the United Kingdom’s Medicines & Healthcare Regulatory Agency (MHRA) has already moved toward a more efficient approach by downscaling requirements for clinical equivalence data for biosimilar approvals. Other regulators are considering similar revisions. These considerations, the authors said, are driven “partly by the typical redundancy of clinical equivalence trials to the conclusion of biosimilarity and the lack of ethical justification for unnecessary trials.”

guidance on the licensing of biosimilar products

 stating that comparative efficacy trials may not be necessary to demonstrate biosimilarity in most cases. The United Kingdom’s post-Brexit guidance on biosimilars also does not require in vivo animal studies to support biosimilarity.

"Almost invariably,” regulators allow sponsors of reference biologics to “support their products’ indications in multiple jurisdictions by submission of the same clinical data,” the authors wrote.

The authors said regulatory requirements for additional layers of evidence (ie, bridging studies) demonstrating equivalence for biosimilars as “unnecessary and tedious impositions upon biosimilar sponsors to generate data whose conclusions are already known.” The same group of authors previously discussed costs associated with bridging studies in a 

“Application of the same calculus to biosimilars as has been applied to reference biologics for decades,” they wrote, “would greatly facilitate the development of new biosimilars with no loss of scientific rigor or safety and no change in the product that is finally approved.”

A critical lever for the improvement of access and control of healthcare costs is the efficiency of development and review, because such improvements in efficiency can allow more competition in the marketplace.

This approach is “a particularly rational approach for biosimilars,” the authors said, in part because regulators would be familiar with the reference product marketed in their jurisdiction and because of the recent advances in analytical techniques: “The orthogonal and replicate nature of biosimilarity data ensures that conclusions are unequivocal and not liable to differ between competent reviewers.”

"Reliance upon a technical assessment conducted in another jurisdiction would not subsequently commit regulators to the same, or indeed any, regulatory action, and they would retain their statutory independence and responsibilities for regulation at all times," they wrote.

Authors of an opinion piece suggest that a "reliance" approach to biosimilar approval could lead to global standards for acceptance that cut down on wasted review time and obsolete clinical investigation. 

Authors Propose Elimination of "Double Standard" for Biosimilars

A cost-efficiency analysis of a hypothetical cohort of 1000 US patients found that converting 2 patients with metastatic breast cancer (MBC) from reference trastuzumab (Herceptin) therapy to a trastuzumab biosimilar (Ogivri) could save enough money to pay for a full year of trastuzumab biosimilar monotherapy for an additional patient.

In the setting of trastuzumab in combination with pertuzumab (Perjeta) and paclitaxel, fewer than 3 patients would need to be converted to trastuzumab biosimilar to generate savings sufficient for a full year of combination therapy (

Arguably, biosimilars approved in well-regulated markets, and therefore regulatorily assured to be equivalently effective and safe, should be recognized internationally as cost-responsible and affordable ways of expanding access to supportive and therapeutic cancer care in economically constrained countries.

The investigators analyzed cost-efficiency and budget-neutral expanded access from conversion of either intravenous (IV) or subcutaneous (SC) Herceptin to biosimilar trastuzumab.

“The marked cost savings achieved by biosimilar conversion to [Ogivri] can be re-allocated to provide expanded access to additional doses or year-long regimens of trastuzumab-dkst on a budget-neutral basis,” the authors wrote.

Trastuzumab is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) that is approved for the treatment of HER2-positive early and advanced MBC. In MBC, trastuzumab is used as monotherapy in patients who have received 1 or more chemotherapy regimens. It is also used in combination with pertuzumab and taxane-based chemotherapy.

, the authors said that although the availability of biologics has “significantly advanced cancer treatment options and outcomes,” the high cost of originator trastuzumab contributes to “significant disparities in access to anti-HER2 therapy in resource-limited communities.”

The investigators calculated savings based on 10% to 100% conversion rates from Herceptin IV and SC formulations to Ogivri in patients stratified by body weight quartiles: 25th percentile, median weight 137 lb; 50th percentile, 161 lb; and 75th percentile, 195 lb. Those weight groupings were labeled Q1, Q2, and Q3, respectively, for purposes of the study.

On a cost-of-drug basis only, conversion from IV Herceptin to the biosimilar produced 1-year savings ranging from $2,272,189 at 10% conversion among Q1 patients to $31,506,804 at 100% conversion rate for Q3 patients. Including both drug and administration costs, the savings were identical: $2,272,189 to $31,506,804.

Conversion from the SC formulation produced an estimated range of 1-year drug cost savings of $2,071,277 at 10% conversion in Q3 patients to $35,775,475 at 100% conversion in Q1 patients. Including both drug and administration costs, savings ranged from $564,347 to $20,706,175. 

