Deana Ferreri, PhD

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

Articles

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.”

Higher standards for HTAs would help to persuade health professionals who “are not convinced by expert opinion in regard to treatment interchangeability and substitution, and the perception that there is a lack of data in relation to efficacy and safety,” they wrote.

The authors identified 70 HTAs for biosimilars from their search of HTA organizations’ websites and noted that HTAs differed according to the extent and depth of information provided, which they said was one of the limitations of these reports. Based on previously established definitions, they classified 2 reports as full HTAs, 4 as mini-HTAs, and the rest—over 90%&mdash;as rapid reviews, “which gave no information regarding any evidence synthesis method.” The authors cited a previous 

 that reported rapid reviews are now the most frequently produced type of HTA and that HTA agencies use widely varying methodologies for compiling these.

“Approximately half of the rapid reviews did not appraise the risk of bias of primary studies or the overall quality of evidence,” the authors said. “All full HTAs and mini HTAs addressed organizational, ethical, social, and legal considerations.” Most full and mini HTAs included an assessment of switching and a discussion of biosimilar education.

The majority of biosimilars addressed in the HTAs were anticancer and immunomodulating agents, most commonly tumor necrosis factor—alpha inhibitors. Infliximab biosimilars were the most frequently assessed, accounting for about 25% of HTAs.

Most HTAs supported the adoption of the biosimilar assessed, and the majority were published recently—46 of the 70 between 2015 and 2018. The authors observed that few countries produce HTAs on biosimilars: About half of all rapid reviews came from a single agency in France, and all 4 mini-HTAs were produced by organizations in Canada.

The authors discussed what they saw as shortcomings of the majority of the HTAs, saying, “Although most reports have supported the adoption of biosimilars, these statements have often been based on reports lacking a systematic literature review and not considering economic issues.”

The authors evaluated each report based on whether they covered safety and effectiveness; economic analysis; financial impact; clinical evidence; quality of evidence; organizational considerations; and ethical, social, and legal considerations.

The 2 full HTAs met all criteria. All full and mini-HTAs included a systematic review of the clinical evidence, compared with just 3% of the rapid reviews. Almost half of rapid reviews failed to evaluate the risk of bias of studies or the overall quality of the evidence, the authors said. Although all full and mini-HTAs addressed ethical, social, and legal considerations, just 39% of rapid reviews did.

A budget impact analysis was conducted in 1 full HTA, 3 of 4 mini-HTAs, and less than 40% of rapid reviews. The authors found the lack of budget impact analyses concerning, because the majority of biosimilars assessed were anticancer agents, immunomodulators, and insulins, which “represent the 3 largest biologic therapy areas, worth $110 billion—over half of all biologic global revenue.” The authors viewed this as a missed opportunity for an HTA to lead to cost savings by making a cost-effectiveness argument for a biosimilar.

Incomplete discussion of biosimilar Issues

In addition to the general criteria for HTAs, the authors evaluated whether HTAs addressed issues of particular importance for biosimilars, such as immunogenicity, switching, and extrapolation to additional conditions. One of the 2 full-HTAs, all 4 mini-HTAs, and about 60% of rapid reviews assessed immunogenicity. Only 20% of rapid reviews discussed switching, 66% discussed extrapolation, and 22% “provided an educational approach about biosimilars to patients, clinicians, or pharmacists,” whereas all 4 mini-HTAs and 1 full HTA addressed all 3. The authors stressed these issues are important for HTAs to address.

The authors also stated that often the same biosimilar may be licensed under multiple commercial names, and that “this situation can cause confusion…and a duplication of work.”

Ascef BO, de Freitas Lopes AC, de Soárez PC. Health technology assessment of biosimilars worldwide: a scoping review. 

. 2020;18(1):95. doi:10.1186/s12961-020-00611-y

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

Investigators Eye Gaps in Biosimilar Assessment Reports

Anti—tumor necrosis factor (TNF) drugs have been used for the treatment of inflammatory bowel disease (IBD) for 20 years. Studies of both originator and biosimilar versions of infliximab and other anti-TNFs have yielded advances in treatment, and in a 

, a group of Swiss and Israeli authors have encapsulated this knowledge to provide what they called a user’s guide.

