Deana Ferreri, PhD

US rheumatologists who prescribe tumor necrosis factor (TNF) inhibitors are familiar with biosimilars; however, there is broad awareness only of infliximab biosimilars, according to a survey. The results suggest most are willing to prescribe a biosimilar for a biologic-na

ve patient who has the condition the biosimilar’s approval was based on, but they are hesitant about extrapolated conditions and nonmedical switching.

The authors cited previous research suggesting “health-care providers in the USA and Europe remain 

” about using biosimilars, and aimed to update the literature with current perceptions of US rheumatologists who prescribe TNF inhibitors.

The 19-question online survey was given to 320 board-certified rheumatologists in the United States. The authors thought it important to gauge the perceptions of rheumatologists because TNF inhibitors “are the cornerstones of therapy for many chronic immune-mediated diseases, such as [rheumatoid arthritis],” and “[rheumatologists] will require education about the biosimilars of these agents before they are comfortable offering them to their patients.”

Survey questions covered rheumatologists’ familiarity with biosimilars, reasons for choosing a biosimilar or its reference product, interchangeability and extrapolation, non-medical switching, and use of biosimilars in different patient scenarios. The survey was administered in May and June of 2019.

Low Awareness of All FDA-Approved Biosimilars

Most rheumatologists (85%) were familiar with the FDA definition of a biosimilar product, but their awareness of FDA-approved biosimilars was “lacking,” according to the authors. Whereas nearly all survey respondents (96%) knew the FDA had approved an infliximab biosimilar, “fewer realized that adalimumab, etanercept and rituximab biosimilars were FDA approved (56%, 62% and 39%, respectively).”

Deciding Between a Biosimilar and Its Reference

Respondents were asked to rank by importance 7 factors they might consider when choosing to prescribe a biosimilar or its reference product: effectiveness, safety, patient cost, immunogenic risk, availability of data on switching, physicochemical and functional characteristics, and durability of response. Effectiveness was ranked first or second by 77% of respondents, followed by safety by 45%, whereas 51% ranked physicochemical and functional characteristics sixth or seventh.

Notably, only 27% of rheumatologists surveyed ranked reduced cost for the patient first or second. 

, in contrast, found cost is a significant issue for rheumatologists, but they considered the savings with biosimilars insufficient to prescribe them in place of their reference products.

Prescribing Biosimilars for Extrapolated Conditions

Only about half (54%) of rheumatologists surveyed were familiar with the term “non-medical switching.” When asked about prescribing for a patient with the same condition the biosimilar’s approval was based on, 73% said they were likely to prescribe a biosimilar to a biologic-

 patient, but only 35% said they were likely to switch a patient who was doing well on the reference product. For an extrapolated condition, rheumatologists were less willing to use biosimilars: 40% rated themselves as likely to prescribe a biosimilar for a biologic-

 patient, compared with 21% if the patient was doing well on the reference product.

Most (84%) respondents knew that FDA approval does not imply interchangeability, and “86% felt it important/very important for interchangeable approval to be on the label.”

The authors said their results suggest that US rheumatologists “understand and accept” biosimilars, especially for biologic-

 patients, but they are cautious about extrapolated conditions and non-medical switching. The authors concluded by arguing that “additional education on biosimilars is required to help inform treatment decisions by rheumatologists.”

Gibofsky A, McCabe D. US rheumatologists' beliefs and knowledge about biosimilars: a survey. 

. Published online November 4, 2020. doi:10.1093/rheumatology/keaa502

Articles

US Rheumatologists Understand and Accept Biosimilars, but Some Hesitation Remains

A new study of specialty drug spending charted the tremendous rise of this prescription category in just a short span of time. Authors of the study, published in 

 highlighted the growth of rebates and how these complicate the job of determining how much is actually being paid for these medicines.

They said biosimilars have “lowered spending,” although they ultimately may be less influential on pricing than generics have been, and both generics and biosimilars “may be less effective when new innovators enter the market and draw patients to newer brand-name drugs and away from [less costly drugs].”

From 2010 to 2017, spending net of rebates on retail specialty drugs tripled for Medicare Part D beneficiaries, more than doubled for people with private coverage, and grew only slowly for Medicaid beneficiaries, according to the study by economists with the Agency for Healthcare Research and Quality (AHRQ). Overall, from 2016 to 2017, specialty drugs made up 38% of net retail and mail-order prescription spending.

Quantifying spending on specialty drugs is difficult, according to the authors, because of the complexity of rebates, whose use is hard to track and has grown rapidly in specialty drug medicine. ”Rebates are not part of the transactions that occur at pharmacies, are not reflected in typical data on spending, and are proprietary.”

