Deana Ferreri, PhD

An attempt to understand whether regulatory and scientific sources are consistent with each other in their reporting of quality attributes (QAs) for biosimilars has demonstrated general conformance between these 2 sources of biosimilar information.

Reporting of biosimilar quality attributes (QAs) is “inconsistent but reasonably complementary” between regulatory and scientific publications, according to the study comparing European public assessment reports (EPARs) from the European Medicines Agency (EMA) with peer-reviewed scientific publications on biosimilars.

Investigators looked at the reporting of 2 general categories of biosimilar QAs: structural and functional. Structural qualities include amino acid sequence, which must be similar between biosimilars and their reference products. They also concern purity of the drugs and physicochemical properties. Functional QAs include immunochemical activity and biological activity, such as antibody binding to the target ligands necessary to achieve a clinical response.

QAs, therefore, “describe specific physical, chemical, biological or microbial properties” of a biosimilar, and although the aims of scientific and regulatory reporting differ, data on QAs should be consistent, according to the authors. Limited information about the consistency and complementarity of QA reporting made this study necessary, they wrote.

“Along with the surge of biosimilars introduced to the European market over the last decade, the need for comprehensive and reliable information among decision makers (eg, clinicians, pharmacists, payers, and regulators) about the justification of biosimilarity has become pertinent,” the authors wrote.

The authors focused exclusively on adalimumab biosimilars for their study because the monoclonal antibody (mAb) to tumor necrosis factor alpha (TNF) “has the largest number of approved mAb biosimilars and the broadest spectrum of therapeutic indications among TNF-α inhibitors.” They studied the reporting of 77 different QAs (53 structural and 24 functional) from reports on 6 adalimumab biosimilars.

The total number of individual QAs reported for adalimumab biosimilars in regulatory and scientific sources ranged from 47 to 60, and the number of QAs reported consistently by both source types varied by biosimilar, ranging from 28% to 75%. Overall, a greater number of QAs were reported in EPARs (range 36-57) compared with scientific publications (range 14-49).

In both EPARs and scientific publications, functional QAs were reported more frequently than structural QAs (96% vs 89%) and more consistently (88% vs 62%, respectively). The authors suggested the reason functional attributes were more frequently and more consistently reported could be that “they reflect the clinically relevant” mechanisms of action of the biologic drugs and are useful in predicting the outcomes of clinical studies.

For example, binding to and neutralizing TNF-ɑ are functional attributes relevant to adalimumab’s mechanism of action, and these QAs were reported consistently in both information source types for all 6 biosimilars.

Regulatory and scientific motives also may have much to do with the type and frequency of information that gets reported. “Regulators...may be more concerned with the consistency and accountability of decisions. Researchers, frequently affiliated with biosimilar companies, might be more focused on presenting positive news—that is, QAs with favorable results in terms of biosimilarity, such as highly similar attributes,” they wrote.

The authors analyzed whether publications included test results, biosimilarity interpretation, or both for each QA. EPARs more commonly included a biosimilarity interpretation without test results compared with scientific publications. The 2 sources agreed, on average, on 90% (range 78%-100%) of QAs in their interpretations of biosimilarity.

The authors noted the QAs with agreement on biosimilarity interpretation “were frequently related to biological and immunochemical activity [functional QAs],” whereas, “the types of QAs with different biosimilarity interpretations in both sources were frequently related to [post-translational] modifications and biological activity.”

The authors advised consulting both sources of information to obtain a “more complete reporting of the biosimilarity assessment” and “an improved understanding of how biosimilarity was established at the molecular level.”

According to the authors, there have been few previous assessments of “whether and how data presented in these 2 publicly available information sources overlap.” However, studies assessing the reporting of safety and efficacy data “have found substantial discord between regulatory reports and scientific publications.” Their study, they said, was probably the first to examine whether the reporting of QAs is consistent or complementary between regulatory and scientific sources.

The authors argued bringing greater consistency to reporting of QAs between sources could ultimately contribute to increased acceptance and use of biosimilars by clinicians. “A comprehensive and consistently reported set of QAs is needed to understand the science behind regulatory approval and increase confidence in biosimilars in clinical practice,” they wrote.

