Deana Ferreri, PhD

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.

Articles

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.

So now what happens? Does the biosimilar have a similar type of auto-injector, or does it even have an auto-injector? I don’t know any of that.

The findings are important as multiple Canadian provinces attempt to switch patients to biosimilars in order to reduce spending on costly biologic drugs. These mandatory switch programs follow years of biosimilar availability but rejection by physicians and patients, many of whom approach switching to biosimilars with fears that they will be less efficacious and result in unpleasant adverse events.

 have each moved forward with mandatory biosimilar switching programs.

The patient perspective on mandatory switching was investigated in a qualitative study of interviews with patients from 2 practices in British Columbia (BC). Investigators concluded that their findings showed patients experienced “apprehension and anxiety” prior to switching from reference biologics to biosimilars, but these concerns could be “addressed with adequate patient-provider communication and support.”

The government of BC, through the BC Biosimilars Initiative, implemented 

 of some patient populations on originator drugs to biosimilars in 2019. In the first phase, patients on reference biologics including etanercept (Enbrel) and infliximab (Remicade) for ankylosing spondylitis, rheumatoid arthritis, and plaque psoriasis were switched to biosimilars. The authors said 78% of patients in this population in BC were switched to biosimilars by March 2020 and noted “this policy change was the first of its kind in Canada and North America.”

To characterize the patient perspective of the BC Biosimilars Initiative, the authors interviewed 9 patients before the switch took place, from October to November of 2019. Three patients did not return for postswitch interviews in July 2020. The average age of the patients was 60.7 (range, 47-80) years. Investigators hypothesized that “patients would be anxious about the switch and reluctant to change to biosimilars for nonmedical purposes, but that if the biosimilars were (as evidence suggests) equivalent, that their perspectives would change post-switch.”

My expectation was it was going to be the same and things would just carry on.

Interviews consisted of open-ended questions regarding patients’ perceptions of the policy change, knowledge of originator biologics and biosimilars, and concerns about the potential effects of the switch on their disease management. In the postswitch interview, patients were asked to reflect on their initial perceptions, expectations, and opinions. Also, because the study duration overlapped with the onset of the COVID-19 pandemic, patients were asked how the pandemic affected their switch to biosimilars and overall care.

Preswitch interview questions included “Do you feel you understand the reason for the change?” and “What do you think are the impacts of switching from originators to biosimilars?”

According to study authors, some of the most common concerns about the switch to biosimilars were whether they would be as effective as originator drugs and whether there would be more adverse events. As expressed by one participant, “Well, I am hoping that it’s going to work as well as the Enbrel, with no side effects, because that’s always a big concern. Any time you switch, it’s not a guarantee that it’s going to work, so it can take you out of any kind of remission that you are in.”

Some patients were concerned about potential disruption to their quality of life from switching and any departure from good results they’d enjoyed with the originator drug. For example, one patient commented, “You have a nice, quiet life going. Everything is working well, and now we’re going to switch drugs. Who knows what’s going to happen?” The authors noted such concerns were common in surveys of patients in the United States and France prior to switching to biosimilars. Those surveys found that almost two-thirds of patients had no knowledge of biosimilars prior to their switch, and more than 40% were not notified they would be switching from a reference biologic to a biosimilar.

Well, I am hoping that it’s going to work as well as Enbrel, with no side effects, because that’s always a big concern. Any time you switch, it’s not a guarantee that it’s going to work, so it can take you out of any kind of remission that you are in.

However, in this survey, participants had a “good grasp of the similarities and differences between biologics and biosimilars” and understood the cost savings rationale for the policy change. One patient described the rationale, “I think the government is just doing it to save money. It’s the same type of drug, just made by a different company.”

Some participants had a positive outlook on the switch, saying for example, “I’m convinced that it’ll be okay.” Others expressed displeasure with the mandatory nature of the switch, saying “No, I am not supportive of the change. It’s being forced upon me,” or, “I have no say in this matter. It’s being decided for me.”

Participants described “an overall positive experience” in postswitch interviews. After the mandatory switch, participants answered questions such as, “What has the biosimilar experience been like for you?” and “Do you feel like any of your prior expectations or opinions regarding the switch have remained the same or changed?”

