Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

Following a public comment period for its draft guidance, Britain’s Medicines and Healthcare products Regulatory Agency (MHRA) has made it official that comparative clinical efficacy (CCE) trials for biosimilar applications will 

CCE studies use a study population and an efficacy end point. The main goal of these is not to determine clinical benefit but to confirm equivalence; however, laboratory-based structural and functional analyses are generally much more sensitive than clinical studies for detecting differences. For this reason, many respected authorities have argued that CCE studies not only are superfluous but also lack significant value.

The MHRA, which in the wake of Brexit has assumed drug approval responsibility from the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP), stated in the guidance that a stepwise approach to biosimilar development can sufficiently begin with comprehensive physicochemical and biological comparability studies, functional (in vitro) analysis, and a confirmatory pharmacokinetic study. The now-official guidance states that CCE studies will not be required “in most cases” and in vivo animal studies also will not be requested.

The public comment response to this guidance was varied, the MHRA reported, coming from innovator product companies (3), biosimilar developers (8), trade associations (8), patient organizations (2), regulatory consultants (2), and others. Most of the public response was supportive of the guidance and its streamlined or "tailored" approach to biosimilar approvals. The agency said it actually was encouraged by some to “take a lead in global regulation of biosimilars,” apparently because the tailored approach is considered 

Some of the commenters were unclear about the scientific rationale for not requiring CCE and in vivo animal studies, and the MHRA directed them to 

 on streamlined biosimilar approvals, one titled Moving on. The guidance was also augmented to provide clarity on current CHMP guidance and how it differs from MHRA guidelines.

Procaps Group, a Barranquilla, Colombia company, said it aims to 

 for insulin and rituximab in 2021. The company has 5000 employees and markets pharmaceutical and nutrition products and hospital supplies in over 50 countries, with a sales concentration in Latin America.

Representatives from Ohio and New York have introduced the 

. If enacted, this would expand the 5-star rating system under Medicare Advantage program to spur more use of biosimilars under Part B and Part D.

The ratings system grades Medicare plans on how well their benefit structures do according to certain goals; in this case, enrollees’ utilization of or access to biosimilars would be the objective measure, and the criteria would be coverage on plan formulary, preferential tier placement or cost sharing, utilization or the proportion of beneficiaries prescribed biosimilars in place of reference biologics. The legislation was introduced by House members Paul D. Tonko (D-New York) and Bob Gibbs (R-Ohio).

Republic of Korea company Huons Lab is intending to develop a 

 using a cell line and purification technology developed by PanGen Biotech, another Korean company, according to a local press report. Denosumab is a monoclonal antibody used for the treatment of osteoporosis and bone loss in patients with cancer.

Denosumab binds with the protein RANKL and inhibits the growth and function of osteophages, which cause bone deterioration. Amgen reported global Prolia sales of $2.76 billion in 2020, with the United States representing $1.83 billion of those revenues.

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Streamlining of biologics license applications (BLAs) in Britain is now official, and in the United States, legislators propose a ratings system to promote biosimilars.

Biosimilars News Roundup: BLA Tailoring, Medicare 5-Star Ratings

The FDA’s interchangeability designation for biosimilars was intended to improve uptake and acceptance of these agents, but so far it has created misperception and confusion, according to Albert Kim, MBA, vice president of the Commercial Division at Samsung Bioepis, of Incheon, Republic of Korea.

“The intention was to put biosimilars at parity to biological originators,” but in effect, the interchangeability designation has created 2 classes of drugs and may ultimately damage the hard-won acceptance that biosimilars have achieved, Kim said in a recent interview.

Samsung Bioepis is the biopharmaceutical arm of Samsung Group and has 5 biosimilars approved and launched in various global markets: etanercept, infliximab, trastuzumab, bevacizumab, and adalimumab biosimilars. The company also has biosimilar candidates in development for ustekinumab (Stelara), denosumab (Prolia), and eculizumab (Soliris).

There are no interchangeables approved by the FDA so far; however, Viatris and Boehringer Ingelheim are hopeful that their applications for interchangeable status for insulin glargine (Semglee) and adalimumab (Cyltezo) biosimilars, respectively, will be approved this year. Interchangeable status is distinctly a United States appellation. There are no interchangeable designations for biosimilars in the European Union, where the European Commission approves biosimilars and member states and countries make their own decisions about pharmacy counter substitution.