TNF inhibitors have been “the mainstay in the treatment of inflammatory bowel disease (IBD),” the authors said. Infliximab (Remicade) was the first anti-TNF biologic available to treat 

 in 1998 and ulcerative colitis (UC) in 2005. In addition to infliximab, adalimumab is used in treatment of CD and UC, plus certolizumab pegol for CD and golimumab for UC. Focusing mainly on infliximab, for which the greatest body of evidence exists, the authors provided what they consider to be the most up-to-date methodology for addressing IBD with anti-TNFs.

Outlining the recommended indications for anti-TNF therapy in CD and UC, the authors noted there has recently been a shift toward introducing these drugs early when treating patients with serious disease. They cited research suggesting initiation of anti-TNF therapy during the first 2 years of CD may be more efficacious than initiating later in the course of the disease.

Investivative studies suggest combination therapy with immunomodulators has superior efficacy compared with anti-TNF agents alone, they said, and noted a greater risk of infection and neoplasms, or cancers, has been associated with combination therapy. The cancers include lymphoma and nonmelanoma skin cancer. This prompted the authors to conclude “The benefits of combination therapy should be balanced with its decreased safety profile.”

The authors also discussed reasons for withholding anti-TNF agents, prescreening guidelines, and recommendations for preventing infection. They recommended a full screening prior to the initiation of biologic agents for IBD.

In their discussion of infliximab infusion protocols, the authors noted that subcutaneous infliximab may soon be available, saying “a phase 1 study in the CD population has been recently conducted” on a subcutaneous formulation of the infliximab biosimilar CT-P13 (Remsima; Inflectra). Subcutaneous CT-P13 was recently 

 for all indications of intravenous infliximab in adult patients.

With respect to safety and the management of adverse effects, the authors acknowledged the “increased risk of infection” associated with anti-TNF therapy, the most common being pneumonia, which they said highlights the importance of immunization. They noted a 13-year follow-up study that showed a relative risk of serious infection of 2.46 (95% CI, 1.80-3.36) in patients who received infliximab. Risk factors for serious infection include prednisone and narcotic use, duration and severity of disease, and infliximab use, but not age, they said.

Their recommendations for reducing the risk of malignancy in patients on anti-TNF therapy for IBD include annual skin exams and limiting the duration of combination therapy with thiopurines, which control inflammation, to less than 2 years. ” If the patient has a diagnosis of malignancy during TNF inhibitor therapy, the situation should be discussed by a multidisciplinary team of clinicians, they advised.

One of the limitations of therapy with TNFs in IBD is that there is a loss of response in as many as 30% to 50% of patients. The authors recommended therapeutic drug monitoring (TDM) to optimize dosing, suggesting TDM could “determine if the loss of response is due to subtherapeutic levels.” They wrote TDM may also be useful when a patient is in remission, either to prevent a flare or loss of response.

In their discussion of biosimilars in IBD, the authors concluded that switching from the infliximab originator product to the CT-P13 biosimilar is "equivalent to continuing [infliximab] originator for IBD patients,” based on the evidence. However, the “IBD-specific literature is lacking” for the infliximab biosimilar SB2 (Renflexis) and adalimumab biosimilars.

Vulliemoz M, Brand S, Juillerat P, Mottet C, Ben-Horin S, Michetti P. TNF-alpha blockers in inflammatory bowel diseases: practical recommendations and a user's guide: an update. 

. Published online July 31. doi:10.1159/000506898

Two decades of using anti–tumor necrosis factor (TNF) drugs in inflammatory bowel disease (IBD) have answered some questions and left others unanswered.
 