Alsamil AM, Giezen TJ, Egberts TC, Leufkens HG, Gardarsdottir H. Comparison of consistency and complementarity of reporting biosimilar quality attributes between regulatory and scientific communities: an adalimumab case study. 

. 2021;S1045-1056(20)30142-1. doi:10.1016/j.biologicals.2020.12.003

Articles

Consistency of reporting quality attributes for biosimilars may differ, complicating the job of getting a full picture of biosimilarity. 

Investigators Weigh Differences in Biosimilar Quality Reporting

Switching patients with inflammatory bowel disease (IBD) from the CT-P13 infliximab biosimilar to the SB2 infliximab biosimilar appears to be safe and effective whether 1 or more switches between biosimilars and the originator product were involved, investigators concluded in a retrospective 

In seeking to elucidate the safety and efficacy of switching, the investigators noted little clinical evidence is yet available on switching patients with IBD between infliximab products. Further, they cited a lack of evidence for SB2 

, saying most of the available evidence “derives from the rheumatologic field.”

They enrolled patients who had originally been treated with CT-P13 or the originator product, but all patients had been treated with CT-P13 before switching to SB2. Clinical activity and adverse events were evaluated; the investigators also compared loss of response (LOR) between the biosimilars.

Originator infliximab (Remicade), a monoclonal antibody to tumor necrosis factor alpha, has been used to treat IBD for over 20 years. CT-P13 (Inflectra, Remsima; Celltrion) was the first approved infliximab biosimilar for IBD—Europe in 2013 and the United States in 2016)—and SB2 (Renflexis; Samsung Bioepis) was approved in Europe in 2016 and in the United States in 2017.

Multiple switches, from the reference product to CT-P13 and then to SB2 are likely to occur, the authors said, because of the lower cost of SB2 vs CT-P13. However, European guidelines do not advocate multiple switches because of a lack of clinical evidence.

Thirty-six patients, 14 with Crohn disease and 22 with ulcerative colitis, were followed for 6 months following a switch from CT-P13 to SB2. Twelve had previously switched from the infliximab reference product to CT-P13, and the rest were naïve to infliximab before treatment with CT-P13. Thirteen patients were treated with adalimumab or golimumab immunosuppressants prior to using an infliximab product.

Clinical activity was assessed 6 months before and 3 months after switching to SB2. The proportion of patients in clinical remission was 58.3% both before and after the switch, and rates of mild clinical activity were not significantly different before and after (27.8% vs 33.3%, respectively; 

 = 0.68). The percentages of patients with normal C-reactive protein levels were not significantly different 6 months before and 3 months after switching (94.4% vs 91.7%, respectively; 

The authors said SB2 treatment for 2 patients was suspended after they achieved clinical and endoscopic remission,” and 2 patients (5.5%) receiving SB2 experienced an adverse event (AE).

After switching from CT-P13 to SB2, 25 patients (69.4%) maintained clinical remission and 11 (30.5%) experienced LOR.

Comparing patients who experienced LOR with those who didn’t, the investigators found that 40% of those without LOR (n = 25) had undergone ≥2 switches (reference product to CT-P13 to SB2) compared with just 9.1% of patients who did experience LOR (n = 11), although the difference did not reach significance. Previous AEs during treatment with CT-P13 were more common among patients who experienced LOR on SB2 (27.3%) compared with those who did not (4%), although these findings also did not reach significance.

In univariate and multivariate analyses, the investigators evaluated the number of switches, AEs during CT-P13 treatment, previous LOR to CT-P13, endoscopic activity, clinical activity, clinical variables, and demographic variables, and did not find significant associations with LOR on SB2.

The authors recommended these factors be studied in a larger population to determine their potential influence on LOR, saying, “The low number of enrolled patients could explain why, at univariate, no significant variable was predictive.”

