Meir Rinde, MS, is a freelance print and radio journalist based in Philadelphia, Pennsylvania.

Articles

Researchers report findings that suggest a different reimbursement system for Medicare Part B biologics could lead to significantly more robust savings. 

Study: Medicare Consolidated Biosimilar Payment Codes Would Save Money

Tony Hagen is senior managing editor for The Center for Biosimilars

In the second setback this year for etanercept biosimilars, the US District Court for the District of New Jersey has ordered Samsung Bioepis to delay marketing Eticovo until 2029. 

NJ Court Decision Means 3 Decades of Product Exclusivity for Enbrel

Regulators are at work clarifying biosimilar guidance and on Capitol Hill, a battle is raging over reforms that could help or hurt biosimilar advancement.

Biosimilars Roundup: November Was Dominated by Legislative and Regulatory News 

Specialty tiers for biosimilars and reforms that address the proliferation of poor-quality patents would help lower costs and improve access, biosimilar industry veterans said.

Biosimilar Industry Critiques Biden's Drug Pricing Reforms

Videos

Karen van Caulil, PhD, president and CEO at Florida Alliance for Healthcare Value, discusses the difficulty her institution has had in getting providers and employers to switch to biosimilars.

Karen van Caulil, PhD, on Biosimilar Uptake in Oncology Patient Care

Sarfaraz K. Niazi, PhD, is an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, and founder of biosimilars companies Karyo Biologics and Adello Biologics. He also founded the biosimilar advisory company PharmSci.

for similar biotherapeutic products (SBP). A year later, the WHO proposed to 

these guidelines, accepting several suggestions that I and perhaps others had made but leaving many out that were just as important, which I have described below. Nevertheless, I hope that the WHO will reconsider, because its guidelines are followed worldwide. Furthermore, any flaws in guidance can result in significant safety and efficacy issues with biosimilars.

The WHO suggests that national regulatory authorities (NRAs) decide the prescribing information (PI) to go with the SBPs; this is not correct; the PI should be identical to the product information for the reference product. Both the FDA and the European Medicines Agency (EMA) provide guidance on how to write the PI.

The WHO guidelines continue using the term “comparability” as it pertains to a guideline published by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance is known as the ICH Q5E, and many NRAs simply adopt this automatically.

With over 100 biosimilars approved, the choice of critical quality attributes should not be left to the developers but to the regulatory agencies. Any selective choice made by the NRAs can create significant safety problems.

The WHO suggests that clinical efficacy testing can be reduced based on results of animal testing, but this is not rational; biological drugs act by receptor binding unique to humans. Their toxicity is an extrapolation of their pharmacologic response. Thus, these types of testing are of little value in deciding biosimilarity. Both the FDA and EMA have agreed to exclude animal testing, and the WHO should follow the same path. Furthermore, the WHO suggestion that animal testing should be designed based on shortcomings in structural variability is also faulty; an animal model cannot tell whether a molecule is different.

One piece of advice from the WHO to NRAs is that, to assure that the reference product is safe, they should wait for a few years before allowing SBPs; this view questions the rigor of the regulatory approvals of new products; it also delays the entry of SBPs into the countries that need them most.

The WHO unnecessarily confuses local or nonlocal reference biotherapeutic products (RBPs) and how to match the two; the RBP must be the first product approved in a developed country using the complete dossier; there is no need to confuse the issue.

While in the past, the WHO had declared that no statistical modeling should be done in analytical similarity testing; now it proposes to use mean+/-x*SDoftheRBPbatchdata as the range, basing the choice of the multiplier (x) on the criticality/importance of the attribute. But the multiplier cannot be arbitrary; the FDA learning this the hard way when it was forced to withdraw earlier 

. The best choice is to use the value of 3, which covers 99% of the range. The WHO further states that if the analytical similarity does not match, then its impact on safety and efficacy should be addressed using functional assays. Unfortunately, the fact is that there is no way to resolve this issue, and the product must be rejected.

The WHO further recommends using in vivo animal studies to resolve relevantdifferences informulation(eg,using excipientsintheSBPnotwidely usedinmedicinalproducts). This is the most irrational suggestion. No animal study can establish the safety of a formulation and its interaction with the active biological entity; a good 

 was the interaction of erythropoietin with surfactants to cause 

. Therefore, an SBP should not contain an excipient that is not used in other products.