I never paid for anything with Enbrel. The first time I go in to fill a prescription, they ask me for $75 over and above my plan.

Overall, the authors said, “participants shared positive attitudes towards their experiences switching to biosimilars.” The initial concerns of some patients were not realized, for example, “I just didn’t know if it would work as well as the other medication I was taking. So that was my only concern, and it hasn’t been an issue.” Others’ expectations for a positive experience were met: “My expectation was it was going to be the same and things would just carry on.”

Not all patients had positive experiences. A change in the needle type accompanying the switch to a biosimilar resulted in increased discomfort or pain at the injection site for a few patients.

Participants reported that out-of-pocket costs either stayed the same or increased. According to one patient, “I never paid for anything with Enbrel. The first time I go in to fill a prescription, they ask me for $75 over and above my plan.” One participant of the 6 interviewed after the switch experienced a reduction in disease control, saying “I’ve had some flare-ups...I don’t think it works as well.”

Regarding the effect of the COVID-19 pandemic on their care, patients reported increased feelings of anxiety, difficulty making in-person appointments, and increased use of telehealth.

The importance of support from family and health care providers during the switch was a theme running throughout these interviews, according to the authors. Participants appreciated their rheumatologists answering their questions and showing confidence in biosimilars: “He answered the question beforehand....He said that, in most cases, there weren’t any real problems, any real transition issues, and that it was just as effective [as the originator]. He also said that ‘If you find that you are degrading, we will get you back on the original.’”

I asked him about the different biosimilars that were coming out. He said that he’d looked at studies in Europe and said that, for the type of arthritis that I have, he felt that Erelzi would be the most effective.

The responses of participants in the preswitch interviews suggested they felt well-informed about biosimilars and the upcoming policy change. The authors said this contrasted with findings from the surveys conducted in the US and France, which revealed poor patient knowledge of biosimilars prior to switching and lack of patient notification that switching would occur.

Authors of the BC study said it was noteworthy that “despite our patient population’s knowledge base, participants still approached their switch to biosimilars with apprehension and anxiety.”

The authors concluded, “proper and effective communication strategies from health care providers to patients regarding the switch [are] integral to the success of their changeover and disease management,” and they said this helps prevent the nocebo effect, which is when patients’ doubts about biosimilar effectiveness appear to diminish the effectiveness of these therapies.

They said these interviews suggested that “for the most part, participants were able to successfully manage their disease regardless of their baseline concerns about efficacy and safety.” The authors acknowledged the small sample size, the narrow sampling from only 2 practices, and failure to complete 3 of the 9 postswitch interviews. However, they view their study as providing valuable insight into the patient perspective “during a limited window of opportunity ahead of the first mandatory switching policy in Canada.”

This information on the patient perspective and patient-physician communication, they said, “can help to inform future nonmedical switching policy changes.”

Chew C, Aguiar M, Bansback N, Law MR, Harrison M. Patient perspectives on the British Columbia Biosimilars Initiative: a qualitative descriptive study. 

. Published online May 7, 2021. doi:10.1007/s00296-021-04874-8

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

Biosimilar Switching Study Demonstrates Value of Patient Support, Education

Investigators in Canada reported positive comparative findings for filgrastim biosimilar use in promoting stem cell regeneration in patients with hematological malignancies. They said the evidence supports the extrapolated use of biosimilars across indications approved for originator drugs.

The filgrastim biosimilar Grastofil was studied in the context of mobilization and engraftment, or stimulated movement of stem cells from bone marrow for collection, storage, and later use to replace bone marrow cells (autologous stem cell transplantation, ASCT) that have been damaged by chemotherapy and radiation (myeloablation).

Filgrastim promotes immune cell production and is the first-line treatment for stem cell mobilization in patients with hematological malignancies who receive myeloablative therapy followed by ASCT, the authors wrote.

The real-world study comparing the biosimilar granulocyte colony-stimulating factor (G-CSF) to its reference product filgrastim (Neupogen) for stem cell mobilization prior to ASCT reported similar CD34+ peripheral blood stem cell collection success rates, engraftment kinetics, and hospital stay periods.