Updated "User's Guide" Published for Anti-TNFs in IBD

 critically evaluated the methodology used by Celltrion Healthcare and the FDA to determine whether Celltrion’s infliximab biosimilar CT-P13 (Remsima, Inflectra) was equivalent to the reference product Remicade for treating rheumatoid arthritis (RA) in the 2013 PLANETRA trial.

In 2016, CT-P13 became the first infliximab biosimilar approved by the FDA. By the second quarter of 2020, sales of CT-P13 achieved a 10.5% share of the US market for infliximab vs 84.1% for Remicade. In Europe, CT-P13 achieved a 57% market share vs 28% for the originator product.

The authors say their objective was to evaluate “if the equivalence margins chosen by Celltrion and the FDA for the first infliximab biosimilar CT-P13 were scientifically valid and clinically justifiable.”

They argued the appropriate equivalence margin for approval of infliximab biosimilars is 5.7 percentage points. Celltrion used an equivalence margin of 13 percentage points in their analysis, and the FDA used 12 percentage points in the approval process for CT-P13 and has recommended the same margin for the evaluation of other infliximab biosimilars.

The authors used the same method the FDA recommends to determine the equivalence margin; however, they contended the clinical trials of the originator drug used to calculate the equivalence margin did not meet the test for constancy, or comparability. The principal of constancy requires that clinical trials being used to estimate an equivalence margin must be similar enough to be pooled together.

In reviewing Celltrion's application for approval, the FDA evaluated data from 5 historical clinical trials involving infliximab to calculate an equivalence margin. However, according to the authors, only 2 of these trials met the constancy assumption. The remaining 3 trials were included in the pooled PLANETRA trial.

The FDA declined a request to comment, saying it does not comment on third-party research, but Celltrion responded with a point-by-point critique of the study.

The authors claim 1 clinical trial violated the constancy assumption because it evaluated efficacy approximately 8 weeks earlier than the others. However, according to Celltrion, which cited the summary of product characteristics for Remicade, “Available data suggest that the clinical response is usually achieved within 12 weeks of treatment and is maintained….Therefore, it is clinically acceptable to use the results of earlier time points.”

In another of the pooled PLANETRA trials, the authors noted, the methotrexate (MTX) dose was only about half that used in the other trials. However, Celltrion responded that this study was conducted in Japan: “It is general practice to use a lower dose of MTX in Asian countries (because of a relatively lower body weight).”  Furthermore, Celltrion noted a subgroup analysis of CT-P13 efficacy in the PLANETRA study “suggests no difference in efficacy by MTX dose.”

Celltrion also refuted the authors’ claim that this trial enrolled “milder” patients than the others, saying, “The average number of swollen joints in the Abe et al study [PLANETRA] was similar to the other trials and serum CRP [c-reactive protein] was the highest in the Abe et al study (4.2 vs 1.6-3.3). In addition, disease duration was the longest in the Abe et al study. Based on this, it is difficult to conclude that slightly milder patients were enrolled in the Abe et al study.”

For the third trial in the PLANETRA pooled trials, the authors reported that the severity of RA symptoms at baseline and the dose of MTX were unclear “solely based on the published information.” Celltrion responded that “the eligibility criteria were in line with other studies,” refuting the idea that this trial was different enough from the others to violate the standard of constancy.

The authors used 6 pooling scenarios to estimate what they considered an appropriate equivalence margin for CT-P13. Three of the 6 scenarios used all 5 trials, similar to the methodologies of Celltrion and the FDA. In these scenarios, equivalence margins ranged from 11.8 to 14.2 percentage points, similar to Celltrion’s 13 and the FDA’s 12 percentage point ranges.

In 3 scenarios, the equivalence margins were 10.5, 9.4, and 5.7 percentage points. The authors contend the equivalence margin of 5.7 percentage points is the most appropriate.

According to the authors, “The equivalence claim for CT-P13 to original infliximab in patients with rheumatoid arthritis did not appear to be supported when the constancy assumption was strictly assessed.”