Although there is no precise definition of specialty drugs, the authors used CMS guidelines to define retail specialty drugs in their study as having a median price greater than $600 over 2010 to 2016 and greater than $670 in 2017 for a 30-day supply.

The authors, from the Division of Research and Modeling of the Center for Financing, Access and Cost Trends at the AHRQ, used 2010-to-2017 data from the Medical Expenditure Panel Survey (MEPS) on spending on retail specialty drugs overall and in 3 payer categories: Medicare Part D, Medicaid, and private insurance. The MEPS data did not include provider-administered drugs, which “include most cancer medications and many injectable drugs that are more likely to be high-cost specialty drugs,” they wrote.”

Between 2010 to 2017, according to the authors, “specialty drugs accounted for a small, but significantly growing, share of retail drug fills and refills.” Specialty drugs increased as a percentage of total retail drug fills for patients in all 3 coverage categories and overall, from 1.0% to 2.3% of total retail drug fills.

The proportion of the insured population who obtained at least 1 specialty drug more than doubled overall from 2.2% to 5.0%. In 2016 to 2017, the percentage was more than twice as high among Medicare Part D beneficiaries (9.7%) compared with those with Medicaid (3.5%) or private insurance (4.5%). The authors suggested this could be due to a greater prevalence of the conditions treated by specialty drugs among people ages 65 and older.

Average annual gross spending on retail specialty drugs more than doubled over the study period, as did net spending, from $49.6 billion to $112.6 billion. In the Medicare Part D population, net spending on retail specialty drugs increased from $11.3 billion to $35.4 billion, and in the privately insured population, from $24.6 billion to $57.6 billion.

In comparison, net spending for Medicaid beneficiaries appeared flat: $7.9 billion in 2010 to 2011 to $8.0 billion in 2016 to 2017. The authors cautioned these data were “imprecisely estimated,” but they said the trend, “in any case, is much lower than the tripling for Medicare Part D [212% increase] and the doubling for private insurance [134%increase].”

From 2010 to 2017, average annual rebates nearly quadrupled, from $11.5 billion to $44.7 billion, and increased from 19% to 28% of gross spending. In 2016 to 2017, rebates made up 30% of Medicare Part D gross spending, 24% of private insurance gross spending, and 53% of Medicaid gross spending on specialty drugs.

As a share of net spending for all retail drugs, net spending on retail specialty drugs more than doubled over the study period, reaching 31.5%, 37.8%, and 43.6% of total net spending for retail drugs for Medicare Part D, Medicaid, and private insurance, respectively.

The authors said their study “highlights the important role of rebates in retail specialty drug spending, especially for Medicaid.” Their data showed rebates made up half of gross Medicaid spending on retail specialty drugs. They noted that average net spending per fill did not increase during the study period, and therefore the growth in net spending was driven by an 

They predicted spending on specialty drugs will continue to increase “as more innovative medicines that are likely to be classified as specialty drugs are predicted to reach the market during the next 5 years than in the past 5 years.”

Specialty drugs pose a challenge for payers trying to hold down spending rather than restrict access to the drugs. The authors suggested the best strategies for containing prices are to bring generics and biosimilars to the market more quickly, give Medicare the authority to negotiate lower prices, and increase price transparency for prescribers.

Hill SG, Milled GE, Ding Y. Net spending on retail specialty drugs grew rapidly, especially for private insurance and Medicare Part D. 

This study of specialty drug spending looks beyond rebates to evaluate growth in spending from 2010 to 2017. 

Study: Specialty Drug Spending Net of Rebates Soars for Private Insurance, Medicare Part D

 for improving biosimilar use from 44 interviews with physicians, hospital pharmacists, nurses, patients (or their representatives), and regulators across Europe.

According to the authors, both health care professionals and patients are reluctant to switch from reference products to biosimilars “because of a lack of trust in and understanding of [biosimilars].”

Their recommendations ranged from individual clinician behaviors to national policies. The recommendations addressed how to implement a switch, minimize the nocebo effect following a switch, communicate with patients about biosimilars, and appropriately incentivize health care professionals to prescribe biosimilars.

The health care professionals interviewed broadly agreed, based on the available data, that patients can be safely switched to biosimilars. However, some patients “requested studies over a longer timeframe to better evaluate the long-term effects of switching.”

Stakeholders preferred a structured and collaborative approach when implementing a switch, citing the need for a clear European regulatory position on interchangeability and switching, along with guidance on multiple switching.

Stakeholders generally opposed forced switching. According to the authors, “forcing a switch was believed to be counterproductive and could result in distrust of biosimilars.”

Patients favored starting only biologic-na

ve patients on biosimilars. Health care professionals agreed this was appropriate in some circumstances, such as shorter treatment periods.