The WHO suggests that pharmacokinetic (PK)/toxicokinetic (TK) studies in animals should be interpreted by considering neutralizing antibodies formed; the fact is that animal model antibodies have little correlation with human response, and a PK/TK study in animals adds little to ascertain the safety in humans. The only species that might bring some value, but only in the PK studies, are the lower primates, but primate studies are discouraged by the WHO. The toxicokinetic studies are useless because they require a dose range of nonlinear responses, making it impossible to differentiate between an SBP and RBP.

One suggestion of the WHO is that if the SBP contains impurities that are not present in the RBP (eg, because of the use of a novel expression system), the developer should justify it based on additional safety data or a scientific rationale; this suggestion is flawed because, unlike chemical drugs, the toxicology of biological products is related to their pharmacodynamics, which makes such a determination impossible. For this reason, the FDA and EMA discourage using alternate expression systems, even though they are allowed. In addition, no unmatched impurity should be present unless this has already been reported in the reference product's literature.

The WHO takes a nonscientific view of immunogenicity and suggests more investigations if the immunogenicity difference is large; but proving that these differences are not clinically relevant is almost impossible, short of extensive human testing. 

, differences may be allowed where the immunogenicity does not affect the drug’s disposition, or bodily elimination, profile. Still, if the difference is large in the immunogenicity, the SBP should be rejected, even if there is evidence that immunogenicity does not affect the pharmacokinetics.


The WHO is not a regulatory agency, but its recommendations are widely adopted globally, mainly by developing countries. The new proposal by the WHO to revise its guidelines is a significant step in bringing these guidelines into accord with FDA and EMA recommendations. Still, the WHO guidance continues to miss out on several key concepts of safety and efficacy. For example, the continued insistence by the WHO that animal testing and clinical efficacy studies, both of which are least sensitive, can be used to justify differences in analytical assessment and clinical pharmacology is fallacious. I hope that the WHO will continue to improve its guidelines as they impact most of the world.

An expert on biotherapeutics recommends more science be applied to World Health Organization (WHO) biosimilar guideline revisions. 

Opinion: One Step Forward, Half a Step Back for WHO Biosimilar Guidance 

Hi, I’m Skylar Jeremias for The Center for Biosimilars®, your resource for clinical, regulatory, business, and policy news in the rapidly changing world of biosimilars.

Here are the top 5 biosimilar articles for the week of November 22, 2021.

Number 5: A study from a free market–focused 

 argued for the elimination of market barriers to biosimilars to tap potentially billions of dollars in health care system savings that biosimilars for 2 widely used drugs could provide.

Number 4: Authors of a review discussed barriers to insulin access and potential solutions as the 

 of the drug's first use for diabetes gets closer.

Number 3: Progression-free survival (PFS) 

 for patients with epidermal growth factor receptor–mutated nonsquamous non–small cell lung cancer who were treated with PD-1 and antivascularization therapy.

 from Samsung Bioepis and Organon took aim at misconceptions about biosimilars and industry practices that hinder their adoption.

Number 1: A European Medicines Agency (EMA) 

 to advise manufacturers how to minimize or avoid clinical trial requirements was based on wrong assumptions about the biosimilar development process.

To read all of these articles and more, visit 

The Top 5 Biosimilar Articles for the Week of November 22

Machine learning shows promise as a complementary approach to chromatographic (mixture separation) techniques for assessing biosimilarity and stability, according to a recent study.

Investigators evaluated machine learning vs chromatographic analysis in the study of 3 trastuzumab biosimilars and their reference product (Herceptin) under control and stress conditions. They concluded the machine learning results correlated with the chromatographic data and revealed patterns elucidating the effects of pH and thermal stress conditions.

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), is approved as a treatment for metastatic breast cancer, early breast cancer, and metastatic gastric cancer. The investigators found that the biosimilars showed high similarity under control conditions, but “differences in degradation patterns were detected under…forced degradation conditions” in the study.

First, physicochemical characteristics of the reference product and biosimilar trastuzumab products (approved for use in Egypt; and referred to as B1, B2, and B3 in the study) were determined by size exclusion chromatography, cation exchange chromatography, and peptide mapping. The biologics were evaluated under control conditions and under pH and thermal stress. The investigators then used unsupervised machine learning techniques to find patterns in the chromatographic data.

The authors said primary structure and size and charge variants are quality attributes expected to affect the quality, safety, and efficacy of biologic drugs including trastuzumab. These attributes were similar in the biosimilars and reference product under control conditions, the authors found.