They added, “The equivalence margin for biosimilars could be determined more conservatively.” The authors recommend the more conservative approach because of the complexity of biologic therapies and the novelty of biosimilars, saying, “This approach can guarantee that patients are protected from any remaining uncertainty or risks with the use of follow-on biological products.”

It is unclear based on the publication what prompted the authors to examine the FDA’s methodology for demonstrating equivalence of infliximab biosimilars. The authors claim no conflicts of interest and no specific funding from commercial or public sectors. The project was supported by the BK21 Plus Program of the National Research Foundation of Korea, which is a faculty-mentored talent development program. The article was peer reviewed.

Celltrion responded, “This study does not reflect the FDA review procedure and the principles of the regulatory guidelines. The constancy assumptions have been evaluated improperly, and the disease is also misrepresented within the evaluation.” Celltrion also pointed out “In addition, the equivalence margin used for PLANETRA study was endorsed by EMA (European Medicines Agency).”

Celltrion has a growing influence on the biosimilar scene. In June, the World Health Organization 

 its rituxumab biosimilar (Truxima), promoting the use of this product among developing nations. In March, Celltrion and Teva Pharmaceuticals USA 

 a trastuzumab biosimilar (Herzuma) on the US market.

Kim S, Kim S, Lee H. A critical review of the United States regulatory pathways for determining the equivalence of efficacy between CT-P13 and original infliximab (Remicade). 

. 2020;14:2831-2840. doi:10.2147/DDDT.S254776

Celltrion finds fault with a critique of equivalence margins used to approve its infliximab biosimilar.

Celltrion Refutes Critique of CT-P13 Equivalence

Authors of a 1-year real-world study on anti—tumor necrosis factor (TNF) originator biologics and biosimilars for 

 (CD) and ulcerative colitis (UC) found anti-TNF therapy overall was more effective for achieving remission in patients with CD compared with those with UC.

Moderate to severe inflammatory bowel disease (IBD) may be treated with the anti-TNF biologics infliximab or adalimumab or their biosimilars, and the introduction of 

 has improved rates of remission and quality of life in IBD. However, the investigators identified a knowledge gap, noting that comparisons of effectiveness, safety, and tolerability of the anti-TNF agents between the 2 diseases have only been performed indirectly through meta-analysis.

The retrospective study included 179 patients, 89 with UC and 90 with CD. Approximately one-third of each group took the infliximab originator (Remicade), infliximab biosimilar (Remsima; CT-P13), or adalimumab (Humira).

Clinical activity and inflammatory markers were measured at baseline, after induction (14 weeks for infliximab, 8 weeks for adalimumab), at 30 weeks, and at 52 weeks. Endoscopic measures were assessed at baseline and 52 weeks.

After the induction period, there was a significant difference (

 = .05) in the percent of patients on any therapy who achieved clinical response between UC (84.3%) and CD (93.3%); the difference between diseases diminished by 30 weeks, and at 52 weeks, 82% of patients with UC and 80% with CD had achieved clinical response, although this finding was not significant (

The rate of steroid-free clinical remission after induction was higher in CD (58.8%) compared with UC (42.7%; 

 = .03). At 30 and 52 weeks, remission rates were higher in CD compared with UC, with 72.2% of patients with CD in steroid-free clinical remission at 52 weeks compared with 60.7% of patients with UC (

Among individual drugs, remission rate differences in the infliximab originator group became significant at 30 weeks between UC (56.7%) and CD (80%). At 52 weeks, remission rates were higher in CD for both the infliximab reference product and biosimilar groups, but the differences did not reach statistical significance (

 = .08). At 52 weeks, steroid-free clinical remission rates for the infliximab originator were 66.7% and 80% in UC and CD, respectively, and 57.1% and 76.7% for the biosimilar.

Differences in remission rates between diseases for patients taking adalimumab did not reach significance at any point in the study. In patients taking adalimumab, the steroid-free clinical remission rates at 52 weeks were 58.1% and 60% for UC and CD, respectively.