Although the majority of studies on switching have not reported any major safety, efficacy, or immunogenicity issues, use of biosimilars is sometimes discontinued by patients who perceive problems. The authors noted, “a number of real-world studies have reported a relatively high therapy discontinuation rate among patients after switching, which was mostly attributed to the occurrence of the nocebo effect.”

Most stakeholders considered physician confidence essential to minimizing the 

. One interviewee commented, “the patient is confident when the physician is confident.”

Although most health care professionals thought patients should not be involved in making the decision to switch, some reasoned involving the patient in the decision-making process would “reduce reluctance, avoid nocebo effects, and build trust.”

Some regulators suggested that clinicians and patients be informed that biosimilars “are only authorized if their efficacy and safety profiles are shown to be equal to those of the reference product.”

Overall, health care professionals said they have a difficult time determining the appropriate amount and type of information to provide to patients. Tailoring the communication to each individual patient was considered important.

Several nurses stressed that communication should not be complicated. Health care professionals overall agreed that communication should focus on “explaining that the biosimilar is equally as safe and effective as the reference product and that patients may expect the same outcomes.” One nurse, speaking of her experience of working with patients who were switched to a filgrastim biosimilar, said, “as it was communicated that the product had all the same side effects and the same precautions were needed, there was no big deal about it.” 

Similarly, some stakeholders argued that putting too much emphasis on the switch and spending too much time discussing the switch could unintentionally cause the patient to worry and trigger a nocebo effect.

Several interviewees stressed the importance of taking patient concerns seriously. They commented on the sensitive nature of switching a patient away from a drug that had brought them into remission from a serious disease.

Patients pointed out that cost savings are a motivator only for some patients. According to the authors, “the willingness to switch may be greater in settings where these medicines are only partly reimbursed.” Other stakeholders stressed, the authors said, “it should be made clear to the patient that less expensive does not equal inferior.”

Physicians and pharmacists also voiced concern that the benefits of biosimilar use are an important motivator, but often are not communicated clearly.

Most physicians and pharmacists favored substitution at the pharmacy level, provided the physician is informed about it. Patients also favored pharmacy substitution, given that the patient is told. Physicians generally opposed automatic substitution. They wanted to be able to know which product the patient received when a problem arises. The nocebo effect was also a concern. The authors said, “this study found that stakeholders are concerned about mandated switching, as this may result in worse patient-perceived treatment outcomes because of a possible nocebo effect.”

Several regulators, physicians, and pharmacists agreed drugs should be used in a cost-effective manner for the common good. However, physicians also noted the substantial time and effort required to switch a patient from a reference product to its biosimilar may discourage prescription of biosimilars.

Most physicians and nurses and some regulators viewed tangible incentives as appropriate but direct financial benefits as inappropriate. The idea of gainsharing, allocating biosimilar savings toward improving patient care, was embraced by most interviewees as a positive motivator, because “savings could partially serve to improve local clinical care.” Some examples of gainsharing mentioned were financial support for a hospital ward, hiring new staff, or reinvesting biosimilar savings to enhance monitoring of patients.

The investigators concluded with 11 key recommendations derived from their interviews:

Addressing health care professionals’ needs regarding switching and biosimilar use

Communicate about study results and clinical experience on switching.

Express a clear, consistent EU regulatory position on biosimialr interchangeability.

Develop a multistakeholder protocol to guide switching in clinical practice.

Develop tangible and intangible incentives for stakeholders to use biosimilars.

Recommendations regarding switching decisions

Avoid mandatory switching but allow communication between stakeholders.

Recommendations for long-term sustainable competition with a biosimilar presence

Raise awareness about drug prices and societal responsibility to prescribe and use drugs cost-effectively.

Actively and publicly communicate the benefits of biosimilar use.

Share biosimilar uptake and prescribing data “to allow peer-to-peer benchmarking.”

Report the savings allocation from biosimilar use transparently.

Develop policies with a long-term vision beyond short-term cost savings.

Barbier L, Simoens S, Vulto AG, Huys I. European stakeholder learnings regarding biosimilars: part II–improving biosimilar use in clinical practice. 

. Published online October 15, 2020 Oct 15. doi:10.1007/s40259-020-00440-z

European investigators have derived a set of core principals for developing higher utilization of biosimilars. 

Europeans Devise Checklist for Promoting Biosimilar Use

Two new publications provide evidence that the rituximab biosimilar CT-P10 (Truxima; Celltrion) could lower costs and expand patient access to biologic therapy for primary Sjögren syndrome (pSS)

 and an expert opinion that CT-P10 is a useful alternative to its reference product for treatment of rheumatoid arthritis.

CT-P10, the first biosimilar to reference product rituximab (Rituxan, MabThera; Roche) to be marketed in the United States, is 

 for treatment of non-Hodgkin lymphoma in the United States and all indications of rituximab in the European Union.