Thermal and pH stress, the authors noted, “are among the most studied stress conditions in forced degradation studies due to their direct effect on the size and charge variant profiles of [monoclonal antibodies] mAbs through deamidation and oxidation.” Under thermal and pH stress, the investigators did find differences in the degradation of the different products.

Based on size exclusion chromatography, B2 and B3 showed a tendency to form high- and low-molecular weight variants under acidic and basic stress, and B2 showed 83% degradation by the 2-week time point under acidic stress. Under thermal stress, B3 showed the greatest degradation, 39% after 2 weeks.

Under acidic stress, the products varied from 19.9% degradation of the main variant of the reference product at 2 weeks to 93% for B2. Under basic stress, all samples showed a comparable increase in abundance of acidic variants. Under thermal stress, the charge variant distribution of B2 and B3 were similar to charge variant distribution for the reference product, while B1 showed a greater abundance of acidic variants.

The investigators used unsupervised machine learning techniques, which find patterns in data with no prior training or predefined subcategories. Principal component analysis (PCA) is a method for reducing complexity in high-dimensional data to a small number of components that explain the greatest percentage of the variance in the data set.

The authors plotted size exclusion chromatography and cation exchange chromatography data on 2-dimensional coordinates representing the 2 components (PC1 and PC2) that explained the most variance to identify patterns in the data. Primary component analysis of chromatographic and peptide mapping data of the control samples showed no outliers, which the authors said supports biosimilarity of the products.

The plot of control and acidic stressed samples showed that the control samples were separated along the primary component 1 (PC1) axis, while the stressed samples were distributed along the PC2 axis. Samples of the same product were clustered “relevantly close to each other,” the authors said, and their PCA results on control and acidic-stressed samples suggested 41% of the variance in the data was due to the applied stress, and 25% was due to inherent differences in the chromatographic profiles of the products.

The investigators also used 2 clustering techniques, k-means and density-based spatial clustering of applications with noise (DBSCAN), on the data from the top 2 PCs from their primary component analysis. According to the authors, cluster analysis is “an unsupervised exploratory technique aiming to find natural grouping in data so that items in the same cluster are more similar to each other than to those from different clusters.”

Due to the “inherent variability” and “large number of possible structural variants” of monoclonal antibodies, the authors said, machine learning–aided approaches have “great value” for assessing their critical quality attributes. They cited previous research using PCA to reveal patterns in the data on biosimilarity and stability of other biologics, recombinant human growth hormone and infliximab.

K-means clustering of the unstressed samples segregated the products into 3 clusters, with the reference product and B2 each forming their own cluster, and B1 and B3 allocated to the same cluster. DBSCAN segregated each product to its own cluster.

K-means clustering was able to separate control and pH-stressed samples into different clusters, although B2 control samples were clustered with the stressed reference product and B3 samples. Cluster analysis suggested B3 was most similar to the reference product under acidic stress, while B2 was most similar under thermal stress, and all products had a similar response to basic pH stress. The greatest variability between control samples was between the reference product and B2.

Finally, application of principal component and clustering analyses to the collective data set from all the applied chromatographic techniques supported biosimilarity of the products, the authors said. This principal component analysis identified no samples that were significantly different from the others; k-means identified 3 clusters (reference product, B1 + B3, and B2), and DBSCAN identified 4 clusters, one containing each product.

The authors concluded their results supported the biosimilarity of the products analyzed, and “highlighted that regarding the charge and size profiles of the studied products, B2 showed higher variability (than B1 and B3) compared to HC under both control and stress conditions.” They said that the chromatographic fingerprints and machine learning results “were correlated and were able to reveal patterns related to the effect of different stress conditions on the different investigated products.” They recommended future studies explore other machine learning tools to interpret physicochemical data on biologic products.

The European Medicines Authority reports on a 

 in tailoring development of biosimilars, or eliminating unnecessary testing, and the World Health Organization 

Shatat SM, Al-Ghobashy MA, Fathalla FA, Abbas SS, Eltanany BM. Coupling of trastuzumab chromatographic profiling with machine learning tools: a complementary approach for biosimilarity and stability assessment. 

J Chromatogr B Analyt Technol Biomed Life Sci

. 2021;1184:122976. doi:10.1016/j.jchromb.2021.122976

A study of trastuzumab biosimilars and the reference product (Herceptin) under control and stress conditions elucidated the value of machine learning. 