Regarding their finding of greater remission rates overall for CD compared with UC, the authors said the differences between the disease activity scoring methods are worth noting. In particular, the Harvey Bradshaw Index for CD takes into account “the intestinal manifestations of illness, present in 48.9% of our patients, and the subjective component of perception of the patients' health status,” which do not factor into the partial Mayo score for UC.

Overall, 13 patients discontinued therapy due to adverse events (AEs). The most frequent AEs were allergic reactions, dermatologic manifestations, and infections. The infliximab biosimilar group had both the greatest number of total discontinuations (3 in UC and 5 in CD) and the most AE-related discontinuations (1 in UC and 3 in CD). The adalimumab group had the greatest number of discontinuations for lack of efficacy.

The authors observed 3 cases of malignant disease during the study, which they say necessitates “careful and comprehensive follow-up of the patient in biological therapy.”

Endoscopic response was achieved by 51% of patients on adalimumab compared with 43.4% on the infliximab originator and 41.7% on the infliximab biosimilar. In the adalimumab group, endoscopic response was more common in UC compared with CD. The authors did note, however, endoscopic data were available for all patients with UC but only about half of patients with CD.

The drugs started out at standard doses, but physicians were later allowed to optimize dosage for the individual patients. At week 30, 20% of patients with UC on the infliximab originator required optimization of therapy compared with none with CD. No other significant differences in optimization between diseases were reported. At week 52, 31.1% of patients taking adalimumab, 16.7% taking the infliximab originator, and 36.2% taking the infliximab biosimilar required treatment optimization.  

Given the real-world setting of the study, the authors found several baseline characteristics were significantly different between groups. They performed multivariate analysis adjusted for those factors, which included endoscopic disease activity, disease duration, percent of biologic-naive patients, extraintestinal manifestations, use of a concomitant steroid, and C-reactive protein level. Multivariate analyses suggested a 3-to-4—fold greater likelihood of clinical remission or steroid-free clinical remission at 30 and 52 weeks for patients with CD compared with those with UC.

The investigators consider their study a step toward greater understanding of anti-TNF agents in IBD and therapy tailored to the individual patient, as well as a starting point for future, larger prospective studies and randomized controlled trials comparing biologics use between UC and CD.

Barberio B, Zingone F, D&#700;Incà R, et al. Infliximab originator, infliximab biosimilar, and adalimumab are more effective in Crohn's disease than ulcerative colitis: a real-life cohort study. 

. 2020;11(5):e00177. doi:10.14309/ctg.0000000000000177

A real-world study on inflammatory bowel disease employing originator and biosimilar biologics suggests anti–tumor necrosis factor (TNF) therapy may be more effective for Crohn disease than for ulcerative colitis.
 

Anti-TNF Biologics Outperform in Crohn Disease 

This study has been updated to note that Avsola launched in July 2020.

The uptake of infliximab biosimilars in the United States is slow but tracks closely to the experience in Europe, where after 2 years infliximab biosimilars assumed a large share of the market, according to a new study.

Infliximab biosimilar uptake has lagged filgrastim biosimilar uptake, and investigators theorized providers find it easier to prescribe a change of medicine in the case of filgrastim, which is for blood cell regeneration following radiotherapy, than for infliximab, which is for rheumatoid arthritis and related conditions. They said physicians are naturally more cautious about changing medicines for chronic conditions that are well controlled with the initial medication.

Investigators analyzed uptake of infliximab biosimilars in the US Medicare population and reported that in the 2 years after the November 2016 launch of the first infliximab biosimilar (Inflectra), “biosimilars captured only 10% of the infliximab market and lowered reimbursements by 17%.” Renflexis was launched in July 2017.

These were the second and third biosimilars to be launched in the United States. The uptake of these biosimilars and the corresponding reduction in costs have not measured up, the authors commented, compared with results of the first biosimilar launch in the country (filgrastim, Zarxio). This biosimilar “had strong adoption after just 2 years, capturing 40% of the market and lowering unit prices by 25%.”