, investigators compared the rituximab originator with CT-P10 in a real-life setting in patients with pSS, a mucosal disease with various extraglandular manifestations. In 5% of patients, pSS evolves into B-cell lymphoma. Investigators noted that rituximab has been used 

The authors discussed the significant role of B lymphocytes in the pathogenesis of pSS, noting that rituximab targets CD20, a B-cell surface receptor, and induces cell death. Rituximab has value in B-cell depletion therapy designed to eliminate malignant cells. 

As of yet, rituximab for pSS has been evaluated in 4 randomized controlled trials (RCTs), plus prospective and case-control studies, and according to the authors, the majority of studies showed improvement in at least 1 outcome, such as disease activity scores, prednisone reduction, or organ-specific response. Most studies showed that rituximab reduced B lymphocyte numbers and activity. However, they said, “the clinical efficacy of B-cell depletion therapy with [rituximab] in pSS remains controversial” and the evidence from randomized control trials “is weak.”

An analysis of data from a separate trial of anti–B-cell therapy in patients with PSS concluded rituximab is not cost-effective for treating pSS. Therefore, guidelines for treating pSS suggest “the use of [rituximab] should be reserved to selected patients with severe, refractory systemic disease.” In light of the high cost of treatment, the authors argued that CT-P10 could be a safe and cost-effective alternative to the reference product and improve access for patients with pSS who have severe, refractory systemic disease.

In this small study in a real-life setting (N = 17), which included 9 patients in the rituximab originator group and 8 in the biosimilar group, the investigators performed a retrospective analysis of 48 weeks of clinical and laboratory data of patients with pSS from a tertiary rheumatology clinic. According to the authors, this is the first study comparing rituximab with its biosimilar in patients with pSS.

Similar disease activity and B lymphocyte numbers between groups

Baseline characteristics, including age, disease duration, and clinical and laboratory parameters, did not differ between groups. Overall, patients had moderate-to-high disease activity and disease duration of less than 5 years.

Measures of disease activity as assessed by clinicians improved significantly from baseline in both groups starting at week 24 and continuing through week 48. Minimal clinically important improvement (MCII) based on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and clinESSDAI (ESSDAI without biological domains) was attained by all patients by 48 weeks.

There was no significant improvement from baseline at any timepoint in patient-reported symptoms in either group, as assessed by the EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI). However, 6 of 8 patients in the CT-P10 group and all 9 patients in the originator group achieved MCII based on ESSPRI (a reduction of at least 1 point or 15% of the baseline value) by 48 weeks.

Similar depletion of CD19+ lymphocytes was reported in both groups.

The authors said safety profiles were similar. Four adverse events were recorded in 4 patients across the 12-month follow-up: 1 mild cutaneous reaction (originator group) and 3 upper airway infections (1 originator group, 2 biosimilar group) that required antibiotic therapy.

The authors said that “given the lack of studies on CT-P10 in pSS, [their investigation] provides important insight to clinicians who will be required to use this compound in pSS patients,” despite the small number of patients and retrospective nature of the study.

Expert Opinion on Drug Metabolism & Toxicology

 evaluated the pharmacokinetics, pharmacodynamics, toxicology, efficacy, and safety of CT-P10 in 

. The authors provided an expert opinion, saying CT-P10 may be a “useful alternative for the treatment of RA in all indications for originator RTX.” They recommended more studies to investigate long-term effectiveness and safety of CT-P10 in real-world settings, as well as research into new indications for CT-P10 and effective ways to counteract the nocebo effect for all biosimilars. CT-P10 is currently approved for RA in the European Union but not in the United States.

1. Pavlych V, Di Muzio C, Alunno A, Carubbi F. Comparison of rituximab originator with CT-P10 biosimilar in patients with primary Sjögren's syndrome: a retrospective analysis in a real-life setting. 

. Published online September 8, 2020. doi:10.3389/fmed.2020.00534

2. Yoo DH, Suh CH, Shim SC, Lee SJ, Kim SH, Park W. A pharmacokinetic evaluation of the rituximab biosimilar CT-P10 in the treatment of rheumatoid arthritis. 

. Published online October 5, 2020. doi: 10.1080/17425255.2020.1832082

Investigators note similar efficacy and safety profiles in real-life study of reference and biosimilar forms of rituximab.

CT-P10 and Reference Rituximab Evaluated in Primary Sjögren Syndrome

Of the 54 biosimilars approved by the European Medicines Agency (EMA) as of August 2019, fewer than half (24) are available in Slovakia, but if the remaining 30 biosimilars were available the nation’s health fund could save €35 million to €50 million (approximately $41 million to $59 million) per year, according to a new study.