We at Samsung Bioepis believe a class of interchangeability products may cause misunderstanding and misinterpretation of the scientific rigor that goes into the biosimilar approvals process.

Biosimilars are approved by the FDA as equally safe and efficacious with no clinically meaningful differences to the originator products they reference. Years of positive clinical experience with biosimilars have justified these approvals. However, the pending arrival of a class of interchangeables—biosimilars that pharmacists can dispense in place of reference products without physician authorization—threatens to give the impression that these agents are somehow superior to standard biosimilars, Kim said.

“We at Samsung Bioepis believe a class of interchangeability products may cause misunderstanding and misinterpretation of the scientific rigor that goes into the biosimilar approvals process,” he said.

Biosimilar candidates undergo multiple levels of testing to gain regulatory approval, ranging from analytical testing for structure and function to human trials to compare safety and efficacy of the product candidates with originator agents. 

 must undergo additional clinical trials to verify that multiple switches from originator to biosimilar and back again will result in no safety or efficacy variations.

At Samsung Bioepis, the consensus is that the evidence requirements for biosimilars alone are already sufficient to qualify these products for interchangeable status.

“Biosimilars have been around now for more than a decade around the world, and there has been no evidence of altered pharmacokinetics data, or heightened immunogenicity response, or increased safety risk, or improved or diminished efficacy in patients who switch back and forth from reference drugs to biosimilars or between biosimilar drugs,” Kim said.

He noted that the company is not seeking interchangeable status for its biosimilars at this time.

“We hold the position that the interchangeability designation is not necessary to drive the adoption of biosimilars in order to lessen the health care burden in the United States," he said.

Although Samsung Bioepis is looking askance at the interchangeability designation, Viatris expects it to give the company’s insulin glargine and insulin aspart products a marketing edge. Viatris anticipates FDA approval of an insulin glargine (Semglee) as an interchangeable by July 2021. The product was approved last year, but not as a biosimilar, as the product application did not go through the biosimilar regulatory approval pathway at the FDA.

“We see this as an opportunity to sort of relaunch this product,” Rajiv Malik, president of Viatris, said in an 

 accompanying the company’s first quarter 2021 earnings report. “Once we have interchangeability, it’s our opportunity to basically relook at the challenges we have faced so far in picking up market share.”

A second class of biosimilars that are considered "interchangeable" could set biosimilars back in terms of acceptance, according to Albert Kim, MBA. 

Samsung Bioepis Executive Reflects on Interchangeable Designation

With the pandemic tapering off in the United States and its sales force vaccinated, Coherus BioSciences, of Redwood City, California, hopes that returning its sales representatives to the field this spring will counter relatively flat sales of its pegfilgrastim biosimilar (Udenyca). 

Udenyca is the company’s sole product thus far, and its market share has hovered around the 20% mark for about a year, while pricing competition from other products, including Amgen’s originator (Neulasta), and inventory buildups have caused revenues to decline to $83 million in the just-ended quarter from $116 million in the comparable year-ago quarter. 

 for Udenyca this year and the strength of additional product launches in coming years to drive revenues higher.

“Over the next 2 years, we anticipate bringing forward new products to market in the United States, complementing Udenyca in our commercial portfolio,” he said.

Coherus BioScience aims to bring 3 biosimilars to market, along with an anti–programmed death 1 (PD-1) antibody, toripalimab, which would target various solid tumors, the company said in its first quarter 2021 earnings statement (

The company has ranibizumab (CHS-201), adalimumab (CHS-1420), and bevacizumab (CHS-305) biosimilar candidates in late-stage development. These would reference Lucentis, Humira, and Avastin, respectively.

 a net loss of $173 million for the quarter, mainly because of a $145 million payment to Junshi Biosciences for the US and Canada marketing rights to toripalimab and charges associated with the recent cancellation of plans to bring an aflibercept ophthalmology biosimilar candidate (CHS-2020) to market. The product would have referenced Eylea.