In 2016, the Saskatchewan Cancer Agency made a switch from the originator filgrastim to Grastofil, the first biosimilar G-CSF approved in Canada, for all indications of the originator drug. However, the authors noted that because data for patients undergoing stem cell mobilization prior to ASCT were scarce, “physician hesitancy prompted many institutions to continue relying upon higher priced originator products.”

The researchers conducted a retrospective chart review of data from The Saskatchewan Cancer Agency. They identified 217 patients who underwent 

 and transplant between 2012 and 2018. Of those, 170 were treated with the reference product before the 2016 switch, and 47 with the biosimilar after. The authors noted “there were no significant changes in the mobilization [procedure] practiced at this institution” across the 2 time periods. They also mentioned that patients treated with the biosimilar were somewhat older (mean age 59.3 years) than those treated with the reference product (55.9 years).

The primary end point was successful CD34+ stem cell harvest, and investigators reported a 100% success rate in patients receiving the biosimilar and 92.4% in those receiving the reference product; the difference was not statistically significant (

In cases of low peripheral CD34+ count the day before the scheduled collection, 

 (Mozobil) was used as a supplemental therapy to increase stem cell mobilization. Rates of plerixafor use were similar in the reference product and biosimilar groups (25.9% and 23.4%, respectively; 

Among patients mobilized with the biosimilar, 59.6% required more than 1 apheresis day compared with 48.8% of those treated with the reference product, a difference that was not statistically significant (

Engraftment was assessed based on absolute neutrophil count (ANC) recovery and platelet recovery, both of which were described as “highly similar” between groups by the researchers. Mean ANC recovery time in both groups was 11.6 days, and mean platelet recovery time was 14.0 days in patients treated with the reference product vs 14.2 days for the biosimilar. Mean total hospital stay lengths was also similar: 22.4 days for the reference product vs 22.3 days for the biosimilar.

Investigators did not detect any significant differences between groups in these outcomes with further analyses based on disease type or use of chemotherapy. They acknowledged their study did not evaluate safety outcomes.

The authors said their real-world data “built upon other real-world evaluations of biosimilar G-CSF products in the ASCT mobilization setting to help extend global evidence supporting confidence in using biosimilar G-CSF across all approved indications.” They also stressed the significance of their study as “one of the first real-world evidence studies using biosimilar G-CSF in the ASCT setting in Canada.”

Aggarwal V, Sabry W, Elemary M, et al. Real world clinical experience of biosimilar G-CSF (Grastofil) for autologous peripheral blood stem cell mobilization: single center experience in Canada following early adoption. 

. 2021;28(3):1571-1580. doi:10.3390/curroncol28030148

A Canada study of the filgrastim biosimilar Grastofil demonstrated equivalence to Neupogen in candidates for autologous stem cell transplantation (ASCT), an extrapolated use.

Study: Grastofil Equivalence Confirmed in ASCT Setting

Investigators who performed a systematic review and network meta-analysis of treatments for Crohn disease (CD) ranked adalimumab higher than other treatments for the induction of remission and the infliximab biosimilar CT-P13 (Inflectra, Remsima) highest for both maintenance of remission and steroid-free remission. The authors concluded, based on currently available data, adalimumab and CT-P13 should be recommended for treatment of active CD.

Providing justification for the study, the researchers noted that the relative efficacy and safety of biologics, biosimilars, and Janus kinase 1 (JAK1) inhibitors has been unclear, “due to a lack of high-quality, head-to-head randomized controlled trials.”

Although previous studies demonstrated biologics inhibiting tumor necrosis factor alpha (TNF) were superior to immunosuppressive agents, they said, there is a lack of direct comparisons between newer therapies, such as biosimilars and small-molecule JAK1 inhibitors, and traditional biologics.

