Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

 the Biosimilar Initiative of the Year award from the publisher Informa and health care analytics company IQVIA. The award is given in recognition of exceptional leadership in expanding access to biosimilars.

In late 2019, Samsung Bioepis, based in Incheon, Republic of Korea, won World Health Organization (WHO) 

 for its trastuzumab biosimilar Ontruzant. The WHO designation helps to build worldwide acceptance of the agent and expands access to populations in need of lower-cost medicine. Also in 2019, Samsung Bioepis expanded its biosimilar marketing activities in Asia and Latin America.

 into the Brazilian biosimilars market, considered one of the fastest growing biosimilars markets among emerging nations.

In the United States, the company launched Ontruzant in April 2020 and has 2 biosimilars approved but not yet marketed: Eticovo (etanercept) and Hadlima (adalimumab). Originator product exclusivity rights are keeping these from market. Samsung Bioepis has 5 drug products approved and marketed in Europe in immunology and oncology.

The Biosimilar Initiative award is given to a company with a biosimilar marketed or approved or under development, actively marketing biosimilars, and working to increase biosimilar use and distribution.

“This award is a testament of the tremendous work that we’ve put toward realizing our vision and commitment to become a globally recognized biopharmaceutical company delivering high quality medicines to the people who need them the most,” said Christopher Hansung Ko, president and CEO of Samsung Bioepis.

Informa, based in London, England, and IQVIA, headquartered in Atlanta, Georgia, sponsor the Global Generics & Biosimilars Awards each year, and this recognition of Samsung Bioepis was part of that. Informa is a publishing company and IQVIA is a data analytics consultant.

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The company has multiple biosimilar products on the worldwide market and in development; in 2019, it gained World Health Organization precertification for a trastuzumab biosimilar (Ontruzant).

Award: Samsung Bioepis Is Recognized for Advancing Biosimilars

There is much effort these days to conduct real-world studies of biosimilars, but findings from these initiatives are not really suitable for confirming safety and efficacy trials used to gain biosimilar approval, said Uwe Gudat, head of clinical safety and pharmacovigilance for Fresenius Kabi, a Germany-based maker of oncology, diabetes, critical care, digestive, and medical products, including biosimilars.

Real-world evidence (RWE) is better suited to answer questions about practical use of products in the real world, Gudat explained at the Terrapinn Festival of Biologics Basel 2020 virtual conference.

RWE cannot do the job of detailed physicochemical characterization and functional assays, he said. “Do we really think that real-world evidence can reassure us more than well-controlled randomized clinical trials? I don't believe so.”

The value of a clinical trial is that it screens out random variables, or “noise,” such as patient comorbidities, that distort whatever “signal” the biosimilar is giving that it can successfully treat the target disease conditions, Gudat said. You can’t get the same results in the real world, because there the background noise is strong, he said. “For the most part, when we’re answering questions, the signal clarifies and the noise distracts.”

In the clinical trial setting, the efficacy of a drug candidate is being evaluated; and in the real world, the actual effectiveness of the drug under conditions of everyday medical practice is being judged.

The analytical comparison of a biosimilar candidate done in a controlled setting can be compared to development of a car and the systematic testing of its constituent parts, he said. In the real world, “we’re taking the car out for a spin.” But it’s then that many other factors come into play. Continuing the car analogy, he explained that road conditions, driver fitness, driving skills, and time of day are variables that have the potential to “confound your comparison,” and the variations from what you observed in a controlled setting could be extreme and not the fault of your product.

Even in a drug trial, it is unlikely that clinicians will get the same results every time. It is a fundamental of statistics that patient outcome samples will vary, and these must be pooled to form a more comprehensive picture of how the biosimilar will perform, Gudat said.

He noted that clinical studies of US- and EU-sourced samples of reference adalimumab (Humira) have demonstrated variations that could be explained by local conditions under which the drugs were administered—not by variations between the US and EU biosimilars. “We don’t believe that studies conducted by one sponsor vs another sponsor are fundamentally different and the products used are fundamentally different; much more, we think there are certain circumstances that the study introduces that drive the observation,” Gudat said. "We have to acknowledge that there’s randomness."