Machine Learning Clarifies Stress-Based Degradation of Biosimilars

Ontario in early 2020 became the third Canadian province to begin switching patients on reference (originator) drugs to biosimilars; however, the move did not mandate switching all patients to biosimilars if they were already started on reference products. In a 

, investigators estimated potential savings from stronger substitution policies.

Using pharmacy claims data for biologics reimbursed under provincial drug insurance, investigators modeled spending and patient utilization according to mandatory nonmedical biosimilar substitution and substitution for new users only. They also considered the availability of adalimumab and insulin glargine biosimilars based on price discounts as low as 25% of the reference product price, which they said was achievable based on studies of biosimilar adoption in other regions.

Their analysis covered the 2-year period from January 2018 to December 2019 and also forecast trends to December 31, 2020.

A mandatory nonmedical biosimilar substitution policy for inflammatory diseases would have affected 7209 patients during the 3-year period and saved $238.6 million. Had the substitution policy applied only to new users, 757 patients would have been affected and the savings would have been limited to $34.2 million. With the hypothetical availability of an adalimumab biosimilar, the 3-year savings under mandatory switching would have increased to $645.9 million, and 12,928 patients would have been affected, based on all biosimilars being priced at 25% of the reference product price.

Not including adalimumab biosimilar savings, the expansion of nonmedical mandatory switching to include an insulin glargine biosimilar would have saved $288.7 million, investigators said.

The importance of biosimilars—equally effective and safe as reference drugs—for savings and access to health care has long been recognized, but in Canadian provinces uptake of these agents has been tepid, and so in recent years British Columbia and Alberta, and now Ontario, have begun mandating that patients use biosimilars. The growth of use of biologics, among the most costly of drugs, also has driven this trend.

In 2018 biologics accounted for 1.5% of claims in Canadian public health programs, but 27.3% of drug costs. In Ontario, use of biologics increased 462% from 2010 to 2019, and public spending on biologics in the province was forecast to reach $1.4 billion by 2021.

“Although biologics are improving outcomes for patients, their increasing use and high costs threaten the financial sustainability of public drug programs,” authors of the study wrote.

The study included publicly funded prescriptions for infliximab, etanercept, and adalimumab for rheumatic conditions or inflammatory bowel disease (IBD). In their analysis of 2018 claims information, investigators found that 84.1% of users of etanercept and 86.7% of users of infliximab were treated with a reference product vs a biosimilar.

When it came to starting treatment for patients with rheumatic conditions or IBD, reference products still retained traction: 39.5% of patients starting etanercept and 59.8% of patients starting infliximab began with a reference product rather than a biosimilar.

International research suggests that policies requiring nonmedical switches or automatic substitutions with biosimilars generally lead to rapid shifts in dispensing patterns and large cost reductions for public payers, but potentially increased costs related to health services utilization

“Overall, the considerable cost savings and number of patients affected by the biosimilar policy changes examined in this study are within the range of estimates found in other jurisdictions, both nationally and internationally,” authors of the study wrote.

“International research suggests that policies requiring nonmedical switches or automatic substitutions with biosimilars generally lead to rapid shifts in dispensing patterns and large cost reductions for public payers, but potentially increased costs related to health services utilization,” they said.

An important factor when contemplating a switching policy is that manufacturers of reference products often provide funding for some patient care and medication administration costs, as well as co-payment assistance, investigators said. “Therefore, any policies introducing mandatory changes in therapy need to allow for scaling up of these services for the corresponding biosimilars,” they wrote.

Although Ontario public drug programs require that new users of infliximab and etanercept start on biosimilars, the reality is this policy is subverted by a hospital practice of starting patients on reference products that are obtained for relatively low cost.

“As our model indicates, considerable additional savings could be achieved if the intended new-user biosimilar policy was fully enforceable,” the authors wrote.

Adalimumab biosimilars became available in Ontario in February 2021.

, investigators shed light on helpful practices and considerations for pharmacists when switching patients to rheumatology biosimilars. 

Authors of a new study estimated significant savings from biosimilars in Ontario based on deep price discounts and mandatory switching programs.

Study Models Biosimilar Savings in Ontario From Mandatory Switching

Authors of a review of 100 years of insulin therapy for diabetes contend that manufacturers have systematically exploited the patent system and market to generate profits at the expense of patients, but they note progress in the development and availability of biosimilar insulin.