Trastuzumab With Pertuzumab and Paclitaxel

Estimated 1-year drug cost savings for conversion from trastuzumab-IV to Ogivri for combination therapy with pertuzumab (all cycles) and paclitaxel (cycles 1-4) in the hypothetical patient cohort ranged from $2,298,610 with 10% conversion in Q1 patients to $32,662,714 at a 100% conversion rate in Q3 patients. Incorporating administration costs, the corresponding range of savings was $2,298,610 to $32,662,714.

For conversion from trastuzumab-SC to Ogivri used in combination with pertuzumab and paclitaxel, 1-year drug cost savings ranged from $1,873,083 with 10% conversion in Q3 patients to $35,322,461 with 100% conversion in Q1 patients. For drug-plus-administration costs, savings were $1,764,255 to $34,234,181.

The investigators went on to calculate the number of patients needed to be converted (NNC) to the biosimilar to generate savings enough to purchase equivalent therapy for 1 additional patient.

Considering drug costs only, the NNC from trastuzumab-IV was 1.71 to purchase a full year of trastuzumab biosimilar monotherapy in all weight categories. The NNC from trastuzumab-SC was 1.09 in Q1 patients, 1.51 in Q2 patients, and 2.61 in Q3 patients.

Including both drug and administration costs of trastuzumab monotherapy, the NNC was 2.23 in Q3 patients, 2.33 in Q2 patients, and 2.43 in Q1 patients for conversion from trastuzumab-IV. For conversion from trastuzumab-SC, the NNC was 2.66 in Q1 patients, 4.18 in Q2

For 1 year of combination therapy (trastuzumab biosimilar, pertuzumab, and paclitaxel), the drug-cost-only NNC from trastuzumab-IV was 4.77 in Q3 patients, 5.46 in Q2 patients, and 6.05 in Q1 patients.

The NNC from trastuzumab-SC to provide 1 full year of combination therapy was 3.94 in Q1 patients, 5.01 in Q2 patients, and 8.32 in Q3 patients. Including both drug and administration costs, the NNC from trastuzumab-IV were 5.03, 5.77, and 6.42, while they were  4.31, 5.51, and 9.31 for conversion from trastuzumab-SC.

At a 100% rate of conversion from trastuzumab-IV to the biosimilar, the simulation model estimated a full, 1-year regimen of biosimilar monotherapy could be provided to 583 additional patients (any weight group) considering drug costs only.

Including administration costs, the estimate was that 412 to 449 additional patients could receive therapy, depending on body weight category.

For conversion from trastuzumab-SC, estimates for expanded access based on drug costs only ranged from 383 to 918 additional patients, based on body weight. Including both drug and administration costs, 80 to 376 additional patients could receive a full year of monotherapy on a budget-neutral basis.

This economic simulation demonstrates that biosimilar trastuzumab is cost-efficient over trastuzumab-IV and trastuzumab-SC across all patient weights in both monotherapy and in combination with pertuzumab and paclitaxel.

For combination therapy, up to 210 (drug costs only) or 199 (drug and administration costs) full-year regimens of combination therapy could be purchased based on a 100% rate of conversion from trastuzumab-IV to biosimilar trastuzumab. For conversion from trastuzumab-SC, up to 254 and 232 patients, respectively, could be provided with a full year of combination therapy.

The investigators viewed their contribution as significant as the “first cost-efficiency and expanded access study” of these biologic drugs. They contended the cost savings and “low” NNC figures estimated by their model could translate into substantial expanded access to biosimilar trastuzumab therapy.

They emphasized that based on their drug-costs-only model, fewer than 2 patients need to be converted from trastuzumab-IV to provide an additional patient with a full year of trastuzumab monotherapy with the biosimilar agent.

McBride A, MacDonald K, Fuentes-Alburo A, Abraham I. Cost-efficiency and expanded access modeling of conversion to biosimilar trastuzumab-dkst with or without pertuzumab in metastatic breast cancer. 

. 2021;24(1):743-756. doi:10.1080/13696998.2021.1928515

Investigators determine that converting at least 2 patients with metastatic breast cancer to a trastuzumab biosimilar could generate savings enough to treat a third patient. 

Trastuzumab Model Measures Expanded Access With Ogivri Biosimilar

Febrile neutropenia (FN) in patients undergoing chemotherapy has long been counteracted with granulocyte colony-stimulating factor (G-CSF) drugs. Models of G-CSF biosimilar use in this setting suggest not only significant savings but also potential for expanded access.

FN is defined as fever and possible infection in combination with a low white blood cell count (neutrophil granulocytes). Guidelines limit the use of G-CSFs as prophylaxis for FN, although during the pandemic in the United States, oncologists broadened use of these agents to reduce hospitalization risk and COVID-19 infection. Savings have been associated with this expanded use. Further, in the Oncology Care Model (OCM), where practices are tasked with reducing costs of care while maintaining quality of care, 

 a 50% increase in use of biosimilar pegfilgrastim from 2014 to 2018.  