The authors first compared biosimilar use among Visegrád Group (V4) countries: the Czech Republic, Hungary, Poland, and Slovakia. Of the 54 biosimilars approved by the EMA, 29 were available in the Czech Republic, 28 in Poland, 27 in Hungary, and only 24 in Slovakia.

Looking at biosimilar availability over time, the authors noted that 6 biosimilars became available in Slovakia between 2013 and 2015, but no new biosimilar drugs were added to the reimbursement list until the second half of 2018. Since then, the Ministry of Health added 15 more biosimilar drugs. Some of these biosimilars were added following expiration of patents on the reference drugs, and others were able to enter the market once Slovakia’s Ministry of Health reduced their compulsory price discount for biosimilars, which took effect in January 2019.

As of January 2019, Slovakia’s Ministry of Health requires that the first biosimilar marketed for a particular active substance to cost 25% less than the reference product (down from 30%). The second marketed biosimilar must cost 30% less than the reference drug, and the third must cost 35% less.

The authors also noted that biosimilar drugs containing the active substances somatotropin, enoxaparin, and insulin lispro are not yet available in Slovakia.

In 2018, filgrastim biosimilars had the greatest market share of biosimilars in Slovakia at 99.93%, followed by erythropoietin biosimilars at 75.44%, insulin glargine biosimilars at 36.29%, infliximab biosimilars at 25.07%, and follitropin alfa biosimilars at 21.11%. Rituximab and trastuzumab biosimilars have been introduced since 2018 but have so far gained paltry market share at 2.31% and 0.07%, respectively.

The authors argued biosimilars could improve health system sustainability in Slovakia, remarking that reference biologics are often too expensive for Central and Eastern European countries, since “the launch price of high-cost biologic medicines is set according to the highest acceptable price by payers in large and high-income countries with the greatest market potential. These prices are frequently not acceptable in lower income countries.”

The researchers calculated potential cost savings using 2018 price data, assumed no increase in the use of biosimilars, and estimated a 25% to 35% lower price compared with reference products, consistent with Slovak Ministry of Health requirements.

Based on data provided by drug distributors to the State Institute for Drug Control, the authors calculated cost savings of between €35.44 million and €49.62 million (approximately $41.60 million to $58.25 million) per year if more biosimilars were more widely available in Slovakia. They validated their calculations using data from payers provided to the National Health Information Center, which resulted in estimated cost savings of €26.65 million to €37.32 million (approximately $31.28 million to $43.81 million) per year.

The authors acknowledged that cost savings are limited by the complexity and expense of the manufacturing process for biosimilars; however, they wrote that “absolute cost savings could still be significant because of the high prices and volumes of the reference medicines.”

The authors also cautioned that Slovakia’s mandatory price discounts and strict rules for international price referencing undermine the overall strategy of trying to lower biosimilar prices by discouraging manufacturers from marketing their products in the country. Most European Union member states, they wrote, regulate drug prices similarly based on referrals from other member states, which may motivate manufacturers “to maintain higher list prices even for less affluent countries, so that list prices do not drop across the European market.”

The authors argued, “It is therefore important for buyers to set appropriate price reduction rules. From an economic point of view, price regulation is needed unless fair competition generates a market price.”

They also pointed out the ultimate goal is the potential benefit to the health of the society, saying “the role of biosimilars is not only about cost-saving potential but improving patient access to needed biological pharmacotherapy and ultimately to improve health status of the society.”

Maximizing the Social Benefit of Biosimilars

The authors concluded with a list of recommended policy practices to maximize the social benefit of biosimilars. These included:

Incentivizing more affordable biosimilars

Expedited pricing and reimbursement processes to facilitate prompt market entry

Prescribing either biosimilars or off-patent biologics as first-line therapy for treatment-naïve patients

Switching patients to biosimilars under medical supervision after the expiration of a patent

Allowing earlier patient access to biologics when justified

Paying the same reimbursement for biosimilars and originator biologics

Providing guidance to physicians for educating their patients about biosimilars

Establishing information exchange regarding clinical use of biosimilars between European Union member states

Tesar T, Golias P, Kobliskova Z, Wawruch M, Kawalec P, Inotai A. Potential cost-savings from the use of the biosimilars in Slovakia. 

. Published online August 21, 2020. doi:10.3389/fpubh.2020.00431

Biosimilars could improve health system sustainability in Slovakia; however, of the 54 biosimilars approved by the European Medicines Agency as of August 2019, fewer than half are available in Slovakia

Potential Cost Savings From Improving Biosimilar Availability in Slovakia

Investigators have concluded that fully realizing the cost-saving potential of biosimilars could “release enormous resources” for other uses in the German health care system. Their analysis also found that although “Germany takes a leading role in the amount of biosimilar prescriptions” in the European Union, the nation could realize much greater savings in the cost of cancer care by expanding its use of biosimilars.