Although the pegfilgrastim market grew 1% in the first quarter of 2021, revenues for Udenyca did not, and in an investor conference call, Lanfear attributed the declining sales and flat market share for Udenyca partly to pricing pressure from competing products, particularly the originator product Neulasta (Amgen), “which now has the lowest average sales price of any type of pegfilgrastim.”

Neulasta has a 67% share of the pegfilgrastim market, and Amgen has achieved a 55% market share for the Onpro wearable pegfilgrastim injector kit, Coherus officials stated. Paul Reider, executive vice president of commercial operations and market access for Coherus, predicted that Onpro dominance would now begin to deteriorate with the slackening pandemic and patients being able to visit their doctors more safely.

“Now that COVID-19 is receding, the medical imperative to use Onpro is greatly reduced,” he said.

Another reason the company is counting on increased Udenyca sales is that its sales force can get into the field again and make in-person visits.

“The majority of our field team has now been vaccinated and has resumed in-person sales calls,” Reider said.

The company hopes to have biosimilars referencing Lucentis, Humira, and Avastin on the market by 2023. A midyear 2021 biologics license application (BLA) filing is anticipated for the company’s ranibizumab candidate. The FDA has accepted the company’s BLA for the adalimumab biosimilar candidate, and FDA action is anticipated in December 2021. Lastly, a pharmacokinetics study is underway for Coherus’ bevacizumab candidate, although the pandemic has slowed patient enrollment and the BLA filing for this candidate has been pushed forward to the first part of 2022, Lanfear said.

Coherus said the FDA has granted breakthrough status for its toripalimab product, for which a BLA has been submitted with an FDA action anticipated in the first half of 2022.

For further reading about Coherus’ struggle to overcome the Onpro advantage, click 

For an earlier story about Coherus and how the pandemic has influenced its operations, click 

With COVID-19 on the retreat, Coherus BioSciences sees the advantage wearing off for Amgen's pegfilgrastim injector kit. 

Coherus Aims to Chip Away at Onpro Dominance

Fighting back against a suit that alleges theft of trade secrets, Alvotech, of Reykjavik, Iceland, has filed suit against AbbVie alleging that key patents for its blockbuster adalimumab drug (Humira) should be invalidated partly on grounds that AbbVie did not invent the processes that were patented. The Center for Biosimilars® has sought a response to the suit from AbbVie.

Alvotech is seeking to be the first to bring a high concentration (100 mg/mL) biosimilar formulation of adalimumab to market in the United States, but contends that AbbVie has thrown up a blockade with the assertion that 62 patents related to adalimumab would be infringed if this product does come to market. 

The high concentration form of adalimumab sold by AbbVie was introduced to market in 2018 and has rapidly gained market share over lower-concentration forms of this agent. The citrate-free, the high-concentration formulation is said to cause patients less pain upon injection and therefore is preferable. There are 6 lower-concentration adalimumab biosimilars approved for sale in the United States, although none of them will come to market until 2023 because each of their developers has settled with AbbVie out of court rather than battle through AbbVie’s “patent thicket” of at least 136 patents on the product.

“This case aims to bring to a just end [the] defendant’s ongoing monopoly on the life-changing drug adalimumab,” Alvotech stated in its filing with the US District Court of the Eastern District of Virginia, Alexandria Division. The company estimated that AbbVie has reaped a combined windfall of well over $100 billion so far from adalimumab, with another $40 billion anticipated through 2022, and said it is high time that competitors and patients could share in the benefits of a competitive market for this product. 

“Any competitor that desires to bring a biosimilar version of Humira to market is threatened with crushing, ruinous litigation on these patents. This abuse of the patent acquisition and litigation process has resulted in AbbVie alone selling adalimumab in the United States, despite the [relevant] patents on this molecule expiring in 2016,” Alvotech alleged.

Adalimumab is a monoclonal antibody used to treat various autoimmune diseases including rheumatoid arthritis and Crohn disease. It was first sold in a 50 mg/mL formulation in 2003. Biosimilar versions of the 50 mg/mL formulation are available in Europe, the suit notes. AVT02, the proposed Alvotech high concentration biosimilar, if approved by the FDA, would be “priced lower than Humira,” the suit states.