Trends in Infliximab Originator and Biosimilar Use

Using Medicare fee-for-service quarterly claims data, the researchers analyzed trends in use, reimbursement, and switching between the reference infliximab (Remicade) and its biosimilars from January 1, 2017, to December 31, 2018.

Total infliximab administrations decreased by 3.9% from Q1 of 2017 to Q4 of 2018. The proportion of biosimilar administrations increased over that time from 0.5% to 10.5% of the total. The authors noted this pattern was similar across approved infliximab indications.

In the first quarter of 2017, reimbursement per 10 mg for the newly launched biosimilar Inflectra was higher than for Remicade ($101.62 vs $86.87). After the second biosimilar (Renflexis) was introduced in May 2017, the relative biosimilar reimbursement began to fall, reaching $65.36 per 10 mg in the fourth quarter of 2018, 17.1% lower than the $78.86 reimbursement for the originator at that time.

The majority of both new and returning patients taking infliximab used the reference product. Among new patients,17.4% used a biosimilar, and 10.8% of returning patients used a biosimilar. Almost all new patients taking a biosimilar took only that biosimilar, and about half of returning patients using a biosimilar had switched from the reference product.

Most physicians (72.8%) prescribed only the reference product compared with just 3.5% who prescribed only biosimilars. Of those who prescribed both, 61.4% had switched some patients from the reference product to a biosimilar.

A “Considerable Minority” of Patients Switched to a Biosimilar

The authors said the reasons for the slower adoption of infliximab biosimilars compared with the previous filgrastim biosimilar are unknown. However, they speculated that “patients and physicians may be more reluctant to switch from a working biologic regimen in a chronic setting than an acute one.”

However, they acknowledged that “a considerable minority of patients did switch between biologic and biosimilar versions in 2018,” and suggested switching could have been the result of cost reductions, such as lower patient co-pays or physician rebates.

Infliximab biosimilars will gain much greater traction in next several years, based on results from Europe, they suggested.  “After 2 years, biosimilar infliximab garnered 13% of European market share, with subsequent uptake increasing steeply to 52% by 5 years.” In the United States, infliximab biosimilars have been available for less than 4 years. In December 2019, Amgen got FDA approval for its Avsola infliximab biosimilar, which launched in July 2020.

There are currently just 2 filgrastim biosimilars on the US market.

 on infliximab biosimilar use in Medicare beneficiaries similarly reported slow uptake but an increase in infliximab biosimilar use over time.

Chen AJ, Gascue L, Ribero R, Van Nuys K. Uptake of infliximab biosimilars among the Medicare population. 

. Published online July 20, 2020. doi:10.1001/jamainternmed.2020.3188

Investigators speculate on why infliximab biosimilars don’t have a larger market share by now.

Study: Slow Start for Infliximab Biosimilars

The authors of a new clinical review article combined evidence-based guidelines and clinical experience to create algorithms to guide decision making on the use of biosimilar anti—tumor necrosis factor (TNF) agents for moderate to severe Crohn disease (CD).

The authors, who see their work as a step toward standardizing care, noted that anti-TNF biologics, infliximab and adalimumab in particular, “constituted a quantum leap in efficacy” in CD treatment, and that access to these drugs “began to improve with the introduction of biosimilars for infliximab in 2013 and adalimumab in 2018.” However, standard procedures for initiating, monitoring, and managing anti-TNF therapy in CD have not yet been established.

The authors have presented their decision-making algorithm visually as a series of flowcharts, beginning with determining which patients are appropriate for anti-TNF therapy, followed by criteria favoring infliximab vs adalimumab and dosing regimens for each. A final set of flowcharts represents real-world scenarios physicians may encounter when monitoring a patient during treatment with infliximab or adalimumab biosimilars, along with recommendations for adjustment of therapy in those scenarios.

Wide variation in treatment patterns for Crohn disease is attributable to failures to translate evidence uniformly and cost barriers. Authors of a new report have formulated algorithms to help reduce heterogeneity in treatment of patients.