Deana Ferreri, PhD

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

Articles

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). 

Deana Ferreri, PhD

Study Supports Switch From Remicade to SB2 in IBD

Authors Propose Elimination of "Double Standard" for Biosimilars

Trastuzumab Model Measures Expanded Access With Ogivri Biosimilar

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