Germany’s advancements in biosimilar uptake and its drug price management have been held up as potential 

 for the United States. Germany has achieved relatively greater savings on biologics through pricing restrictions, negotiations with drug manufacturers, and robust biosimilar competition.

In Germany as elsewhere, improved understanding of cancer biology has led to advanced treatments. However, costly drugs still have driven up health expenditures. The authors argued that additional cost savings from biosimilars could “offset financing of new innovative therapies,” such as chimeric antigen receptor T-cell therapy, which in the United States can cost well over 

The investigators quantified the potential savings on cancer drugs in Germany by examining costs in specific disease indications for each of 3 biologics: rituximab, trastuzumab, and granulocyte colony-stimulating factors (G-CSFs; filgrastim and pegfilgrastim). They calculated the cost savings associated with treating all newly eligible patients with a biosimilar rather than a reference biologic for 1 year using existing health economic analyses, estimates of annual cancer incidence in Germany, pharmacy wholesale prices, and current market share.

The biosimilars analyzed in this study already have sizable 

 in Germany: in 2019, “61.8% of trastuzumab prescriptions, 79.1% of rituximab prescriptions, 35.5% of pegfilgrastim and 76.7% of filgrastim defined daily doses were biosimilars,” the authors wrote

Still, they calculated potential annual cost savings of $5.75 million for rituximab, $112.12 million to $140.88 million for trastuzumab, and $65.93 million for pegfilgrastim. Filgrastim, already at 82% market share, generated $47.35 million in savings in 2018, according to the authors.

For rituximab, calculations were based on the potential use of biosimilars for follicular lymphoma. There are about 3100 new cases of follicular lymphoma in Germany every year, of which approximately 70% will be treated with rituximab during the course of the disease. The annual cost of the reference product (Mabthera, Roche) is $38.59 million, and the cost of the 2 currently available biosimilars (Rixathon and Truxima) was an estimated $32.84 million by the authors, a savings of $5.75 million.

The authors drew from multiple estimates of the number of patients with HER2-positive breast cancer receiving trastuzumab yearly in the (neo-)adjuvant and metastatic setting, from which they determined the range was 6985 to 12,250 patients. Based on these figures, annual savings of $112.12 million to $140.88 million were projected “if all patients received the least expensive trastuzumab biosimilar compared to the original drug.”

There are currently 5 trastuzumab biosimilars on the market in Germany, the least expensive of which is Pfizer’s Trazimera, “with costs 10.8% below that of the reference biologic,” Roche’s Herceptin.

Filgrastim and pegfilgrastim are indicated for prevention of neutropenia. Because filgrastim already has 82% market share, the authors were able to estimate the actual cost savings in Germany during 2018. The total cost of filgrastim use was $127.40 million, and the authors estimated “without biosimilar usage and implementation of fixed reference pricing due to significant biosimilar penetration,” costs would have been $174.75 million, a savings of $47.35 million.

Total annual costs for pegfilgrastim were $245.91 million in 2018, and the authors estimated the cost would have been $179.99 million if biosimilars had been prescribed exclusively, saving  $65.93 million. The first pegfilgrastim biosimilar authorized in Europe became available in Germany in October 2018 and reached market share of 22% in June of 2019.

Cost Savings Could Be Reallocated “to Facilitate Optimal Patient Treatment”

The investigators recommended that cost savings from the use of biosimilars be used to improve treatment for patients, for example, to “improve access to care in underserved areas” and “offset financing of new innovative therapies.”

They see additional positives to increasing biosimilar use, arguing that more biosimilar manufacturers means “stronger competition between suppliers” and, globally, “the presence of multiple biosimilar manufacturers ensures the security of supplies.” Plus, “biosimilars contribute to lower prices of the drug group including the reference product, thus further relieving the financial burden on the health care system.”

The authors pointed out that some of their savings projections may be underestimates, because “due to individual discount agreements, the actual costs for biosimilars may be lower.” Additionally, they cautioned that the numbers of patients they used in their calculations are based on estimates and that inpatients were not considered in their analyses.

From their results, the investigators concluded, “the adoption of biosimilars has the potential to improve sustainability of health care in oncology, which is particularly important as the incidence of cancer increases worldwide.”

They also noted that in Germany, classes of biosimilars not included in the study have substantial room for growth. Insulin lispro and insulin glargine biosimilars have just 3.3% and 11.5% of their respective markets in Germany, the authors said.

Hübel K, Kron F, Lux MP. Biosimilars in oncology: effects on economy and therapeutic innovations. 

. Published online September 17, 2020. doi:10.1016/j.ejca.2020.07.037

Germany could eke out more gains from biosimilars on top of its already impressive savings, investigators write. 