Semglee (insulin glargine), for example, was originally launched in 2020 as a standalone drug, but its status was 

 to “interchangeable biosimilar” in 2021, potentially giving it access to a larger share of the market for reference product Lantus. The official relaunch of the product as a biosimilar was November 16, 2021, and this made Semglee the first official insulin biosimilar available in the United States.

In tandem with the redesignation of Semglee, which has an identical amino acid sequence to Lantus, the pharmacy benefit managers (PBMs) 

 have announced intentions to give this product preferred formulary status, boosting access to patients and, potentially, savings.

Semglee was the first biosimilar to receive interchangeable status. An interchangeable can be dispensed at the pharmacy counter instead of higher-priced reference products without physician authorization. According to AmerisourceBergen, there are multiple rapid-acting and long-acting insulin biosimilars in development that could potentially complement the price-reducing effect of Semglee.

Insulin was discovered in 1921 in Toronto, Canada, and first used to treat diabetes in a human in January 1922. Recognizing insulin’s value for human health, its discoverers famously sold their patent rights for $1 each to keep insulin “accessible and affordable for everyone with diabetes”; yet after nearly 100 years of insulin, fewer than half of patients with diabetes worldwide can’t access or afford the drug, and up to 30% of individuals in the United States with diabetes report rationing or skipping insulin doses because of cost, according to authors of the review, which explores why insulin remains expensive and how its cost could be controlled.

“Insulin prices and expenditures have increased dramatically over the past decade in the United States, and high prices and out-of-pocket costs are barriers to insulin treatment for people with diabetes,” the authors wrote.

They cited several factors that are driving up the cost of insulin, including clinicians’ prescribing practices, price increases across all insulin products, regulatory and policy barriers, and a lack of transparency throughout the supply chain. They outlined strategies at clinical, policy, and regulatory levels to improve access to and affordability of insulin.

A Shift in Clinician Prescribing Practices

First, they noted increasing use of more expensive insulin analogs in place of human and animal insulins, which has “negatively affected the affordability of insulin for health systems and individuals around the world.” 

Insulin prices and expenditures have increased dramatically over the past decade in the United States, and high prices and out-of-pocket costs are barriers to insulin treatment for people with diabetes.

Clinicians should weigh the benefits and costs of insulin analogs (laboratory grown and genetically modified to accelerate or control the drug’s effect), because less-expensive human insulins “may be appropriate alternatives” for some patients, the authors said. They cited research suggesting that insulin analogs did not reduce the risk of hypoglycemia or improve glycemic control compared with human neutral protamine Hagedorn (NPH; isophane) insulin in patients with type 2 diabetes.

The authors recommended regulatory changes, saying that “although patents and exclusivities serve to promote innovation, they can negatively impact competition.” For example, they recommended regulatory action to discourage manufacturers from applying for multiple patents on the same drug or making slight modifications in product to extend patent protection.

Additionally, they advised that manufacturer agreements that block the launch of generics or biosimilars (pay for delay) “should be curtailed,” and they said the 180-day exclusivity period for the first manufacturer to apply for a generic drug application “should be revised to close loopholes that limit competition beyond 180 days.” Plus, they said regulators should contemplate shortening the allowable period of market exclusivity for original biological products and removing market barriers to biosimilar entry.

Flexibility of Payers to Negotiate Drug Prices

The federal government’s limited flexibility to negotiate drug prices is another contributor to rising insulin costs, the authors said. Medicaid is permitted to negotiate drug prices “and by doing so is able to provide beneficiaries with an extensive choice of medications at low out-of-pocket costs,” but Medicare Part D is prohibited from negotiating drug prices. The authors recommended that “all federal drug benefit programs be given greater flexibility to negotiate medication prices with manufacturers and PBMs to capitalize on their market shares and volumes.”

Under the Build Back Better Act, currently under negotiation in Congress, Medicare Part D would be allowed to negotiate the prices of the highest cost drugs once they have been on the market for a certain length of time. The market exposure time for small molecule (generic) drugs would be 9 years, and the time limit for large molecule (biologics) would be 12 years. Medicare could negotiate up to 10 drugs per year in 2023, and in succeeding years the total could climb to 22 drugs negotiated.

For every $100 spent on retail drugs, $41 goes to parties in the distribution chain: wholesalers, pharmacies, pharmacy benefit managers, and insurers.