The authors evaluated 29 randomized controlled trials (RCTs) on anti-TNF biologics infliximab, adalimumab, and certolizumab pegol; the infliximab biosimilar 

; the integrin monoclonal antibody vedolizumab; the IL-12/IL-23 monoclonal antibody ustekinumab; and JAK1 inhibitors tofacitinib, filgotinib, and upadacitinib. They excluded the infliximab biosimilar 

Efficacy outcomes were induction of remission, maintenance of remission, and steroid-free remission; safety outcomes were serious adverse events (AEs) and infections. The researchers used Bayesian methods to make pairwise comparisons between treatments based on a common comparator and ranked the probability of outcomes across all treatments.

In the authors’ model, infliximab, adalimumab, CT-P13, vedolizumab, ustekinumab, and filgotinib were significantly superior to placebo for the induction of remission. There was no statistically significant difference between the biosimilar CT-P13 and other biologics for induction of remission.

Pairwise comparisons suggested both infliximab and adalimumab were superior to certolizumab pegol and tofacitinib. The authors reported the rank probability result favored adalimumab over other treatments for induction of remission.

When the authors limited their analysis to biologics-naive patients, “only infliximab and adalimumab showed statistically significant superiority for the induction of remission.”

The Bayesian model suggested infliximab, adalimumab, certolizumab pegol, CT-P13, vedolizumab, and ustekinumab were superior to placebo for maintaining remission. Furthermore, pairwise comparisons suggested infliximab, adalimumab, certolizumab pegol, CT-P13, and vedolizumab were superior to filgotinib. Upadacitinib was not assessed due to lack of data. The authors said their rank probability results favored CT-P13 and adalimumab over other treatments for maintenance of remission.

For steroid-free remission, infliximab, adalimumab, vedolizumab, and CT-P13 were all superior to placebo, with no statistically significant differences between these treatments in the Bayesian model. The difference between ustekinumab and placebo was nonsignificant. Based on the rank probability results, CT-P13 was favored over the other treatments. The authors said they excluded JAK1 inhibitors from the analysis of steroid-free remission because of lack of data.

In the maintenance phase, rank probability results suggested tofacitinib was associated with a higher probability of infections compared with other treatments, and compared with JAK1 inhibitors, biologics, and the biosimilar CT-P13 were associated with lower probability of AEs and infections.

However, the authors suggested interpreting their safety results regarding JAK1 inhibitors cautiously, “because insufficient real-life data and phase 3 RCT evidence [are] available for evaluating their safety profile.” Furthermore, they acknowledged study findings were limited by a lack of real-world safety data.

The authors noted, “The performance of the novel drug CT-P13 in our study is worthy of mention.” Although there is “little information” about efficacy and safety of CT-P13 compared with treatments other than the infliximab originator or placebo, the authors said their analysis helps to clarify where CT-P13 stands among treatments for CD. They mentioned its lower costs compared with the reference product and reiterated that CT-P13 appeared as effective as other biologics for induction of remission, was favored over all other treatments for maintenance of remission and steroid-free remission, and had lower probability of AEs in their model.

The authors concluded adalimumab, which ranked highest in their model for induction of remission, and CT-P13, which ranked highest for maintenance of remission and steroid-free remission, should be recommended for treatment of active CD. They also said future head-to-head RCTs comparing biologics, biosimilars, and JAK1 inhibitors are warranted.

The authors declared they had “no commercial or financial relationships that could be construed as a potential conflict of interest.”

Wu G, Yang Y, Liu M, Wang Y, Guo Q. Systematic review and network meta-analysis: comparative efficacy and safety of biosimilars, biologics and JAK1 inhibitors for active Crohn disease

. Published online April 14, 2021. doi:10.3389/fphar.2021.655865

Investigators ranked biologics and Janus kinase 1 inhibitors based on past findings. 

Inflectra Stands Out in Meta-analysis of Agents for Crohn Disease

Whether or not estimated failure rates of the pegfilgrastim onbody injector (OBI; Onpro, Neulasta) are factored in, pegfilgrastim biosimilars have the potential to generate significant savings, investigators found in a model simulation analysis. Their study evaluated the potential savings of the pegfilgrastim biosimilar Fulphila used as prophylaxis treatment against chemotherapy-induced neutropenia (CIN).

The OBI, an Amgen follow-on product to Neulasta, is designed to automatically deliver a pegfilgrastim injection outside the clinic, but failure rates for this device have ranged from 1% to 7%, according to authors of the study. Use of the OBI has surged during the COVID-19 pandemic because of the convenience of at-home injections.