Report: Germany Has Not Fully Realized Its Biosimilar Potential

Comparative biosimilar efficacy trials are unnecessary to demonstrate that drug candidates are equivalent to reference products (RPs), authors of an analysis argue in a new paper. The group from the UK’s Medicines and Healthcare Products Regulatory Agency contends that, except in extreme cases, analytical testing and a pharmacokinetic trial are sufficient to demonstrate biosimilarity.

They propose a streamlined approval process for biosimilars to accelerate patient access, in which “efficacy trials are reserved for exceptional circumstances.” 

“Little Additional Evidence of Biosimilarity”

The approval processes for biosimilars in the United States and Europe do require extensive analytical testing to determine similarity, followed by in-human pharmacokinetic (PK) and pharmacodynamic investigatory studies and efficacy, safety, and immunogenicity trials. However, “the discriminatory power of these studies decreases in this order,” the authors contend.

“In 2020, it is increasingly questioned whether clinical efficacy trials of biosimilars are still necessary. Revisiting the requirement for efficacy trials appears timely because significant technological advances have been made over the past 10 years and considerable scientific and regulatory experience has been accrued since the first biosimilar was licensed in 2006,” they wrote in a prepublication draft for 

The authors note limitations of comparative efficacy trials, such as limited statistical power to detect small treatment effects or differences in safety and immunogenicity. They said that to detect all clinically relevant differences between biosimilar and originator, “up to a few thousand” patients would be required, whereas most comparative efficacy studies for approved biosimilars have enrolled between 350 and 900 patients. Enrolling sufficient numbers of patients is especially challenging for orphan drug or pediatric indication trials, which the authors said leads to underpowered studies and difficulty drawing conclusions.

In addition to these limitations, the authors argue that clinically meaningful differences in efficacy, safety, or immunogenicity between a biosimilar candidate and its RP “would be unlikely once analytical and PK comparability has been shown.” Therefore, they claim that comparative efficacy trials are “neither an effective discriminating tool for the comparison between biosimilar and RP, nor an efficient use of limited resources.”

To determine whether differences found in comparative efficacy trials changed the course of biosimilar approvals, the authors analyzed 20 complex biosimilars related to 6 reference products approved in the European Union as of the end of 2019. Regarding that analysis, the authors wrote, “we have not found any publicly available results of an efficacy trial being the critical reason for not submitting a marketing authorization application for a biosimilar candidate.” They added that differences detected in clinical trials “did not, on their own, preclude the approval of the biosimilar.”

The authors suggest that in-depth knowledge of “crucial aspects of efficacy, safety, and immunogenicity of the RP that emerged during clinical development” can help predict potential issues with a biosimilar. Additionally, they said that technological advances have allowed analytical tools to detect small, potentially clinically relevant differences between reference products and candidate biosimilars.

They also argue that differences between biosimilar and RP that might affect immunogenicity are better detected via analytical tests, “which are more sensitive than the evaluation of the human immune response because of multiple confounding patient- and disease-related factors.”

Multiple batches of RP are evaluated to establish a baseline range within which the biosimilar candidate must fall as evidence of equivalency. The authors write that the variability of the reference product range “is unlikely to be of clinical relevance” and neither should there be a concern if the biosimilar candidate falls within that range. 

“Therefore, we contend that, in most cases, an efficacy trial is no longer required to establish biosimilarity once comparability has been demonstrated through the analytical and clinical PK studies,” they wrote.

Their proposed approval process would use in-depth understanding of the RP and advanced analytical testing to minimize clinically relevant differences between RP and biosimilar. They acknowledged this would require extensive knowledge of the RP’s mechanism(s) of action; physicochemical and functional properties likely to be clinically relevant; PK, efficacy, safety, and immunogenicity profiles; and impact of antidrug antibodies on pharmacokinetics.

The authors also recommended extensive quality data must be generated for both the reference product and its biosimilar candidates, with analysis of multiple batches of the originator biologic over months to years to take into account manufacturing variability, and comparison of each batch of biosimilar to the reference product.

The authors still consider a confirmatory PK trial necessary for comparing bioavailability between biosimilar and reference product, as the 2 products by definition will not be identical. Importantly, they argue that the PK trial “provides some safety and immunogenicity information from exposure in humans.”

Regarding safety, they said robust pharmacovigilance will be required; however, they reiterated that safety issues not identified via analytical or PK testing are unlikely, saying “more than a decade of clinical experience indicates that a new safety signal solely identified with a biosimilar is extremely unlikely unless there are additional factors unrelated to the active molecule itself (eg, different excipient or device).”

The authors claim this expedited approach to biosimilar approvals “provides a streamlined pathway for expediting approval of biosimilars, thereby promoting wider patient access to these crucial therapies.”