G-CSF drugs include filgrastim (originator, Neupogen) and the pegylated, longer-acting form pegfilgrastim (originator, Neulasta), both of which are available as biosimilars. The pegfilgrastim reference product is available as a prefilled syringe (PFS) or an 

 (OBI) that automatically delivers a single dose of pegfilgrastim. Biosimilar G-CSF pegfilgrastim and filgrastim products addressed in the current study were Ziextenzo and Zarxio, respectively.

According to the authors of a recent study published in 

, clinical guidelines clearly indicate G-CSF for patients at high risk of FN; however, the recommendations for patients at intermediate risk “are less clear.” These call for clinical judgment based on the individual patient’s situation. The authors cited recent evidence suggesting that routine, primary prophylaxis with G-CSF in patients at intermediate risk “may lead to reductions in health care utilization and costs.” A major reason for lower rates of prophylaxis with G-CSF products, they said, could be the historically high costs of reference G-CSF drugs.

The investigators conducted their simulation with the OCM in mind. OCM practices receive performance-based payments if they meet their quality and cost-savings goals. The authors hypothesized that a reduction in drug-related costs through the use of biosimilars and in FN-related hospitalizations through expanded access of intermediate-risk patients to G-CSF prophylaxis would help practices meet these goals. 

Their economic analysis simulated cost savings in a US practice associated with (1) switching from originator G-CSF products to biosimilars and (2) switching to biosimilars and expanding access to 10% more intermediate-risk patients. They conducted a 1-year economic analysis of real-world drug costs and health care resource utilization (HCRU) in 500 patients in a hypothetical US oncology practice.

The simulated cohort of patients had a “heterogeneous mix” of nonmyeloid cancers and received 6 cycles of chemotherapy over a 1-year period. Patients were classified as being at high risk of developing FN (greater than 20%), intermediate risk (10%-20%), or low risk (< 10%). The proportions of patients receiving G-CSF prophylaxis were based on previously published real-world evidence: 27 of 45 (59%) patients at high risk, 70 of 240 (29%) patients at intermediate risk, and 24 of 215 (11%) patients at low risk were treated with G-CSF. Of these 121 patients treated with G-CSF, the model estimated 6 would experience an FN event.

Drug costs were derived from current wholesale acquisition costs and administration costs from physician fee schedules, published by the Centers for Medicare and Medicaid Services in April 2020. Nursing labor costs were estimated using national average nurse wages in 2020.

In Model 1, the authors simulated the cost savings associated with use of biosimilars compared with originator G-CSF medications. FN-related costs were not considered and access to G-CSF prophylaxis was not expanded. The cost savings ranged from $537,000 for use of a biosimilar in place of filgrastim to $1.68 million for a biosimilar in place of pegfilgrastim OBI. They noted that the cost of pegfilgrastim OBI is the same as pegfilgrastim PFS; however, administration costs are higher, accounting for the greater savings when switching from pegfilgrastim OBI to biosimilar pegfilgrastim (

In Model 2, in addition to the conversion to biosimilars, hypothetical cost savings were reinvested to provide 10% more patients (n = 24) at intermediate risk of FN with biosimilar G-CSF. The number of high- and low-risk patients receiving G-CSF prophylaxis was unchanged. In this model, it was estimated 7 patients who received G-CSF would experience FN events.

Total cost savings in the expanded access scenario simulated in Model 2 ranged from approximately $25,000 for a change from originator to biosimilar short-acting filgrastim to $1.19 million for a change from pegfilgrastim OBI to a biosimilar. In Model 2, cost savings in HCRU were realized, because the expanded access to G-CSF allowed for reduced FN-related costs (

The investigators said their analysis demonstrated both “substantial” cost savings and improved clinical outcomes from the use of biosimilar G-CSF drugs in patients undergoing myelosuppressive chemotherapy and that these findings are especially relevant to oncology practices striving to meet OCM goals.

“Conversion to biosimilar G-CSFs would allow more patients at intermediate risk of FN to be treated with prophylactic biosimilar G-CSF, with fewer patients experiencing FN events and still generating savings to the practices and health care system,” they said.

Wang W, Li E, Campbell K, McBride A, D'Amato S. Economic analysis on adoption of biosimilar granulocyte colony-stimulating factors in patients with nonmyeloid cancer at risk of febrile neutropenia within the Oncology Care Model framework. 

. Published online May 7, 2021. doi:10.1200/OP.20.00994

Wider use of granulocyte colony-stimulating factor (G-CSF) biosimilars is recommended for patients at risk of febrile neutropenia (FN). 

Analysis: G-CSF Biosimilars Could Reduce Costs While Improving FN-Related Outcomes

Through a series of patient interviews, investigators in Canada say they have discovered what others around the global biosimilars community are discovering. Namely, that well-supported switching to biosimilars, in the form of solid education efforts about biosimilar equivalence, leads to successful clinical outcomes and, importantly, patient acceptance of these agents.

Investigators in British Columbia surveyed patients for their impressions of biosimilars before and after mandatory switching. 