The nvestigators said it would have been “helpful to evaluate the value of infliximab trough levels and the detection of anti-infliximab antibodies,” to more precisely evaluate the potential association between previous AEs to CT-P13 and LOR to SB2. However, they were unable to perform this analysis due to the retrospective nature of the study and recommended future investigation into this potential predictive factor.

They concluded that switching from CT-P13 to SB2 is safe and effective in patients with a single switch or multiple switches among infliximab treatments. The authors described their efforts as “one of the initial studies investigating the efficacy and safety of the SB2 administration to IBD patients in a real-life setting.”

Lovero R, Losurdo G, La Fortezza RF, et al. Safety and efficacy of switching from infliximab biosimilar CT-P13 to infliximab biosimilar SB2 in patients with inflammatory bowel disease. 

. 2021;32(2):201-207. doi:10.1097/MEG.0000000000001988

A need for clinical evidence on the efficacy and safety of infliximab switching led the authors to pursue this investigation.

Infliximab Biosimilar Switching Study Yields Evidence of Safety, Efficacy

Could machine learning (artificial intelligence) be used to help predict outcomes for specific patients treated with biosimilars? Authors of a 

of studies on machine learning speculated on that potentiality and noted many other ways in which an adaptive computerized study of biosimilar use in the real world might be used to elucidate the value and qualities of individual biosimilars and inform providers to improve practice.

Because of the complex nature of biosimilars, they wrote, there are minute differences between them and their reference products that need to be more fully understood to build a practical understanding of these agents and their effects on patients. For example, patients might have immediate reactions to specific biosimilars or experience adverse events only after repeated treatments. Machine learning could track and interpret this information, although they said this relies on being able to “teach” computerized systems to interpret data collected across diverse health care systems with different protocols for recording patient data. 

“Unwanted immune reactions may be induced for numerous reasons, including product variations. However, it is challenging to assess these unwanted immune reactions because of the multiplicity of causes and potential delays before any reaction,” the authors wrote.

It has long been accepted that the analysis of drugs should not end with the clinical assessments done to achieve FDA approval for commercialization. Follow-up should continue long afterward, especially with biosimilars, regulators and patient advocates have said. Due to their complex manufacturing and derivation from living organisms, biologic drugs are mutable and batches of drug will vary over time.

the use of artificial intelligence technologies, which it says ”have the potential to transform health care by deriving new and important insights from the vast amount of data generated during the delivery of health care every day.”

Authors of the review said they hope to spur a broader discussion about machine learning with respect to biosimilars and include insight into maintaining patient safety amid the economic incentives that play a large role in which biosimilars get used. Biosimilars may offer discounts from originator products as deep as 30%; however, “economic incentives to use biosimilars and questions from the clinical community regarding unwanted immunogenicity can be incompatible,” the authors wrote.

“Machine learning, which is one type of artificial intelligence method, refers to programs that can adapt the instructions being used to produce the outcome. Here, the human aspect is its ability to learn and adapt the program’s code to experience,” the authors wrote. In particular, they suggested machine learning be used to identify risk factors for immune reactions, which they said could ensure safe biosimilar use while supporting their associated cost savings.

Machine learning, the authors explained, has the potential to detect important patterns or predict outcomes, but machine learning models require a learning process, just as humans do, to employ data in a way that enhances the accuracy of their predictions. The authors identified recent articles discussing machine learning applications in health care, but they noted that none have applied to biosimilar safety. Machine learning algorithms are a better fit for assessing immunogenicity than traditional statistical models, the authors suggested, because of the complexity and volume of the data involved. Immunogenicity assessments involve the characterization of human immune responses between biosimilars and reference products, in order to understand how patients might react to these agents.

The authors advocated for the use of real-world data to supplement clinical trial data on safety and immunogenicity. Although clinical trials measure safety metrics and antidrug antibodies, which may impair biosimilar performance, they “cannot provide a full picture of the safety profile,” the authors wrote, “because they are performed on a standardized population during a limited period.”