The authors also discussed the Part D Senior Savings model, “a promising new model for pharmacy payment,” launched by the Center for Medicare and Medicaid Innovation in January 2021. This savings model offers beneficiaries “broad access to multiple types of insulin at a maximum copay of $35 per insulin per month.”

With value-based pricing, “the price paid for medication is based on the benefits to the patient as indicated by clinical or financial measures.” The authors encouraged the use of value-based pricing for insulin or alternatively, value-based insurance design (VBID), which is intended to promote cost-efficient health care and consumer choices, with the goal of lowering costs and improving health care quality. The authors noted that VBID principles are already in place in the Affordable Care Act, which requires health plans to cover certain preventive services with no patient co-pay. 

The authors noted the growing difference between the list price and the net price of insulin due to rebates and discounts, saying “for every $100 spent on retail drugs, $41 goes to parties in the distribution chain: wholesalers, pharmacies, pharmacy benefit managers, and insurers.” They urged “greater transparency and simplicity” in insulin pricing “to eliminate distortions that are currently beyond individual payers’ ability to address.”

Herman WH, Kuo S. 100 years of insulin: why is insulin so expensive and what can be done to control its cost? 

. 2021;50(3 suppl):e21-e34. doi:10.1016/j.ecl.2021.09.001

Authors of a review discuss barriers to insulin access and potential solutions as the 100-year anniversary of the drug's first use for diabetes gets closer. 

High Cost, Low Access Still Plague Insulin Market at 100-Year Anniversary

Investigators have reported significant improvement in progression-free survival (PFS) for patients with nonsquamous non–small cell lung cancer (NSCLC) treated with sintilimab and Byvasda, a bevacizumab biosimilar, in combination with chemotherapy.

 at the European Society for Medical Oncology Virtual Plenary meeting this month. In the phase 3 ORIENT-31 trial, patients who progressed on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy were treated with sintilimab (a programmed death inhibitor), a bevacizumab (which inhibits tumor vascularization) biosimilar, pemetrexed, and cisplatin.

Sintilimab, marketed as Tyvyt, and Byvasda are approved in China, and the EGFR-mutated nonquamous NSCLC study was conducted at multiple sites in China. Tyvyt was developed by Innovent Biologics and Eli Lilly, and Byvasda was developed by Innovent Biologics.

Investigators said that in the intent-to-treat patient population, those who received sintilimab plus the bevacizumab biosimilar in combination with chemotherapy demonstrated a statistically significant improvement in PFS compared with patients who received just chemotherapy (HR, 0.46; 95% CI, 0.337-0.639; 

 < .0001). The median PFS was 6.9 vs 4.3 months, respectively.

They said a third cohort of patients was administered sintilimab and chemotherapy, but findings did not achieve statistical significance in comparison with the sintilimab-plus-bevacizumab- biosimilar-and-chemotherapy cohort.

The investigators said key secondary end points for objective response rate and duration of response showed improvement in the sintilimab-plus-bevacizumab-biosimilar arm vs chemotherapy alone. Safety results were consistent with those previously reported for sintilimab and Byvasda.

Innovent said that it will file an investigational new drug application with China’s National Medical Products Administration based on the findings from ORIENT-31.

The results are important because the prognosis for advanced EGFR-mutated NSCLC is very poor, investigators said.

“Despite initial clinical response to EGFR-TKI therapy, virtually all advanced EGFR-mutated NSCLC [cancers] inevitably acquire resistance mechanisms and progress after treatment with an EGFR-TKI,” said Shun Lu, MD, PhD, principal investigator from the Oncology Department of Shanghai Chest Hospital.

The current standard of care for EGFR-mutated advanced nonsquamous NSCLC is platinum-based chemotherapy, although this offers little benefit. “New treatment options are imperative for this unmet medical need,” Lu said.

Investigators said ORIENT-31 was the first prospective, double blind, phase 3 study to demonstrate an improvement in this patient population with sintilimab and bevacizumab in combination with chemotherapy.

"Lung cancer is one of the most prevalent cancers and remains the leading cause of cancer-related mortality both in China and worldwide. EGFR-mutated NSCLC is the most prevalent molecular subtype in Chinese lung cancer patients, accounting for 40% to 50% of nonsquamous NSCLC,” said Hui Zhou, PhD, senior vice president of Innovent.