Genuine product characterization involves pooling multiple samples of patient outcomes to form a statistical curve. Most of the samples will cluster in the center of this curve, but inevitably there will be outliers. The confidence interval, or the probabilistic margins of drug performance, cuts away the outliers, but those outliers still reflect what could happen when patients use the drug being studied, he said. “This is important, because it helps us understand what kind of numbers we’ll be looking at and what they mean or don’t mean.”

The real-world differences observed between US- vs EU-sourced Humira could be explained by non-drug–related variables, such as improper drug administration or the geographic dispersal of study populations and their epidemiological history—ie, tuberculosis, Gudat said.

For those reasons, he said, RWE doesn’t really help evaluate for biosimilarity. “It compares the products embedded in a multitude of circumstances. You have to look at the whole package. I’m really illustrating why the signal-to-noise ratio in the real-world setting is actually not necessarily conducive to generating comparative evidence for a biosimilar. You’ve just got so much noise; and if you do see a difference, you’ve got no idea where it’s coming from.”

That doesn’t mean RWE is of no value. There are questions that RWE can answer and should be used to answer, he said.

RWE studies can provide important information along the lines of who has gained access to the biosimilar, when is it being used in real world practice, how it is administered, and in what settings the biosimilar has been embraced, Gudat said.

By following this line of inquiry, real-world studies can complement clinical efficacy studies, he said.

Gudat suggested a number of potential real-world studies that would accomplish this objective:

Characteristics of patients treated with biosimilars

Health care practitioners’ attitudes and acceptance of biosimilars

Practitioners’ knowledge of biosimilars

Changes in the order of use of biologics (treatment lines)

Impact on patient outcomes (public health consequences)

“These are other questions equally important or also important that [RWE] can help us to answer,” Gudat said.

Expecting real-world evidence to confirm safety and efficacy of biosimilars is asking too much, Uwe Gudat, a pharmacovigilance expert from Fresenius Kabi, said at the Terrapinn Festival of Biologics Basel 2020.

Expert Cautions on What to Expect From Real-World Biosimilar Evidence

Orphan drugs are often significantly more costly than other biologics, and the presumption might be that biosimilar orphans could bring down the cost of these agents significantly, but the realities undermine that theory, said Roman Drai, MD, PhD, research and development director with Geropharm of Saint Petersburg, Russia.

However, it’s possible that with some modifications in evidence requirements by regulators, the cost of developing biosimilar orphans could be bought down significantly, and this savings could be passed on to patients, Drai said at the Terrapinn Festival of Biologics Basel 2020.

Under ordinary circumstances, competition helps to spur innovator companies to develop better drugs, with patients reaping the benefit, Drai said. “An innovator company might produce first-in-class and best-in-class drugs if they have someone pushing behind them, such as a biosimilar company.”

This doesn’t necessarily happen with orphan drugs, and the costs of development are the reason, Drai said. The costs of developing orphan drugs may be 4 times higher than costs for nonorphan drugs, he said. “The cost for ultra-orphan drugs could be 12 to 20 times higher.”

Orphan drugs are priced high in large part because they are intended for rare conditions and a small population of patients is eligible for treatment with these drugs. Further, the high costs of development must be offset within the same product exclusivity window as applies to common originator and biosimilar drugs, depending on patents, Drai said. This need for a return on investment is factored into the price of orphan drugs.

Another reason for the high cost of developing orphan drugs, both biosimilars and originators, is that for pharmacodynamic (PD) and pharmacokinetic (PK) studies, roughly 40 patients would be needed, but residual uncertainty needs to be resolved via efficacy, safety, and immunogenicity studies, and for this as many as 380 patients would be needed, he said. “You could not just enroll 50 patients to compare with a biosimilar; this is not enough to exclude the uncertainty.”

For that combined patient population (N = 420), an estimated $7.74 million would be needed to perform the PK/PD, efficacy, safety, and immunogenicity studies in Russia—roughly 7 times higher than for nonorphan drugs. In addition, those confirmatory studies would come after more basic studies to establish pharmaceutical and comparative quality and to perform comparative nonclinical evaluation.

Time is another factor that adds to the cost. Enrollment is prolonged because it isn’t easy to get patients to switch to a biosimilar for an orphan drug study, and enrollment may have to be conducted across multiple geographic zones to get the minimum number of patients. An immunogenicity study alone might stretch out to 12 months, Drai said.