For purposes of informing and programming artificial intelligence systems, real-world data on biologic and biosimilar use and patient outcomes would be drawn from multiple sources, such as hospital systems and payers. Machine learning systems are best equipped to manage such a flood of data and help to make accurate and useful interpretations, the authors said. They suggested that “neural networks” would be capable of such functionality. 

Using immune reactions as an example, the authors outlined a hypothetical neural network model for identifying risk factors for developing an immune reaction after a switch from a biologic reference product to a biosimilar. For a patient treated with reference biologic and then switched to a biosimilar, the model would consider the spectrum of medications the patient has received, the biosimilar prescribed, the reference biologic previously prescribed, drug batch information, and other data. The neural model would classify patients according to predefined categories of immune reactions and hone its power to predict an immune response for an individual hypothetical patient. 

Proper handling of patient information is also a challenge of making a system like this work, the authors wrote: “Any machine learning application needs to comply with the ethical guidelines laid down by national ethics committees.” Complying with data privacy regulations in each country could be challenging, they said, but using aggregated and anonymized data would reduce the risk of violating those regulations.

One problem with neural networks, the authors wrote, is a lack of transparency, which may raise questions about how the machine learning systems arrived at their conclusions during the sifting of patient data. Neural networks use protocols that are layered one on top of another, and each of these folds involves a leap to a new level of interpretation whose workings may be hidden from clinicians trying to understand the reasoning process. “As a result, the black box might create conflict between processing by the neural network model and human interpretation,” the authors wrote. 

In addition to immunogenicity studies, machine learning models could be used to automate pharmacovigilance processes, detect safety signals, make risk assessments to facilitate decision-making on dose regimens or switching, and compare switching initiated by a clinician vs substitution at the pharmacy, which could inform policy on substitution, the authors suggested. They concluded that machine learning technology “should be seen as a tool to learn more about biologic drugs after clinical trials and the medical practices during their uses.”

Perpoil A, Grimandi G, Birklé S, et al. Public health impact of using biosimilars, is automated follow up relevant? 

. 2020;18(1):E186. doi:10.3390/ijerph18010186

Authors of a new study conclude that artificial intelligence could improve the selection of biosimilars for therapy. 

Study: Machine Learning Could Optimize Biosimilar Therapy

the “totality of evidence” for the bevacizumab biosimilar Mvasi (ABP 215) found “no clinically meaningful differences” between the biosimilar and its reference product, and they also concluded “robust data” from multiple trials support extrapolation to all indications of the reference product.

Mvasi is approved in the United States and European Union for several oncology indications, including metastatic colorectal cancer, metastatic cervical cancer, and metastatic nonsquamous non–small cell lung cancer (NSCLC). The authors stated they had no role in any of the human or animal studies included in their review.

Mvasi, an Amgen product, is a monoclonal antibody that binds with vascular endothelial growth factor A (VEGF-A) to retard blood vessel growth that contributes to tumor development. Mvasi was the first bevacizumab biosimilar approved in the United States (2017) and European Union (2018). In the United States, the biosimilar was launched in July 2019.

According to the authors, analytical tests that compared Mvasi with reference product samples from the United States and European Union showed biosimilarity in physicochemical properties, including primary structure, secondary structure, and thermal stability.

Functional properties also were similar. The authors outlined studies that demonstrated Mvasi’s comparable binding affinity to VEGF, inhibition of VEGF binding to its receptor, and inhibition of proliferation of endothelial cells in vitro. “These findings indicate that [Mvasi] and the [reference product] have the same mechanism of action (MOA),” the authors wrote.

The authors cited 2 studies in healthy individuals that indicated comparable pharmacokinetic properties between Mvasi and its reference product. Safety and tolerability in these studies also were similar. None of the enrollees developed binding or neutralizing antidrug antibodies, investigators said.

A comparative clinical trial (MAPLE) involving 642 patients with stage IV or recurrent nonsquamous NSCLC who also received carboplatin and paclitaxel also demonstrated biosimilarity. The primary efficacy end point was the risk ratio of objective response rate (ORR, defined as best overall response). Objective responses were observed in 39.0% and 41.7% of patients receiving Mvasi and reference product, respectively, and the 2-sided confidence interval for ORR fell within the prespecified margin, indicating similar clinical efficacy.