The study model simulated a panel of 15,000 US patients at risk for CIN or febrile neutropenia (FN) and estimated the savings from converting patients from pegfilgrastim with OBI to the pegfilgrastim biosimilar. The savings ranged from $481,259 for converting 10% of patients for 1 cycle of prophylaxis to $29 million for converting 100% of patients for 6 cycles. 

When authors of the study adjusted for potential pegfilgrastim-OBI device failure and associated FN-related hospitalization costs, the estimated savings for 6 cycles ranged from $2.9 million for 10% conversion and a 1% failure rate to $32.2 million for 100% conversion and a 7% failure rate.

The authors also quantified the expanded access to pegfilgrastim prophylaxis or antineoplastic treatments that would be possible with these savings. Based on their analysis of 100% conversion to the biosimilar and a 7% failure rate, up to 11% more patients could receive a 6-cycle regimen of prophylaxis with the biosimilar, or 5% more patients could receive antineoplastic treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

For patients undergoing myelosuppressive chemotherapy, CIN and FN are “potentially life-threatening complications,” the authors said, and treatment with granulocyte colony-stimulating factor (G-CSF), which stimulates production, maturation, and survival of neutrophils, is used to reduce the risk of these conditions in many patients. Pegfilgrastim is a pegylated G-CSF, a long-acting form of filgrastim, available as originator pegfilgrastim, OBI, or biosimilar.

The authors noted that pegfilgrastim treatment for CIN/FN prophylaxis is recommended 24 to 72 hours following chemotherapy, which presents a logistical challenge, because patients must return to the oncology clinic the day after their treatment. Real-world data suggest that same-day administration “is becoming increasingly common.” In 2015, the FDA approved the Amgen OBI device for pegfilgrastim administration, which is attached to the patient on the same day as chemotherapy treatment and is designed to automatically deliver a pegfilgrastim injection the next day, approximately 27 hours later.

The authors explained that because the device administers a single dose of pegfilgrastim, “a missed or partial dose resulting from device failure may significantly increase the risk for FN and FN-related hospitalizations.”

In the study, cost savings were calculated first without and then with hypothetical OBI device failure and associated FN-related hospitalization costs. The medication costs were based on average sales prices from 2020, and costs of administering the medications were included. Costs were calculated from the payer’s perspective; patient costs such as co-pays were excluded. FN-related hospitalization rates and costs were based on existing data for US patients with non-Hodgkin lymphoma.

Cost Savings in 15,000 Hypothetical US Patients

The authors estimated that per-patient treatment with pegfilgrastim biosimilar rather than pegfilgrastim-OBI would save $321 for 1 cycle and $1925 for 6 cycles (

). Across the panel of 15,000 patients, the model calculated potential cost savings ranging from $481,259 if 10% of patients converted to the biosimilar in 1 treatment cycle to $28.9 million for 100% of patients converted over 6 cycles.

By reallocating the savings over 6 cycles, if 10% of patients received pegfilgrastim biosimilar instead of pegfilgrastim-OBI, 919 additional doses of pegfilgrastim biosimilar could be purchased; if 100% of patients received pegfilgrastim biosimilar, 9191 additional doses could be purchased, allowing an additional 1532 patients to be treated with the biosimilar. Alternatively, if cost savings were reallocated to purchase additional doses of anticancer therapy with R-CHOP, at a 100% conversion rate for 6 cycles, 744 additional patients could be treated.

The number of patients needed to convert (NNC) from pegfilgrastim-OBI to pegfilgrastim biosimilar to purchase 1 additional dose of the biosimilar was 9.79 patients for 1 cycle and 1.63 for 6 cycles. To purchase 1 additional dose of R-CHOP, the NNC was 20.17 patients for 1 cycle and 3.36 patients for 6 cycles.