Getting past these issues is possible with some structural changes in the way this development work is traditionally performed, he said. This can be accomplished by lowering residual uncertainty prior to phase 3 studies: Phase 3 studies could be waived altogether, they could be postponed until after marketing authorization, and a smaller-than-usual number of patients could be enrolled for phase 3 studies, Drai said, suggesting 3 alternatives.

The prerequisites for allowing such a bypass would be as follows: the existence of a simple molecular structure; high binding affinity between the molecule and antigen; low disulfide bridges; and moderate hydrophobicity, or molecular attraction to water. If these conditions are met, the phase 3 studies could be deemed unnecessary, Drai said.

Further, identifying biomarkers could ease the process by providing surrogate clinical end points for helping understand the drug’s mechanism of action, he said.

“We need to have smart approach to orphan biosimilars and develop guidelines for orphan biosimilars,” he said. “This would lower costs, and often a biosimilar orphan drug could cost less than an originator and it would make the therapy available all over the world.”

Biosimilar orphan drugs might not be cheaper than innovator orphan products, owing to multiple factors, but modifications to regulatory policy could change this, a presenter said at the Terrapinn Festival of Biologics Basel 2020.

Getting Orphan Biosimilars to Market at a Lower Price

Over 15 years of regulatory experience with biosimilar approvals, evidence has accumulated that phase 3 comparative efficacy studies may not yield useful data, panelists said at the Terrapinn Festival of Biologics Basel 2020. However, these studies play an important role in convincing providers to use biosimilars, they added.

Further, biosimilar immunogenicity studies also serve a doubtful role, and product drift, or variation in reference product quality over a period of time raises the question whether originator biologics should be subject to repeat testing over time to verify that they still meet the standards by which they were approved, panelists said.

The discussion was moderated by Lawrence Hill, chief development officer of Gan & Lee Pharmaceuticals in New Providence, New Jersey; and panelists included Sridevi Khambhampaty, vice president of Intas Pharmaceuticals in India; Bert Thomas, senior vice president of business development of Bio-Thera Solutions in China; and Sundar Ramanan, a global regulatory affairs executive with Biocon Biologics in India.

“The phase 3 studies may not really be essential for biosimilars,” Khambhampaty said. “A good amount of analytical similarity, coupled with a pharmacokinetic study, which proves the bioequivalence of the product, would be adequate for the licensure of some of the biosimilars, because the phase 3 studies are not really adding value in terms of demonstrating similarity.”

Analytical studies look at differences at the amino acid level. “There’s a whole battery of biological assays that speak to the efficacy of the molecule. With these high-resolution studies, it’s really questionable whether clinical efficacy studies would be able to find out more of importance,” 

However, she added that postmarketing studies can elucidate important characteristics of a biosimilar and how it’s really used in the real-world setting.

For these reasons, she voiced approval for a move toward less emphasis on clinical efficacy studies for biosimilar approval, as is being made by the UK Medicines and Healthcare Products Regulatory Agency. “We have to see how the other agencies across the world are going to embrace this. We have seen some movements in the insulin guidance from the FDA. They do not want to do phase 3 studies anymore.”

Hill responded that for generics these confirmatory efficacy studies traditionally have not been done, and doubts have been raised that generics are as effective as the originator products. If phase 3 efficacy trials were abolished for biosimilars, these drugs could be vulnerable to the same kinds of arguments by originator companies, he said.

“Arguments have to be backed by data,” Khambhampaty said. “There is adequate data for the safe use of biosimilars, and the wealth of data there is now for the biosimilars that have been in the market for 10 years would be adequate to argue against that.”

 studies are going to be adequate to demonstrate biosimilarity. But he noted that “by setting the bar high” and requiring comparative clinical efficacy studies, “it does give regulators some credence that biosimilars are what they say they are,” which is equivalent in safety and efficacy to originator products.

“Some doctors and patients don’t really understand the difference between small molecules and biologics and don’t really appreciate the nuances there,” he said. Efficacy studies help with the balancing act of getting biosimilars into circulation even if they don’t contribute much on the scientific level toward understanding the relative differences between originators and biosimilars, he said.

Hill agreed with the point, adding that the move toward a more purely scientific evaluation of biosimilars makes sense, but there’s always going to be “a small cohort” of doubters who want the efficacy studies.