Safety and immunogenicity indicators were also similar between groups. Among patients receiving Mvasi, 26.2% experienced a serious adverse event (AE), vs 23.0% for the reference product cohort; 18.8% and 17.2% of patients on Mvasi and the reference product, respectively, experienced an AE leading to discontinuation.

Anti-VEGF toxicities, such as hypertension, gastrointestinal perforation, or wound healing complications were similar between groups. Immunogenicity was low in both treatment groups, with 1.4% in the Mvasi group and 2.5% in the reference product group developing antidrug antibodies, which were transient in 1.0% and 1.1% of subjects, respectively. No patients tested positive for neutralizing antibodies.

The authors concluded the totality of evidence supports the extrapolation of Mvasi to all approved indications of the reference product, as “no clinically meaningful differences were found in function, purity, potency, PK, clinical efficacy, safety, or immunogenicity.”

They said these studies “should provide oncologists with assurance about using [Mvasi] in treating all approved indications per the prescribing information in their country or region.”

Providers should feel confident using Mvasi, a bevacizumab biosimilar, for all indications of the reference product (Avastin), reviewers stated. 

Reviewers Consider "Totality of Evidence" for Mvasi

, authors call for stronger regulatory action to frustrate tactics used to delay the market entry of biosimilar products in the United States. They call for policy improvements on substitution of biosimilars for reference products, and they argue the case for greater extrapolation of indications for biosimilars so that they automatically cover orphan drug designations of the originator brands.

The review was conducted by members of the Southern Network on Adverse Drug Reactions, an international collaboration of physicians, surgeons, lawyers, scientists, and pharmacists, who who examined various aspects of the biosimilar landscape in the United States, European Union, and Japan—3 of the world’s largest biologics marketplaces.

The authors noted that 27% of new cancer drug approvals in the European Union, United States, and Japan are for biologics. Biosimilars have become available as 

 for the trastuzumab, bevacizumab, and rituximab originator products.

The first therapeutic oncology biosimilar candidates were submitted for European Medicines Agency (EMA) and FDA approval in 2016 and to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) in 2017. These regions “account for the majority of biological pharmacotherapy use worldwide” and invest the most in research and development for biologics, according to the authors.

The EU, which has the longest history with biosimilars, accounts for 90% of global biosimilar sales. In total, 33 biosimilars for oncology have been approved by the EMA, 16 by the FDA, and 10 by Japan’s PMDA. Between 2017 and 2019 the European Union approved 13 biosimilars to bevacizumab, rituximab, and trastuzumab; the United States approved 9; and Japan approved 7. The EMA and FDA have also approved supportive care oncology biosimilars to filgrastim, pegfilgrastim, and epoetin alfa.

The policy review examined variations in approval policies, interchangeability, pricing, and barriers to competition among the 3 regions. The potential cost savings for oncology biosimilars are immense, according to the authors. “Medical spending savings of more than $110 billion by 2029 are projected among the European Union, the United States, and Japan, with the use of oncology biosimilars in place of reference biologics accounting for most of these savings.”

Extrapolation, Interchangeability, and Substitution

The authors noted that the United States approaches extrapolation distinctly differently from how the European Union and Japan regard it. EU and Japanese regulators allow biosimilar manufacturers to “ask for oncology biosimilar approvals to be extrapolated to indications that in the USA had been designated as an orphan drug setting.”

The authors recommended the United States adopt “full extrapolation for each clinical indication approved for the reference biologic” to encourage a competitive market for therapeutic oncology biosimilars.

Regulatory approaches to interchangeability also differ among the 3 regions. In the European Union, interchangeability and substitution policies are decided by individual countries, many of which allow substitution of a reference biologic with a biosimilar at the pharmacy. Biosimilar substitution is not permitted in Japan. In the United States, substitution is not permitted unless the biosimilar has met the requirements to be designated as interchangeable, which no biosimilar has yet.