Although 62 patents have been asserted by AbbVie in defending its franchise against AVT02, Alvotech contends that the key patents on the product not only have expired but rightly were not AbbVie’s to begin with—they were the result of development work by German company BASF AG, which sold the rights to the drug in 2001 to AbbVie’s predecessor, Abbott Laboratories, as well as other companies, such as Amgen.

“Despite having played no role in inventing adalimumab and having enjoyed a lengthy and profitable monopoly supported by BASF AG’s original patents, AbbVie has nonetheless sought and obtained over 100 additional patents of dubious validity related to adalimumab that have lawlessly extended AbbVie’s monopoly,” Alvotech stated.

Alvotech has whittled down the portfolio of 62 patents AbbVie intends to litigate to just 4 patents that the Icelandic company feels are appropriate to litigate, because those 4 stand in the way of actual marketing of AVT02. This smaller number of patents relate to the self-buffering formulation for the 100 mg/mL formulation of adalimumab and treatment of ankylosing spondylitis and Crohn disease. Alvotech contends these patents should be invalidated.

AbbVie has filed 2 suits against Alvotech this year. One alleges that in 2018 a former AbbVie employee took trade secrets related to the manufacturing of high concentration adalimumab when he went to work for Alvotech and shared that information with Alvotech. Alvotech responded that it began developing AVT02 long before, in 2013. The second suit alleges patent infringement related to AVT02.

Alvotech has asked the court to declare that the patents asserted by AbbVie in this case are invalid and unenforceable. The company seeks a jury trial.

AbbVie has long faced attacks over its lucrative adalimumab franchise, and company CEO Richard Gonzalez has 

 before Congress in defense of the company’s patent thicket defense strategy. Gonzalez is scheduled to testify again before the Committee on Oversight and Reform on 

The committee claims to have obtained internal documents that prove AbbVie has deliberately suppressed competition for Humira and other drugs.

Alvotech is not the only biosimilar developer that is working to bring a high concentration formulation of adalimumab to market. Celltrion Healthcare 

 in February 2021 to bring the first high-concentration, citrate-free adalimumab biosimilar (CT-P17, Yuflyma) to the European Union markets. According to IQVIA, AbbVie’s high-concentration formulation accounts for 60% of the total adalimumab market.

After being sued for allegedly stealing adalimumab process information, Alvotech fires back. 

Alvotech Files Suit to Invalidate Humira Patents

A tailored approach to biosimilar approvals is conceived as the next big leap for regulatory advancement in getting these drugs to market efficiently, but in both the United States and Europe there are factors slowing this advance. The tailored approach would do away with automatic requirements for the comparative clinical efficacy study, which has been described as a “blunt instrument” compared with analytical investigative studies that are considered more sensitive tools.

The COVID-19 pandemic has been a big impediment to progress of the tailored approach in the European Union, where regulatory attention has been distracted by more pressing priorities, said a panel of experts assembled by Medicines for Europe. In the United States, a tailored approach has been considered, but, separately, biosimilar acceptance has been slow and the US health care system does not seem to be ready for reduced reliance on comparative clinical trials, whether scientifically justified or not, said Sarah Yim, MD, director of the Office of Therapeutic Biologics and Biosimilars at the FDA.

“I do think that there’s some additional knowledge that needs to be accrued before everyone’s going to feel comfortable with tailoring things, but I think we’re getting close with monoclonal antibodies,” she said.

In 2017 the European Medicines Agency (EMA) instituted a 

 for biosimilars that would allow biosimilar developers to meet with agency officials prior to submitting an application and decide, based on the product development plan and available evidence, what types of information would need to be gathered for a successfully comprehensive data package. This would allow a case-by-case adjustment in data requirements rather than a one-size-fits-all approach.

In the stepwise approach to biosimilar development, comparative quality studies involving assessments of physical and chemical properties are combined with functional assessments of biological and pharmacological activity. Next come comparative nonclinical studies for pharmacodynamics and toxicology, and finally, comparative clinical studies using human populations that assess efficacy, safety, and immunogenicity along with pharmacokinetic and pharmacodynamic properties, in comparison with the originator products the biosimilar candidate is based on.

COVID-19 has diverted a lot of regulatory attention and resources, so tweaking the biosimilars approvals process is not a priority, said Ana Hidalgo-Simon, MD, PhD, head of Advanced Therapies for the EMA. “We’re still in what we call the BCP—the business continuity plan. We do not have the right conditions to start setting dates, but the conversation is there, and the line of progression [toward tailoring] is fairly clear.” 