Immunogenicity studies help to evaluate the immune response to a monoclonal antibody. The panel discussed whether these studies also contribute to the weight of useful scientific evidence. Although complex molecules, biosimilars are much more easily characterized than previously as science has advanced, and tweaks can be made during the manufacturing product to produce very precise changes, as needed, said Ramanan.

“We need to ask the question at this point in time what need is there for an immunogenicity study?” he said. “Data and knowledge should drive the amount of data required for a biosimilar to be approved.”

The decision whether to require these studies should be “judicious,” he added, because patients taking monoclonal antibodies are often in advanced stages of disease and their safety and well-being are critical. “The bar should be set high.” However, it does appear that scientific knowledge and process reliability have advanced to the point that “we can begin to move away from the immunogenicity study.”

Panelists noted that regulatory bodies may require biosimilar developers to conduct studies using biosimilar reference product source from the markets in which they will be marketed. For example, a developer may have to demonstrate equivalence to Herceptin (trastuzumab) from both Europe and the United States. In theory the reference drug should be the same no matter where it is sold. “It’s nonsensical,” Thomas said, noting the added time and expense needed to gather data that may be completely redundant.

However, from this argument comes the issue of product drift, or batch variation, Thomas noted that the assumption generally made is that the originator product is going to be the same. It has been demonstrated that reference product quality varies over time, which makes it more difficult for biosimilar manufacturers to hit the target on equivalence. 

“For us biosimilar manufacturers, it’s a huge issue.” Maybe originator products should be checked on a regular basis for consistency, he said.

Certain biosimilar studies are performed out of an abundance of caution and good marketing sense, although science has leapfrogged the need for these trials, panelists said at the Terrapinn Festival of Biologics Basel 2020.

Panelists Question Efficacy, Immunogenicity Studies for Biosimilars

The way Sarfaraz K. Niazi, PhD, looks at it, doing comparative efficacy studies in humans to confirm that a biosimilar candidate is equivalent to a reference product is, in most cases, a complete waste of time. But many biosimilar companies still do these studies. The reason? The comparative clinical data may have little value in getting regulators to approve their products, despite helping with future marketing.

“Clinicians don’t understand all the steps to establish biosimilarity. They want to see clinical data,” said Niazi, an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, and a founder of biosimilars companies.

Regulatory authorities in the United States and Europe may not require clinical efficacy studies if they feel satisfied that other evidence presented by biosimilar developers is adequate to make the case for approval. Niazi argues that if earlier-phase pharmacodynamic (PD) and pharmacokinetic (PK) studies haven’t provided the needed evidence, it probably isn’t a good idea to proceed with in-human efficacy trials.

So many large companies have been doing these costly comparative trials that smaller companies may falsely believe it’s incumbent upon them to carry out these trials also, he says.

“Unfortunately, the larger companies do this to support their marketing efforts and not their scientific efforts. And that has caused a significant drawback for smaller companies, who begin to think that this is the norm—this is how we need to do the work,” Niazi said.

European Union regulatory authorities follow a stepwise approach to biosimilar approval that involves comparative quality studies based on functional and analytical attributes of the drug candidates, followed by comparative nonclinical studies concerning pharmacodynamics and toxicology. Only then do biosimilar developers move on to comparative clinical studies, which include PK and PD analysis, and potentially efficacy, safety, and immunogenicity studies.

, “The aim of studies in humans is not to demonstrate safety and efficacy in patients, as these have already been established for the reference medicine.”

“Residual Uncertainty” Is the Trigger

 for doing additional studies is whether there is “residual uncertainty” that the product is equivalent to its reference drug. Niazi contends that biosimilar developers would be hard put to discover any specific requirement for “clinical efficacy” trials in FDA biosimilar guidance.

“The FDA can require additional studies [not necessarily clinical efficacy]. The onus is on the FDA to define what is residual uncertainty. Unless you get that answer, you should not be eager to do an efficacy study,” he said.

Arguments such as these have been behind increasing calls lately to do away with comparative clinical efficacy testing for biosimilars. In September 2020, the International Generic and Biosimilar Medicines Association 

 for regulatory authorities to scale back any requests for efficacy testing on the assumption that other forms of testing can provide more exact and convincing evidence of biosimilarity.