The authors recommended the PMDA “consider liberalizing its policies on substitution.” In the United States, they recommended the FDA modify its requirements on interchangeability “to help achieve this designation for an increasing number of therapeutic oncology biosimilars.” They also called for US states to reconsider prohibitions on biosimilar substitution, “as it creates an undue burden on providers and raises patient concerns with little safety benefit.”

In the European Union, biosimilar price discounts average 30%, and in Japan, discounts are 30% or, if the biosimilar has at least 10 approved indications, 40%. In the United States, discounts range from 10% to 33%; however, rebates and “preferred positions on formularies often result in reference biologics being the least expensive option.”

The authors said pay-for-delay agreements, in which the biosimilar manufacturer is paid by the reference biologic manufacturer to delay entry of the biosimilar to the market, are common in the United States and Europe. In the United States, they noted, pay-for-delay agreements were entered into by manufacturers of 4 FDA-approved trastuzumab biosimilars. They commented that this practice delays patient access to more affordable treatment.

The reviewers recommended the US Federal Trade Commission (FTC) review nontransparent rebates and pay-for-delay agreements “for their potentially anticompetitive nature,” noting that there are “similar concerns” in the United Kingdom.

Patent Challenges and Anticompetitive Practices

The authors reported that oncology biosimilar launches in the United States have been more adversely affected by patent challenges than in the European Union and Japan. Patent challenges, they wrote, are rare in the European Union and are made only occasionally in Japan, whereas patent challenges have occurred for 56% of approved oncology biosimilars in the United States, and “many” therapeutic and supportive oncology biosimilars were not launched after winning FDA approval, “because patent litigations or administrative patent challenges were ongoing.”

In addition to patent litigation, the authors discussed delays due to inter partes reviews (patent legitimacy reviews), which they described as “narrower in scope and less expensive than litigation,” but still able to delay market launches for years, “thereby negatively affecting patient access to health care products.”

The reviewers recommended sweeping changes in the United States to preclude makers of reference biologics from delaying the introduction of biosimilars. In the United States, they wrote, “large changes [are] needed to the so-called 

 and to the frequent filing of administrative challenges (inter partes reviews).”

The reviewers did note that the FDA and FTC have recently agreed to strengthen their efforts to reduce and discourage anticompetitive behavior. “This agreement is key to facilitating robust competition within the biologics marketplace by decreasing health care costs of oncology biologics,” they wrote.

Overall, the authors advocated encouraging competition by minimizing pay-for-delay agreements and patent challenges, while supporting physician and patient education on biosimilars. They also cited a need for long-term pharmacovigilance, “particularly with respect to immunogenicity.”

The authors closed by arguing that addressing their identified barriers to oncology biosimilar launch, “would improve the regulatory approval process, improve access to therapeutic biologics and biosimilars, and potentially lead to cost savings that have been anticipated since 2015.”

Bennett CL, Schoen MW, Hoque S, et al. Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated policy review from the Southern Network on Adverse Reactions. 

. 2020;21(12):575-588. doi:10.1016/S1470-2045(20)30485-X

An international group of physicians, surgeons, lawyers, scientists, and pharmacists weighs in on biosimilar policy differences and deficiencies in the United States, Europe, and Japan.  

Policy Review Cites Need for Regulatory Clampdown on Pay-for-Delay Tactics

In 2009, the World Health Organization (WHO) Expert Committee on Biological Standardization created a set of recommendations and guidelines to help its member states implement regulation of biologics and biosimilars. However, member states still face regulatory challenges, based on a 2019-2020 WHO survey of participants in 20 countries. The WHO report on this recommends steps to overcome these challenges.

Progress has been made since an earlier, 2010 survey, the authors said. The challenges identified in the 2010 survey have largely been resolved, but the 2019-2020 survey identified 4 remaining challenges: unavailability or insufficient reference products in particular countries; lack of resources; problems with the quality of some biosimilars; and difficulties with interchangeability and naming of biosimilars.