Although biosimilars in Europe got a foothold 5 years earlier than in the United States, some stakeholder education would be required to clear a path in Europe toward a tailored approach, said panelist Martin Schiestl, global head of Regulatory Affairs and Policy at Sandoz. There’s still a tendency to want to follow the established routine rather than modify the biosimilar acceptance policy so that it conforms to what makes the most sense. “Moving away from this tick-the-box mentality to a real scientific evaluation and discussion, I think, is important,” he said.

In the United Kingdom, where the Medicines and Healthcare products Regulatory Agency (MHRA) now reviews drugs for approval independently following Brexit, a deemphasis on the comparative clinical efficacy trial for approvals will not necessarily bring an end to demands for relaxed requirements, said panelist Anne Cook, PhD, an expert quality assessor for the MHRA.

“Quality is the foundation of the whole biosimilar package. We need a good package of data on which to make that decision. Just because there are shortcuts in other areas of biosimilar development, where you’re not leading animal studies, for instance, you do need your PK.” UK regulators have had to be firm with pharmaceutical companies in order to get the data they need for reliable decisions, she said.

In the FDA, there still is some respect for the type of confirmation that a clinical efficacy study can provide, Yim said. “There’s a wide variety of biologics, and there are some biologics for which we don’t know everything about their mechanism for the various conditions that they’re approved to treat,” she said. When a biosimilar candidate doesn’t conform to established ranges for equivalence to reference products, comparative clinical studies can help to answer the question whether that incongruity is clinically meaningful or not, she said. 

However, in 2015 guidance for biosimilars development, the FDA did suggest the possibility of tailoring, and there may be more about this in pending guidance updates, Yim said. “I think that we will put a greater emphasis on tailoring where it’s possible. We have to bring our clinical regulators on board with that, and they’re not all at the same place."

If comparative efficacy testing were dropped in favor of a tailored approach in the United States, there would be some catchup required to get stakeholders on the side of biosimilars approved this way, said Yim.

The same applies in the European Union, said Hidalgo-Simon. “We are not there in Europe. We would like to be there, and we are optimistic. When you look at the biosimilar uptake figures, you wonder why they are not higher than they are, considering how good these drugs are and how many marvelous life changes they can achieve. I don’t think that tailored development is going to be a huge jump. I think it’s another step in the same road, and the road goes through gaining the confidence of all the users now. We’re ready to do it, but we will still be talking about it in 2 years’ time,” she predicted.

In the United Kingdom, biosimilar acceptance has been pretty robust, Cook said. That was partly attributable to efforts to convene stakeholders and boost awareness of the underlying scientific rationale for these agents. “We had a lot of workshops, meetings, information, and studies. If you looked at the uptake of infliximab, an early biosimilar, that was fairly slow, because people weren’t sure what they were dealing with. And then you move to the uptake of rituximab and then some of the newer biosimilars as they’ve come on, and the uptake has been faster and faster. A lot of this is around confidence in using the products, but you have to start somewhere, and I think this interaction with all the different stakeholders was very important,” she said.

“We were very lucky that we had quite a few people who were very keen to try things but also to carefully monitor, and I think that’s the other point. There’s very careful pharmacovigilance to make sure that what you’re saying is what you’re seeing, and so I think that really helped with the uptake in the United Kingdom.”

For more coverage of the Medicines for Europe panel discussion, click 

During a talk at the Medicines for Europe Biosimilar Medicines Conference, US and EU regulators discuss the potential for tailored approach to bring biosimilars to market sooner with less expense and wasted effort. 

US, EU Regulators Discuss Tailoring Biosimilar Approvals

This year is the 15th anniversary of biosimilar availability in the European Union, and in an overview sponsored by the generics and biosimilar trade association Medicines for Europe, experts from regulatory and business venues discussed some of the major achievements and hurdles yet to be crossed.

One of the biggest advances in biosimilars has been the improvement in the consistency of manufacturing, said Elena Wolff-Holz, medical assessor for the Paul Erlich Institute in Germany and chair of the European Medicines Association Biosimilar Medicinal Products Working Party. Whether biologics are sourced in the United States or Europe, they are dependably similar in quality, and that applies also when you compare products over a span of time, she said. “Humira [adalimumab] manufactured 5 years ago is the same as Humira today.”