In October 2020, the United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) issued 

 indicating that these trials are unnecessary in most cases. The draft document was supported by a recent position paper from members of the MHRA contending that biosimilarity can usually be demonstrated by analytical testing and a PK trial. Exceptional cases only should be the measure for whether comparative efficacy trials are necessary, they argued.

“In my opinion, clinical efficacy studies do not give you the confidence that the product is bioequivalent,” Niazi said. One reason is that the margins for efficacy outcomes in a human trial are, to some degree, arbitrary. Should the margins for biosimilar performance be within 10% of reference product performance or 40%? he asks. Niazi said he has seen margins set at both those extremes for biosimilars that have been approved by regulatory authorities, from the United States to India.

These tests are not exact. “If you have to do a clinical efficacy study, you’ve already lost the game,” because such a study is not going to provide the evidence you need to demonstrate biosimilarity, he said.

The “Least Powerful” Measurement Tool

The issue is also intriguing to Paul Cornes, BM, BCH, MA, MRCP, FRCR, a UK-based oncologist who was part of the team that developed and presented evidence to the FDA's Oncologic Advisory Drugs Committee for the first successfully approved US biosimilar. Cornes recently lectured on clinical efficacy testing before the UK Royal Pharmaceutical Society.

“The UK position is just the same as the US one at a scientific level, and follows on from many statements given by both the FDA and European Medicines Agency that clinical comparative trials are the least powerful steps for determining biosimilarity and that they may not always be needed,” Cornes said.

The essential point to discover in qualifying a biosimilar is whether it is identical to the reference product to the point of not having any meaningful differences, and that requires highly sensitive testing. “In many instances, a [PD] end point will be a far better measure of potential difference than a clinical one,” he said.

Providing an example, Cornes said, “We use trastuzumab because it increases 5-year overall survival with high-risk, HER2-positive breast cancer by 5% better than chemotherapy alone. Pharmacologically, it does this by killing HER2-positive overexpressing cancer cells, which we can see in neoadjuvant treatment or in treating metastatic breast cancer where the effect is greater than 20% better than chemotherapy alone. So, a trial with the [PD] end point of breast cancer shrinkage is 4 times more likely to discover a meaningful difference between the 2 drugs than a clinical end point trial.”

The same applies to evaluating biosimilarity for insulin products, he said. An evaluation of “serial serum glucose levels over time is likely to be more sensitive than waiting to compare the clinical effects of diabetes to declare themselves.”

Looking at it another way, Cornes said, there are multiple anti-inflammatory biologics brands for rheumatoid disease, and in a study, The National Institute for Health and Care Excellence of Great Britain found that each of these drugs produced a similar response in patients in terms of arthritis control and toxicity events. “If you cannot clinically differentiate different drugs, how can you hope to clinically differentiate different versions of the same drug?” he asked.

The United Kingdom, which in January 2021 will make independent regulatory approval decisions about drugs following the country’s exit from the European Union, is “reasonable” in its recent draft guidance that places less emphasis on the importance of comparative efficacy trials, said Nancy Globus, PharmD, vice president of regulatory affairs at the Accreditation Council for Medical Affairs.

“If the overall sentiment of the industry and the regulators is to increase patient access to these products, then let’s make it a little easier for the manufacturers so that they do not necessarily have to comply with a framework that may not have been designed with these types of molecules in mind.” Such studies may be more suitable for generics, which are simple molecules, Globus said.

Another downside to comparative efficacy trials is that they require large patient populations to achieve statistical significance and they are costly. A recent study indicated that these comparative efficacy trials are costing more than pivotal trials for originator drugs. “That is just completely contrary to the whole reason why manufacturers are trying to get biosimilar products to market,” she added. “If the whole point is not to spend the same amount of time and money that the innovator did, doing them just to check a box strikes me as a little bit ridiculous.”

Cornes agreed, adding that other issues are also important to consider when it comes to comparing biosimilars with reference products. When changes are made in the manufacturing process, it’s easy for different batches of the same reference product to differ from one another. These changes “are often recorded to show greater differences in critical attributes than would be permitted for biosimilars,” he said.

Manufacturers, not regulators, may be the holdouts when it comes to eliminating comparative clinical efficacy trials, according to experts interviewed by The Center for Biosimilars®.