“While immunotherapy has greatly changed the treatment paradigm for many malignancies, it has not yet conquered driver genes–mutated cancers. Drug resistance is unavoidable for patients with EGFR-mutated advanced NSCLC after first-, second-, and third-generation EGFR-TKI treatments, with limited treatment options, representing a large unmet medical need. The ORIENT-31 data at this year's ESMO indicate the potential of combination therapy to prolong the lives of these patients,” he said.

Innovent was founded in 2011 and has offices in Suzhou, China, and San Francisco, California.

Progression-free survival (PFS) was improved for patients with epidermal growth factor receptor–mutated nonsquamous non–small cell lung cancer who were treated with PD-1 and antivascularization therapy.

Sintilimab and Bevacizumab Biosimilar Improve PFS in Advanced Lung Cancer

The Center for Biosimilars® interviewed Steven Yates, MD, a medical oncologist and medical director at Intermountain Healthcare in Las Vegas, Nevada. Three years ago, Intermountain hired him to lead its biosimilar adoption effort.

Yates says incentivizing providers to prescribe biosimilars is good for community oncology. He explains how much more receptive oncologists have been to biosimilars compared with other providers, especially since the onset of the COVID-19 pandemic. Over 50% of biosimilar adoption has occurred in community oncology and Yates believes this will only increase. Yates also compares the European Union experience with biosimilars with that in the United States. Overall, biosimilars are contributing to savings and as a result, many oncologists have been willing to utilize them.

The utilization rates for biosimilars in community oncology have been much higher than for other disease categories and are only expected to rise, says Steven Yates, MD.

Dr Steven Yates Discusses the Need for Biosimilar Incentives in Community Oncology

 from Samsung Bioepis and Organon takes aim at misconceptions about biosimilars and industry practices that hinder their adoption. The companies held 3 virtual panel sessions with doctors, nurses, pharmacists, policy experts, and patient advocates.

Authors of the paper hold up Cleveland Clinic as a model of a health system that has achieved success in converting patients to biosimilars from reference products.

Key to the success of Cleveland Clinic's program, the authors explain, was educating stakeholders and setting up direct communications so that patients and providers could learn what they needed to know about biosimilars.

Some of those stakeholders were nurses, who were given specific training so that they could “reassure patients about the quality of care they would be receiving and answer any questions patients might have.”

In the broader health care community, “many physicians still lack confidence in biosimilars,” the authors wrote. In oncology, biosimilars have been embraced by physicians and patients, but in gastroenterology, there are lingering concerns about whether these agents will serve patients as well as their reference products.

“Many gastroenterologists who prescribe biologics for their patients with inflammatory bowel disease are concerned about biosimilar safety, immunogenicity, and indication extrapolation,” the authors wrote.

Another health care institution that has successfully transitioned patients to biosimilars is Kaiser Permanente, authors of the whitepaper said.

“Kaiser’s approach starts with a rigorous review of available biosimilar evidence, including data from manufacturers, FDA approvals, and real-world data from countries where biosimilars have already launched,” they wrote.

Kaiser Permanente got biosimilars into circulation by building physician confidence, a strategy that 

Having these data on hand is critical to informing physicians and other stakeholders so they can more readily embrace biosimilars, the authors wrote.

However, those informational materials need to be digestible. “A gastroenterologist participating on the panel who has published on the merits of biosimilars in treating inflammatory conditions shared that many physicians are too busy to study in-depth clinical trial data and would prefer to receive easily digestible educational materials demonstrating a biosimilar’s safety, equivalence, and cost savings,” the authors wrote.

Samsung Bioepis has developed and gained regulatory approval for multiple biosimilar versions of reference products, and it relies on Organon for assistance with marketing these products. Some of Samsung Bioepis’ biosimilars include etanercept (autoimmune), infliximab (immunosuppressive), adalimumab (autoimmune), and other products. The company has a robust pipeline of biosimilars in development, including aflibercept (ophthalmology), denosumab (endocrinology), ustekinumab (immunology), and eculizumab (hematology) candidates.

Stakeholder education programs and robust data on clinical studies are key to building patient and provider support for biosimilars, according to a new whitepaper. 

Samsung Bioepis White Paper Describes Biosimilar Barriers to Adoption

Here are the top 5 biosimilar articles for the week of November 15, 2021.