For more recent opinion on FDA biosimilar guidelines, 

Bielsky M, Cook A, Wallington A, et al. Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial. 

Much of the groundwork for establishing equivalence is established in the pharmacokinetic evaluation. Further studies add less and less to the body of evidence for biosimilar approval, UK regulators write. 

UK Regulators Contend Biosimilar Efficacy Trials Are Redundant

A new study suggests the FDA’s naming convention for biosimilars and patients’ inability to switch to a biosimilar at the pharmacy limit biosimilar uptake by causing patients to perceive biosimilars as less similar to reference products.

Whereas generic drugs have the same nonproprietary name as their reference products, the FDA requires the addition of random 

 to the nonproprietary names of biosimilars. This practice differentiates biosimilars by name from their originators and from one another. Also, unlike generics, a prescription for a reference biologic is not 

 with one for the biosimilar at the pharmacy level; a new prescription is necessary for a patient to switch from the reference biologic to a biosimilar.

The investigators pointed out these policies are unique to the United States, saying “the United States is the only country in which a 4-letter suffix must be added to nonproprietary names of biosimilars and biologics and the only country in which biosimilarity and interchangeability have different regulatory requirements.”

Despite the potential of biosimilars to reduce costs, the authors wrote that patient interest in biosimilars is low, citing surveys suggesting “80% of patients taking biologics prefer not to switch to a biosimilar and are concerned about biosimilars’ efficacy and safety.”

The investigators evaluated the effects of the naming convention and interchangeability on patient interest in biosimilars with 1306 participants standing in as hypothetical “patients.” Participants were asked to assume they had type 2 diabetes and that their disease was well-controlled with a fictitious reference biologic. They were then randomly assigned to view different versions of an advertisement for a fictitious biosimilar. The nonproprietary name of the biosimilar either had a 4-letter suffix or not. The advertisements either stated that the biosimilar requires or does not require a new prescription for patients currently taking the reference product, or did not mention interchangeability at all.

After viewing the advertisement, participants were asked to rate on a scale of 1 to 7 how likely they were to take the advertised biosimilar, to ask their doctor or payer about the biosimilar, or to research it online. They were also asked to rate how effective they thought the biosimilar was and how similar they thought it was to the reference biologic.

Based on average ratings, participants reported they would be more likely to talk to their doctor or payer, research the biosimilar, and use the biosimilar when they were told it would not require a new prescription. They also rated the biosimilar as more similar to the reference product under this scenario. When there was no mention of interchangeability, participants rated themselves more likely to use the biosimilar when the suffix was excluded from the nonproprietary name.

The authors say their findings suggest that 4-letter suffixes and the lack of interchangeability diminishes patients’ interest in biosimilars by lessening their perception of similarity between the reference product and biosimilar. Of the 2, interchangeability at the pharmacy appeared to be a stronger signal conveying similarity. “When given interchangeability information, patients rely on that signal alone, not on the biosimilar suffix, to infer drug similarity and form an opinion about the biosimilar,” they wrote.

The investigators acknowledged limitations of their study, in particular that it measured the attitudes of hypothetical patients, which may not necessarily reflect those of a real-world population with type 2 diabetes.

They added that the FDA’s policies on these matters have recently changed. Regarding the 

, as of March 2020, a 4-letter suffix will be added to the nonproprietary names of all newly approved biologics as well as biosimilars. For biosimilar insulins, current guidance from the FDA indicates that comparative clinical immunogenicity studies may still be needed to support immunogenicity, but 

, based on availability of convincing evidence supported by state-of-the-art technology that proposed biosimilar or interchangeable insulin products are “highly similar” to their reference products and there would be “little or no residual uncertainty.”

Based on their results and these policy changes, the investigators recommendedthat “future research could examine whether the new policy translates to reducing barriers to use biosimilar insulins and whether the naming convention adds more 

Socal MP, Garrett JB, Tayler WB, Bai G, Anderson GF. Naming convention, interchangeability, and patient interest in biosimilars. 

. 2020;33(3):273-279. doi:10.2337/ds19-0065

The random jumble of letters that the FDA attaches to new biologics and biosimilars plays a big role in patient acceptance of these drugs, investigators report.

Study Suggests Biosimilar Suffixes Influence Patient Willingness to Switch 

In an evaluation of health technology assessments (HTAs) for biosimilars, investigators found that the 

 of HTAs lack systematic reviews of existing literature, appraisals of the quality of evidence, and cost analyses. The paper was published in 

The authors concluded there is a substantial need for standard, minimum methodological criteria for the development of HTAs for biosimilars to help support public understanding of these agents and enable clinicians to “make more informed decisions about adopting biosimilars.”

Health technology tssessments play an important role in building confidence for use of biosimilars, yet very few meet criteria for thoroughness.