Regulatory Policy May Not Stop Comparative Efficacy Trials

The hunt for biomarkers to add precision to efforts to determine biosimilar equivalence will get an added boost from a 

between the FDA and SomaLogic of Boulder, Colorado.

The agreement involves the use of a highly sensitive protein measurement tool to assess changes in circulating proteins in patient blood samples following treatment with reference biologics. These same measurements will be compared with protein levels in samples from patients using biosimilar drug candidates. This type of large-scale analysis of proteins is called proteomics.

“Circulating proteins, when measured at the broadest scale, provide system-wide information on the dynamic effects of drug exposure-response,” Stephen Williams, MD, chief medical officer at SomaLogic, said in a statement. “Comparing the 'blood protein fingerprint' of a biosimilar to a reference biologic has the potential to be more efficient and precise than clinical observations for establishing biosimilarity.”

The agreement involves collaboration between SomaLogic and the FDA’s Division of Applied regulatory Science.

The FDA has been working to develop and validate the use of pharmacodynamic (PD) biomarkers for use in determining biosimilarity. Greater reliance on biomarkers for demonstrating biosimilarity is considered an avenue to greater accuracy in comparing biosimilars with reference products and also a means of avoiding costly comparative clinical trials, which use parameters of measurement that are less exact and add to the amount of time and expense needed to assemble evidence for biosimilar approval.

SomaLogic noted that the 28 biosimilars approved so far in the United States for a limited number of reference products has been disappointing and proteomics holds out hope for accelerating this process. “Regulatory approval of a proposed biosimilar requires demonstration that it is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product, a process that can take several years. The research at the center of this agreement aims to advance the use of novel tools and approaches that could streamline biosimilar development,” the company said.

The collaboration will span 5 years and, in addition to identifying circulating PD biomarkers, SomaLogic will seek to develop analytical approaches usable for demonstrating that biosimilar candidates are equivalent to their reference products.

If successful, this proteomic strategy could reduce the need for costly and lengthy comparative clinical studies. This, in turn, should streamline the development of biosimilars and thus accelerate delivery of safe, effective, and affordable biosimilar treatments to patients.

The use of PD biomarkers to establish equivalence has been modest at best, authors of a 2019 clinical article 

. In exploring the rationale for developing and using PD biomarkers in biosimilar development, the authors 

 that up until July 2019, PD similarity data had been employed to demonstrate biosimilarity for just 5 approved biosimilars, and these were dose-dependent PD markers: absolute neutrophil count for filgrastim and pegfilgrastim, CD34+ cells for filgrastim, and reticulocyte count and hemoglobin level for epoetin alfa.

A collaboration with the FDA could lead to new forms of pharmacodymamic measurement that improve speed and efficiency of biosimilar development and approval.

SomaLogic Inks Proteomics Deal With FDA for Biomarker Development

Physician groups and patient advocates are opposing a “co-pay accumulator” initiative by UnitedHealthcare (UHC) they contend would force providers to report funding assistance patients receive so that it cannot be applied toward co-pays and maximum out-of-pocket requirements.

The provider groups contend the policy, which goes into effect on January 1, 2021, would increase levels of patient financial distress, leading to therapy abandonment, and place physicians in an awkward ethical position.

“Our organizations oppose this change as it would endanger patients’ access to care and undermine the doctor-patient relationship,” they said in a 

 to UHC. “We urge UHC to explore other pathways to rein in drug costs without jeopardizing patients’ health.”

Chris Phillips, MD, chair of the Insurance Subcommittee for the American College of Rheumatology (ACR), noted that biologics for the treatment of chronic conditions such as rheumatoid arthritis and lupus are costly and, increasingly, payers are establishing specialty drug tiers that force patients to shoulder part of the costs of these agents.

“If co-pay assistance funds are no longer counted towards deductible and out-of-pocket maximum requirements, patients will have to pay these additional costs. This is particularly concerning for rheumatology patients, because the medications they require are often single-source therapies with no equivalent generic product or therapeutic alternative that is cheaper,” the ACR said in a statement.