Number 5: Conservative think tank Pacific Research Institute (PRI) calculated 

Number 4: The Institute for Clinical and Economic Review (ICER) stated in its latest Unsupported Price Increase report that when it comes to 

Number 3: Kathy Oubre, MS, a cochair of the biosimilars committee of the Community Oncology Alliance (COA), explained findings from a 

 of biosimilar use in oncology practices.

 of the FDA's efforts to clarify the role of the interchangeable biosimilar designation, improve communication with manufacturers, and pay for biosimilar regulatory reviews.

Number 1: In its first quarter of independence from Pfizer, Organon 

 in biosimilars revenue; Sandoz' biosimilar portfolio has been touted as a growth driver amid talk of a spinoff from Novartis.

The Top 5 Biosimilar Articles for the Week of November 15

 to advise manufacturers how to minimize or avoid clinical trial requirements encountered challenges from the lack of mature quality data that applicants could provide, but participants nonetheless valued the feedback process and the agency will continue offering developers “tailored” scientific advice, the EMA said in a report.

Tailoring the development of biosimilars is of growing importance in light of the advances in knowledge and the emergence of more precise technologies for determining bioequivalence. Protein mass spectrometry, for example, is 10-million-fold more sensitive than it was a decade ago, and comparative clinical trials are now viewed as imprecise tools for determining likeness between biological agents.

The quality data submitted by 4 applicants were immature for reasons such as the limited number of batches or because the data were not obtained with material from the proposed commercial process, the report said.

That made it difficult for reviewers to make recommendations on questions such as the number and population of patients and the efficacy margins required for clinical trials.

A key insight of the pilot was that the regulatory guidelines anticipated a “stepwise” approach to comparability studies, in which early uncertainties about biosimilarity are used to determine whether and which further analyses are required. In reality, however, that analytical process occurs at the same time as clinical development, the report said

“Employing such tailored scientific advice requires adaptations in development by having a mature quality and in vitro nonclinical data package prior to the conduct of animal or clinical studies, in order for its utility not to be restricted to simple scientific advice ‘quality checks’ on the available data throughout the development,” the agency said.

For the pilot, which ran from February 2017 to April 2020, the Scientific Advice Working Party, Biologics Working Part, and Committee for Medicinal Products for 

Human Use agreed to conduct a more extensive scientific review than is standard.

The reviewers could give advice on differences identified at the quality level and their potential impact on the suitability of the biosimilar approach or on the need for and design of additional preclinical or clinical investigations. They could also advise whether a simplified clinical development program, such as a waiver of a clinical trial, could be granted.

Four applicants submitted 6 requests regarding biosimilar monoclonal antibodies, with one submitting 2 separate development plans and another requesting initial and follow-up advice for the same plan. The latter applicant’s second submission had a more “mature and comprehensive data package,” the report said. One applicant was a small/medium-size enterprise.

The advice given had, in most instances, more impact on the generation of quality data per se and less impact on clinical data requirements than anticipated. It would therefore need to be seen how biosimilar development programs can be adapted to allow potentially reduced animal and clinical study requirements.

Eight other prospective applicants expressed interest in participating. Over the same period, the agency also received 71 requests for standard advice on biosimilars.

The report said the participants appreciated the opportunity to discuss their quality comparability data with regulators and considered the comprehensiveness of the advice “very important” to gain clarity and confidence in their biosimilar programs. However, due to the immaturity of the data, the advice ultimately given had more impact on the generation of data and less on clinical data requirements than anticipated.

Thus it still remains to be seen “how biosimilar development programs can be adapted to allow potentially reduced animal and clinical study requirements to be considered,” the agency said.

EMA will continue to offer tailored scientific advice as part of its regular operations, in order to further develop the advice process using specific cases and to allow the continuation of useful scientific discussions.

The report noted that the pilot completed 6 sets of advice, as planned. The initial uptake was slower than expected, which the agency said is not unusual for new types of engagement opportunities.

Asked how well their expectations for tailored scientific advice were met, 4 applicants who responded to a feedback questionnaire gave an average rating of 3.7 of 5.

The World Health Organization is currently revising guidelines for biosimilar development, in part to incorporate a tailored approach. The Center for Biosimilars

, policy and science officer for Medicines for Europe, a trade organization, about the value of this process for bringing more competition to markets for orphan drugs and other therapeutics. 

European Medicines Agency (EMA) officials said their pilot was based on wrong assumptions about the biosimilar development process. 