Deana Ferreri, PhD

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

Articles

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.

According to the authors, anticipation of a request from a regulatory agency in a specific country or region is the top reason biosimilar manufacturers conduct in vivo animal studies. They noted “conducting in vivo studies may take less time than waiting for feedback from regulatory authorities in some countries that may then request such data be included for evaluation of similarity.”

The paper summarized in vivo studies conducted for 6 of 8 Amgen candidate biosimilars (neither the FDA nor EMA required in vivo studies for the other 2). All 6 candidate biosimilars and their reference products were tolerated by animals. There were no unexpected safety or toxicity findings, and toxicokinetics were similar between biosimilars and reference products. The authors noted similar findings were reported in a review of in vivo studies conducted by Covance and of in vivo data from European Public Assessment Reports.

The investigators concluded, “Nonclinical studies to support biosimilar development should be reserved for the rare cases in which a targeted toxicology study could address specific questions around residual uncertainty that are unanswered by analytical and in vitro assessments.” For example, in Amgen’s development of an aflibercept biosimilar (ABP 938), “a toxicity study was considered justifiable based on the novelty of the formulation used and injection into the eye, a very sensitive compartment.”

Apart from that example, the investigators wrote, “In vivo studies usually do not have the power to resolve residual uncertainties following analytical and in vitro studies or changes in formulation,” whereas clinical studies can provide that statistical power.

They recommended, “In general, clinical trials should be conducted to determine whether residual uncertainties, after analytical and functional in vitro assessments, confer clinically meaningful differences between a proposed biosimilar and its reference product.”

Mihalcik L, Chow V, Ramchandani M, Hinkle B, McBride HJ, Lebbrec H. Use of nonclinical toxicity studies to support biosimilar antibody development. 

. Published online March 1, 2021. doi:10.1016/j.yrtph.2021.104912

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

Investigators Question Use of Animal Toxicology Studies for Biosimilar Development

Government policies for generics and biosimilars drive down prices too far and fail to incentivize the use of these lower cost medicines, the Association for Accessible Medicines (AAM), a manufacturers’ trade group, argues in a new 

that calls for multiple revisions in public payer policy.

Top among challenges faced by generics and biosimilars are rapid price deflation, anticompetitive practices, and government policies that contribute to both shortages of older generics and slow adoption of new generics and biosimilars, the AAM argues. Among the report’s key recommendations is that policymakers update Medicare to better incentivize the use and production of generics and biosimilars.

The Association for Accessible Medicines argues that “imprudent or out-of-date government policies” undermine the market for less expensive generics and biosimilars and recommended a list of changes, including:

Place generic drugs in Medicare Part D on generic formulary tiers with lower cost-sharing than brand name drugs

Ensure Medicare beneficiaries have access to new generics

Update Medicare Part D to include a dedicated specialty tier for generics and biosimilars

Reward Medicare health plans for encouraging use of lower-cost generics or biosimilars and eliminating barriers to access

End brand “rebate traps” that prevent use of generics and biosimilars

Increase the Medicare Part B add-on payment to providers who use biosimilars

Encourage adoption of biosimilars with a shared savings program

Repeal or amend the Medicaid drug price inflation penalty for generics

The report also made recommendations for emergency preparedness: to support the expansion of the Strategic National Stockpile; to include domestically produced medicines that will be necessary during public health emergencies; and to support local manufacturers of essential medicines “by ensuring the economic conditions exist to justify the use of currently existing local manufacturing capacity.”

The AAM also calls for beefing up domestic production of medicines so that the United States is better equipped to ride out supply disruptions, such as those that occurred during the early stages of the COVID-19 pandemic; however, a yet-unpublished IQVIA study cited by AAM reveals that the US pharmaceutical sector quickly increased supply in response to a demand spike shortly after the pandemic arrived.

Penalties for drug price inflation may apply to generics but not brand name drugs, the group argues, contending this is one reason manufacturers may not launch new generic products and, actually, may discontinue production of generic products, further contributing to supply shortages. Also, the AAM argues, a handful of large wholesaler purchasers in the United States dominate the marketplace and make business conditions even rougher by effectively blocking some drugs from market.

Noting brand specialty drugs and biologics make up approximately 2% of prescriptions but almost 50% of spending on prescription drugs in the United States, the AAM argued that competition from generics and biosimilars is “critical to the long-term affordability of these medicines.” The AAM noted biosimilars “lower the price of the brand-name biologic as a result of competition” and “are directly responsible for increasing patient access to therapy by as much as 5%.” They cited research estimating biosimilars and specialty generics saved patients and taxpayers more than $67 billion in 2019, with projected savings amounting to $100 billion between 2021 and 2025.

Prices for older, commoditized generics have fallen steadily, creating what the report termed “financial pressure” on their producers. The AAM blamed this price decline in part on government policies intended to control the costs of prescription drugs.

One example is a Medicaid inflationary rebate penalty that imposes financial penalties on manufacturers when generic prices under Medicaid increase faster than the average. The AAM contends generics manufacturers are often wrongly penalized because the formula for calculating price increases doesn’t take into account simple price variability caused by “changes in customer mix, not price increases.”

The AAM also blames heavy competitive pressure in markets crowded with producers. Often, newly approved generics simply fail to launch, or might be launched a year or more after they are FDA approved, it said 

Medicare Part D formulary placement is another challenge to a sustainable market for generics, according to the report 

. Patients may pay more at the pharmacy even if the price of their generic drug has fallen, the AAM said, “because Medicare plan formularies now place more generics on brand formulary tiers with higher cost-sharing requirements.”

According to AAM, Medicare Advantage and Part D formularies may prefer brand name drugs over generics and biosimilars. An AAM examination of launches of newly approved generics “found that only about half were included on formularies of Medicare Part D plans.” They found that even when these medicines are added to formularies, they are routinely placed on expensive brand drug tiers with higher patient copays, and that it typically takes nearly 3 years after introduction to the market before first generics are covered on 50% of Medicare Part D formularies.

AAM says that biosimilars, despite being “on average 30% less expensive” than their reference biologics, “have yet to realize the full potential of savings through broad adoption.” The report noted new biosimilars face adoption barriers that “stem largely from payment policies that do not encourage biosimilar adoption or that actively reward use of higher-priced brand drugs.”

Despite their competitive cost, biosimilars in some cases have been slow to win significant market share, which the report attributed largely to rebate traps and other Medicare payment policies. The report singled out Medicare Part B for paying providers the same administration fee regardless if they prescribed more expensive treatment.

“While this ensures providers are not penalized for using a lower-cost biosimilar, it also means providers have no incentive to use the lower-cost option,” the report noted.

Unsustainably low prices for generics are preventing some manufacturers from producing them, while biosimilars are blocked by policies that favor originator drugs, the Association for Accessible Medicines (AAM) argues. 

AAM Seeks Changes to CMS Policy on Generics, Biosimilars

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

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

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

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

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

Comparable pharmacological and clinical parameters

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

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

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

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

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

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

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

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

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

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

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

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

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

Study: Trastuzumab Biosimilar IV Offers Better Value Than Reference SC

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

There are limited data regarding any increased risk of 

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

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

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

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

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

Optimizing Benefit-to-Risk Ratio of Treatments

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

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

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

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

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

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

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

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

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

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

, both from the same cohort of patients in Italy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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