According to UHC, the proposed co-pay accumulator plan would require providers to report the use of drug manufacturer coupons for specialty drugs covered under the UHC commercial medical benefit. “These drugs tend to be subject to a high co-pay/cost share and the coupon may pay for part (or all) of the member’s financial responsibility on a claim. However, if the portion paid by the coupon isn’t recorded, the member’s deductible or annual out-of-pocket payments won’t accurately reflect the amount paid by the member,” UHC said in a 

UHC notes that coupon use by patients may affect the “you may owe” amounts and “what’s been paid toward their annual deductible and out-of-pocket maximum.”

In addition to the ACR, signing organizations included the American Academy of Dermatology Association, American College of Gastroenterology, American Gastroenterological Association, Arthritis Foundation, Association for Clinical Oncology, and Council of State Rheumatology Organizations.

What makes the co-pay accumulator policy particularly onerous for patients, the groups said, is that there are limited alternative medicines for the specialty drugs affected by this policy, “meaning patients do not have lower-cost options.”

“As deductibles and out-of-pocket maximums rise, co-pay assistance programs allow patients to access these life-altering medications without regard to their personal financial status. When health plans block co-pay assistance funds from being applied toward patient deductibles, the funds are depleted mid-year and patients face thousands of dollars in unexpected medical bills. This predictably leads to discontinuation of treatment, often with disastrous consequences,” the letter stated.

“These concerns have already led at least 4 states to prohibit accumulators in individual and small group health plans,” the group said.

The American College of Rheumatology (ACR) has joined with other provider groups in opposing a UnitedHealthcare (UHC) plan that could increase patient out-of-pocket costs.

ACR: UHC's New Co-pay Policy Is "Disastrous" for Patients

Being in the position of both selling and competing with biosimilars, Amgen had mixed financial results to report for the business quarter just ended. The company saw significant sales increases for its newly launched biosimilars, but its established originator brands saw continued revenue erosion because of biosimilar rivals.

Amgen’s follow-on Onpro pegfilgrastim injector kit maintained a dominant share of the pegfilgrastim market, although the company’s originator pegfilgrastim product (Neulasta) suffered a sales decline. The same was true for Amgen’s reference etanercept (Enbrel), which faces competition in Europe but not in the United States.

Overall, the company said that it anticipates rising competition from biosimilars for both its originator brands and its biosimilars. Amgen also provided updates on ustekinumab and rituximab biosimilar candidates it has in development.

 about the results that whereas the US market was previously discouraging for biosimilars developers, the company’s own recent experience has proved that it is possible to succeed with biosimilars in this country.

“A lot of people question whether we had an efficient functioning biosimilar market in the United States because I think they were overinterpreting some of the early biosimilar launches,” Murdo Gordon, executive vice president for Global Commercial Operations, said. “I think what you can see now is that we have an efficient market….When there is clear value on the table, health care systems, providers, and payers are able to capitalize on it, and that’s what’s driving, of course, the uptake of our biosimilars.”

Ironically, he said, the company has seen how biosimilars have captured market share from its own reference products and learned from that how to push its biosimilars through sales channels with success.

However, usage patterns have been different from what was anticipated. “Of the [purchasers] that have opened up biosimilar usage, initially we thought they might be using biosimilars for new patients going forward, but we’ve actually seen them use our biosimilars both for new patients and switching patients, who are in the midcourse of treatment, to biosimilars as well.”

In oncology, significant absorption of biosimilars has been observed both within and outside the 340B Drug Pricing Program, which makes discounted drugs available to a broad swath of the US hospital network, Gordon said. The same has not been true for inflammation biosimilars, whether self-administered or infused.

At Amgen, third-quarter biosimilar revenues were $480 million, driven by market share growth for Mvasi (bevacizumab) and Kanjinti (trastuzumab). These were cited as chief contributors to the company’s 12% increase in global revenues, to $6.4 billion, compared with the third quarter of 2019.

Mvasi sales were $231 million vs the third quarter of 2019, up 34%, and the product now has a 44% share of the US market, although competition led to a decline in the selling price for this product and the company said it anticipates biosimilar competition.

Kanjinti sales were $167 million, up 36%, also since the third quarter of 2019, and the US market share for the trastuzumab market was 34%, Amgen said.