Incorporating OBI device failure rates of 1% to 7% and the associated FN-related hospitalization costs into their simulation, the authors projected that over 6 cycles of prophylaxis, cost savings in 15,000 hypothetical patients would range from $2.9 million for a 10% rate of conversion to the biosimilar and device failure rate of 1% to $32.2 million for a 100% conversion rate and 7% failure rate. FN-related hospitalization costs based on a 7% OBI failure rate over 6 cycles would add up to $3.4 million (

The model’s results suggested reallocating those savings could provide up to 10,261 additional doses of the biosimilar or 4982 additional doses of R-CHOP.

The authors concluded that “biosimilar pegfilgrastim is a clinically relevant, cost-efficient, and safe alternative to reference pegfilgrastim-OBI for CIN/FN prophylaxis,” that the cost savings “increase markedly when also accounting for pegfilgrastim-OBI failure and associated FN-related hospitalizations,” and these cost savings could allow “significant numbers” of additional patients to access prophylaxis with the biosimilar or antineoplastic therapy with R-CHOP.

McBride A, MacDonald K, Fuentes-Alburo A, Abraham I. Conversion from pegfilgrastim with on-body injector to pegfilgrastim-jmdb: cost-efficiency analysis and budget-neutral expanded access to prophylaxis and treatment. 

. Published online April 18, 2021. doi:10.1080/13696998.2021.1916863

The savings from pegfilgrastim biosimilars rapidly add up, according to a study simulation that accounted for hospital costs associated with the on-body injector.

Investigators Measure Pegfilgrastim Biosimilar Savings Potential

The story of biologics and biologic copy products in India is very much a story about a work in progress. Although some companies are producing genuine biosimilars on par with international standards, many products fall into categories that are not comparable to biosimilar quality in the West. Recently, Indian regulators have endeavored to provide a pathway toward biosimilar development that meets international standards.

Newer, more comprehensive guidelines issued by Indian authorities in 2016 were intended as an upgrade to standards from 2012 that governed 

, India’s term for biosimilars. “A similar biologic product [in India] is that which is similar in terms of quality, safety, and efficacy to an approved reference biological product based on comparability,” the authors of a recent paper explained.

The authors noted India’s success in providing access to biologics, stating that approximately 60 biologics have been approved in India, almost half of which are similar biologics. In India, the cost of similar biologics “is approximately half the cost of innovator products,” and patient assistance programs address affordability and improve access.

However, there is also the potential for compromise: almost 20 similar biologics to infliximab, etanercept, adalimumab and rituximab were approved based on the less-stringent 2012 guidelines and were supported by limited clinical data.

The authors discuss the difficulty of producing biologics and true copies of originator products in a country that does not have the resources that the West does. “It remains a big challenge for a biosimilar manufacturing company to develop a similar product, as detailed information on the process of manufacturing of the original drug is patent protected and also because the same cell line is not available to the biosimilar manufacturer. Any changes in the manufacturing process such as use of different cell lines, growth medium, and protein purification processes can also result in variations in the final product,” the authors wrote.

Further, doubts about the quality of biologics persist and small patient population sizes during trials conducted to demonstrate bioequivalence to reference products may not produce the volume of data necessary to satisfy the need for statistical clarity, the authors wrote.

“In controlled clinical studies of biologics, particularly biosimilars, safety concerns may occur beyond the study completion. Long-term evaluations, such as postmarketing studies of biological agents, are required as there are only limited patient experiences available during approval in terms of safety and immunogenicity. Side effects related to the long-term use, off-label use, drug-drug interactions, or use in comorbid conditions can only be identified on exposure to the drug after its approval,” they said.

, need to be distinguished from similar biologics to prevent physician and patient confusion. They cite significant differences in the approval process for these products. Unlike similar biologics, intended copies do not undergo comparative clinical studies or analytical studies to demonstrate similarity to the reference product and have not been equated with similar biologics under the 2016 regulatory guidelines. With so little data, patients “face a greater risk of therapeutic failure and side effects” from these products, the authors reasoned.

Similar biologic products were evaluated on a case-by-case basis prior to the first approval guidelines for similar biologics released by India’s Central Drugs Standard Control Organization (CDSCO) in 2012. The 2016 guidelines were developed with some input from the World Health Organization (WHO) and “expert consensus opinion.” The goal of the 2016 rules was “to provide a well-defined pathway at par with international regulations,” although there is lingering controversy over whether India’s current guidelines achieve international standards.