 “Even for the very simple biosimilars, there was a very huge resistance initially from prescribers to extrapolate.”

The same holds true for Humira and biosimilar versions of adalimumab. “We can exchange one medicine for another, and it will have the same clinical effect in a given clinical setting and any patient,” she said.

Methods of assessing whether biosimilar candidates are equivalent to reference drugs have improved a great deal from 10 or 15 years ago. For example, the growing confidence in analytical tests for functional and structural characterization of biosimilars has enabled regulators to lower requirements for comparative clinical efficacy trials, which are not as sensitive.

“We continue to accrue so much experience and knowledge and across certain classes of biologics, like monoclonal antibodies, and that’s been really foundational in enabling confidence and reliance on analytical results for demonstrating products are biosimilar or interchangeable with their reference products,” said Sarah Yim, director of the Office of Therapeutic Biologics and Biosimilars at the FDA. “I think the experience is going to be exponential. A lot more people are going to start being comfortable with biosimilars,” she said.

According to Hye-Na Kang, a scientist on the Norms and Standards for Biological Products team in Health Products Policy and Standards at World Health Organization (WHO), countries these days are much more consistent with one another in how they define biosimilars. “This trend is welcome because it avoids confusion with other products that are not biosimilars,” she said. “Not all products called ‘biosimilar’ are at the same level of quality.”

Also positive is that there are many more biosimilars by low-cost producers on the market in countries that used to be dominated by large originator companies. However, problems remain in WHO countries that Kang monitors. Some of these have insufficient supplies of even originator biologics and lack resources to conduct evaluations of biosimilar candidates.

Early biosimilars (epoetins, bone marrow growth factors, somatotrophins) were simpler molecules compared with monoclonal antibodies (manmade proteins that behave like antibodies), but it took a while before tools emerged for adequate analysis of these second-generation agents, said Anne Cook, an expert quality assessor for the UK Medicines and Healthcare products Regulatory Agency.

“It was the advances in technological areas that made it possible to analyze some of these bigger molecules, because before that it hadn’t been possible. This has really led to an explosion in the number of monoclonal antibodies and fusion proteins that have been approved,” she said.

These new technologies allow analysis in much greater detail than before, although for that detail to be of practical value “the next step is to work out what is important and whether that’s going to have a clinical impact,” Cook said. “It’s understanding how these products work within patients and how best to examine the differences, because you’ll always see some differences. You’ll see batch-to-batch variation.”

“There was an awful lot of discussion in the early days as to what was acceptable and what we needed to do in order to approve these products, and there was some unease about whether this was going to be OK, but I think the last 10 years have proved that we have the analytical tools,” Cook said.

“There was an awful lot of discussion in the early days as to what was acceptable and what we needed to do in order to approve these products, and there was some unease about whether this was going to be OK."

Ana Hidalgo-Simon, head of Advanced therapies for the European Medicines Agency, said biosimilars have proved themselves in Europe over 15 years. “For me, the weight of history has shown how good they are; how, if we are careful and approve them with the highest standards that we have, we can be very comfortable with them.” The challenge going forward is to transmit this confidence to decision makers and patients. “Biosimilars are very complex, and a lot of doctors are comfortable with part of it, but they will always want to learn more.”

When biosimilars were introduced, stakeholders were reluctant to embrace them, recalled Martin Schiestl, global head of Regulatory Affairs and Policy at Sandoz. “There was a lot of controversy and anxiety around this class of drugs. I remember in 2009 when there were leading experts in academia who said you will never see biosimilar antibodies, so this is reflecting how fast things can move. The idea of physicians inferring that biosimilars approved for one indication of a reference product could be used for other indications of that product—known as extrapolation—was anathema, he said. “Even for the very simple biosimilars, there was a very huge resistance initially from prescribers to extrapolate.”

Another major advance was the realization that comparative clinical efficacy trials (using study populations and efficacy end points) were neither essential nor even very useful for biosimilar equivalency assessment.