“Moving forward, we expect volume growth will be offset by a decline in net selling price due to increased competition,” the company said in a 

On the originator product side, Neulasta Onpro (follow-on) held onto a 55% market share, but Neulasta (originator) sales declined 22% since the third quarter last year, caused by biosimilar competition. The company said Neulasta’s average selling price in the United States declined 19% since this time last year and 6% over the quarter just ended.

Amgen also is the reference producer for filgrastim (Neupogen), which has seen a 19% decline by sales volume since the third quarter last year. A 1-year decline for epoetin alfa (Epogen) sales was noted (31%), caused by sales volume declines and a lower net selling price, Amgen said.

Sales of Enbrel declined 3% compared with the third quarter last year, and the company said conditions caused by coronavirus disease 2019 contributed to that reduction; however, there was no change in the net selling price for the product.

The company’s adalimumab (Amgevita) biosimilar saw a 31% increase in sales compared with the third quarter of 2019.

“Amgevita continues to be the most prescribed adalimumab biosimilar in Europe,” Amgen said.

In its development pipeline, the company’s ustekinumab biosimilar candidate (ABP 654) has advanced to the phase 3 trial level and its rituximab biosimilar (ABP 798) is under review for approval by the FDA, with a scheduled action date of December 19, 2020.

In a recent assessment of the US biosimilars market, Amgen looked at uptake for multiple brands of biosimilars and original products. Details of that report can be found 

In addition, a discussion of the report and its implications is available in an 

 with Amgen’s director of marketing and team leader for global biosimilar launches, Chad Pettit, MBA.

Amgen said its sales results for Mvasi (bevacizumab) and Kanjinti (trastuzumab) give it confidence that the US market for biosimilars is more viable than generally perceived.

Mvasi, Kanjinti Add Heft to Amgen's Third-Quarter Sales

Third-quarter earnings for Pfizer revealed a strong upward pattern for biosimilar penetration, despite the coronavirus disease 2019 (COVID-19).

Biosimilar revenues climbed to $424 million (up 80%), driven mainly by the recent launches of biosimilars for rituximab (Ruxience), bevacizumab (Zirabev), and trastuzumab (Trazimera) products in the United States and elsewhere, Pfizer said in an earnings 

The company also cited ongoing growth in revenues from its epoetin zeta biosimilar (Retacrit), mainly in the United States.

sales declined 21% overall for its reference product 

Enbrel (etanercept) owing to competition in Europe, Japan, and Brazil, where biosimilars of this drug are available.

Biosimilar and generic competition for Pfizer’s products that are losing or have lost patent protection was cited for an anticipated “negative revenue impact of $2.4 billion” for the full year 2020. However, success with Pfizer’s own biosimilar launches contributed to 4% overall operational revenue growth, the company said. Third-quarter revenues totaled $12.1 billion.

“In the first 9 months of the year, our biopharma business grew 7% operationally, despite a COVID-19–related negative impact of approximately 2%, driven by the strong performance of many of our key brands,” said Frank D’Amelio, chief financial officer and executive vice president of Global Supply for Pfizer.

The strong growth of biosimilars Pfizer recently launched in the United States are part of the success story, although reference etanercept (Enbrel) sales have seen major erosion.  

Pfizer's Biosimilar Revenues Soar 80%

a $65 million investment in its parent company that will help to further ongoing development of biosimilar candidates. Alvotech is based in Reykjavik, Iceland, and its parent company is Alvotech Holdings.

The funds were raised among a number of new investors and existing shareholders and are part of a larger, $100 million fundraising goal; Alvotech said it expects to close on the remaining funds shortly.

“Through strategic commercial partnerships with many of the top global and regional pharmaceutical companies, Alvotech is well positioned to accelerate the introduction and adoption of new biosimilars for patients around the world,“ said Robert Wessman, founder and chairman of Alvotech.

Alvotech has a pipeline of biosimilar candidates that include monoclonal antibodies and fusion proteins for treatment of autoimmune diseases, cancer, and inflammatory conditions.

The new investors include Shinhan, Baxter, and Athos (Strüngmann Family Office). Alvogen and Aztiq Pharma continue as ongoing investors. The majority shareholder is Aztiq Pharma, and CVC Capital Partners and Temasek have “significant” stakes in the company, Alvotech said. 

With a sizeable round of fresh capital, Alvotech hopes to bring monoclonal antibodies and fusion proteins through the development pipeline. 