The authors compared CDSCO’s 2016 guidelines with those of the FDA, the European Medicines Agency (EMA), and the WHO. Like the guidelines from the FDA, the EMA, and the WHO, India’s require demonstration of similarity to the originator product in nonclinical studies, a comparative pharmacokinetic and pharmacodynamic study in humans, a comparative clinical efficacy and safety trial in a relevant medical condition (India’s guidelines specify the trial should include more than 100 patients), and postmarketing safety monitoring.

The authors also highlighted “key considerations” regarding the current guidelines, which they say should be addressed in future iterations.

Interchangeability is not addressed in India’s biosimilar guidelines, and the authors noted that reference products are often switched for similar products “randomly by the prescriber or pharmacist based on the product cost and assumed patient affordability.” In 

, interchangeability is determined by individual member states. The United States has a process for biosimilar products to demonstrate 

, but no biosimilar has yet met this standard.

Nomenclature is also not addressed in CDSCO’s 2016 guidelines. The authors commented that accurate safety monitoring of biologics and biosimilars depends on identifiability “with easily distinguishable product names.” The WHO recommends a 4-letter suffix with the international nonproprietary name to distinguish a biosimilar from its reference product and other biosimilars to that reference product. However, 

 have been controversial, as they are thought to cause patient hesitance or confusion.

The authors also expressed concern about transparency in labeling, saying the package insert for a similar biologic should clearly disclose the extent of similarity to the reference product with respect to safety, immunogenicity, and efficacy.

Overall, the researchers view the 2016 regulations as successful in improving “stringency” in the approval process and more closely matching the safety requirements of international guidelines. However, some experts consider the 2016 requirements less stringent than EU and US standards.

Jois R, Mukherjee S, Rajeswari S, Rath PD, Goyal V, Gupta D. Similar biologics in India: a story of access or potential for compromise? 

. 2020;152(5):456-467. doi:10.4103/ijmr.IJMR_43_18

India has tightened up guidelines for biosimilar development in a quest to achieve standards equivalent to those in Europe and the United States. 

Indian Biosimilar Standards: A Work in Progress

In vivo animal studies of biosimilars “have added little evidence to provide clinically relevant information for biosimilar development,” concluded investigators in an 

 of the company’s findings from nonclinical animal studies during the development of 8 biosimilar candidates.

Demonstrating biosimilarity uses a “totality of evidence” approach. This starts with assessing structural and functional characteristics in analytical studies, possibly followed by 

 comparing the reference product and candidate biosimilar in animal models. Human clinical studies follow in the form of a clinical study to evaluate comparative pharmacokinetic and pharmacodynamic parameters and, potentially, a comparative clinical efficacy and safety study.

The authors shared their experiences and perspectives on the value of nonclinical toxicology studies, concluding animal studies “have provided little information to meaningfully inform clinical efficacy, safety, or immunogenicity.” They said that comparative clinical studies are the best way to confirm similarity in pharmacokinetics and pharmacodynamics, efficacy, safety, and immunogenicity between a biosimilar candidate and a reference product.

Different Approaches to Nonclinical Toxicology Studies

The authors noted the requirement for nonclinical toxicology studies differs by regulatory agency. In the United States, evidence from animal studies supporting biosimilarity is sought when the FDA considers that “uncertainties remain regarding the safety of the proposed product that need to be addressed” after analytical similarity has been demonstrated.

In contrast, the European Medicines Agency (EMA) requires animal toxicological studies only in some situations, such as “when the proposed biosimilar is produced in a different type of cell or organism, or when the formulation includes new [nondrug substances] not previously used.”

In Japan, the Pharmaceuticals and Medical Devices Agency determines if animal studies are required depending on the extent of biosimilarity demonstrated by analytical studies and the “degree of residual uncertainty” regarding similarity between the originator and biosimilar. World Health Organization guidelines are similar.

Animal toxicology studies contribute little to demonstrations of biosimilarity and yet these studies frequently must be done to satisfy international regulatory requirements, investigators conclude. 