The authors recommended potential solutions, noting that resolving these challenges will require cooperation between regulatory authorities in different countries. Their proposed solutions included exchanging information on biologics with other regulatory authorities, avoiding unnecessary duplication of studies by accepting foreign-licensed and -sourced reference products, relying on approvals from other regulatory authorities or using joint review to facilitate approval of biosimilars, reassessing products approved before the biosimilar regulatory framework was in place, and establishing regulatory oversight for good pharmacovigilance.

Challenges Associated With Reference Products

The authors noted that many of the challenges identified by the 20 surveyed countries were related to reference biologics, including limited access to information on the reference biologic, financial constraints due to the price of the reference biologic, and difficulty of obtaining reference biologic samples to assess comparability.

The authors noted some countries accept reference biologics that are foreign-licensed and -sourced, whereas others require a domestically licensed reference product or bridge studies for a foreign-sourced reference product. The authors commented that bridge studies are costly and often result in unnecessary duplication of studies.

To address these challenges, the authors recommended exchanging information with other national regulatory authorities, accepting foreign-sourced reference products, and avoiding unnecessary bridge studies. They said, “if data and information are available in the public domain and are sufficient to establish this bridge, the additional study might be waived and would result in reducing the cost of biosimilar development.” They noted that some countries have already implemented information-sharing processes with other national regulatory authorities.

Insufficient resources for national regulatory authorities were a commonly cited challenge. The authors commented that building capacity and expertise in a national regulatory authority is “a lengthy process,” and shorter-term measures are needed, such as reliance on information from other regulatory authorities or a joint review process. Some countries have already implemented these strategies to facilitate the biosimilar approval process. Ghana, India, Iran, Jordan, Malaysia, Peru, and Zambia rely on the expertise of other countries which have previously approved reference biologics and biosimilars. Joint review to share the work between regulatory authorities has been implemented in Africa. The authors recommend using these short-term measures to improve efficiency of biosimilar approvals.

In some countries, there are biosimilar products on the market that were approved prior to the establishment of a regulatory framework for approving biosimilars. This has led to problems distinguishing between “real” biosimilars and what the authors called “nonbiosimilar, noninnovator products.” The authors recommended reassessment of these products with regard to the established biosimilar approval process. They noted that several countries have already begun reevaluating nonbiosimilar, noninnovator products.

According to the authors, “the hottest topic in biosimilars has moved on from establishing a suitable regulatory framework to the practice of interchangeability.” They noted that the FDA’s requirements for interchangeability “are very challenging and no such products have been approved by the FDA to date.” They report each regulatory authority has its own approach, but no other national regulatory authority has adopted the FDA approach. Only Iran and Japan establish interchangeability immediately upon approval of the biosimilar, with most other countries either relying on the decision of prescribers or basing the decision on clinical evidence provided by the manufacturer.

The authors cited interchangeability as a difficult issue, especially for health care professionals. They argued interchangeability is “more of an issue to be considered and decided by physicians and patients rather than a regulatory issue,” and that “the role of regulatory authorities in this is to inform physicians and patients about the regulatory assessment and decision as a prerequisite for switching products on the market.”

The authors pointed out “there is still no consensus among countries on the naming and labeling of biosimilars,” and the WHO does not provide specific nomenclature for biosimilars. They reported many countries use the brand name and international nonproprietary name (the same name as the reference biologic), while others use a suffix or other identifier as part of the name.

The authors stressed that naming and labeling are important for good pharmacovigilance, which is “essential for establishing the safety and efficacy of interchangeability of biosimilars.” There are concerns, they say, about “prescription mix‐ups, unintentional switching, and questions on traceability.” To address these concerns, the authors recommended biosimilars be clearly identifiable, using a unique brand name with the international proprietary name, and the lot number be provided.

Kang HN, Thorpe R, Knezevic I, et al. Regulatory challenges with biosimilars: an update from 20 countries. 

. Published online November 21, 2020. doi:10.1111/nyas.14522

A survey of 20 countries highlights the remaining regulatory challenges facing biosimilar adoption.

WHO Survey Identifies Global Regulatory Challenges for Biosimilars

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

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

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