“This was, I think, a huge finding, and this opens up the door to more efficiency in the future. Specifically, for each data element in the biosimilar assessment, we should ask, ‘What is the purpose? What is the scientific question?’” Schiestl said.

Advances in analytical testing have improved confidence in biosimilars, according to a Medicines for Europe panel.

Regulators Look Back on 15 Years of Biosimilars in Europe

Rebates that manufacturers use to incentivize formulary placement of their products by payers and pharmacy benefit managers (PBMs) have long been seen as an obstruction to patient access to biosimilars. An innovator drug company can manipulate the market for its products through rebates and thereby undercut the market absorption of biosimilars.

In remarks issued with 2021 first quarter earnings statement, Pfizer Chairman and CEO Albert Bourla said the company continues to work with legislators to ensure that manufacturer rebates are passed along to patients in the form of savings, rather than going into the pockets of payers and PBMs. 

“At the state level, we have focused our efforts on meaningful solutions to directly address patient affordability challenges. This includes legislation to require that 100% of negotiated rebates be passed through to consumers at the pharmacy counter. We have also worked with state policymakers to advance legislation in several states ensuring that patient assistance provided by manufacturers will count toward the patient’s deductible and out-of-pocket maximums,” Bourla said.

On the national level, Pfizer is working with the Biden administration and lawmakers to improve patient access also, Bourla said. “Specifically, there are 3 key areas where we would like to see Congress and the administration focus: rebate reform, capping beneficiary cost-sharing in Medicare Part D, and incentivizing the uptake of biosimilars.”

first quarter 2021 revenues of $14.6 billion, up 45% from the comparable year-ago quarter, and stated that increased biosimilar revenues partly helped fuel this growth, although the bulk of the revenue increase stemmed from $3.5 billion in sales of Pfizer’s COVID-19 vaccine, BNT162b2. Net income was $4.9 billion, also a 45% improvement. Without the vaccine revenue, Pfizer’s sales increased 8%.

The company said biosimilar revenues climbed 79% to $530 million, led by recent launches of rituximab (Ruxience), bevacizumab (Zirabev), and trastuzumab (Trazimera) biosimilars, as well as growth from the more established epoetin biosimilar Retacrit.

During the first quarter, Pfizer announced it was 

from biosimilars production within the China market. In 2016 it began an ambitious $350 project to build a biosimilars manufacturing center in Huangzhou. The factory was built, but Pfizer said in March it had made a difficult decision to discontinue production activity in China and sell the installation to WuXi Biologics, a China-based company. Although Chinese government reforms have improved the market for biologics producers, it remains challenging for foreign producers.

Organon Officials Introduce Their Biosimilars Strategy

Organon, the planned Merck biosimilars and women’s health products spinoff slated to go public in June 2021, was featured in a 

. Officials of the new Organon enterprise said they are counting on sales growth from the following biosimilars: Renflexis (infliximab) in the United States, Aybintio (bevacizumab) in the European Union, and Hadlima (adalimumab) in Canada and Australia. Hadlima is scheduled to launch in the United States in 2023. 

Organon will also market the etanercept biosimilar Brenzys, which the company says is the market share leader in Canada. 

Organon will sell these biosimilars in partnership with Samsung Bioepis of Republic of Korea. Merck is also handing its trastuzumab (Ontruzant) biosimilar franchise over to Organon.  

Three of these 5 products represented over $0.3 billion in full-year 2020 revenue for Merck: Renglexis, $135 million; Brenzys, $74 million; and Ontruzant, $115 million.

Organon said it aims to launch Aybintio in the European Union. The US launch of Hadlima is scheduled for 2023. Additionally, Organon will partner with more biosimilar manufacturers and aims to launch 1 to 2 biosimilars each year, particularly by strengthening its existing 8-year partnership with Samsung Bioepis.

Ontruzant has demonstrated strong sales in select European markets. Hadlima represents the largest biosimilar growth opportunity for Organon, as it will be among the first 2 adalimumab biosimilars to launch in the United States (June 2023). Joseph Azzinaro, commercial lead for biosimilars at Organon, predicted that PBMs will rapidly convert patients to adalimumab biosimilars. 

For starters, Organon will focus on capturing a larger share of immunology and oncology markets for biosimilars, but it is also interested in the ophthalmology biosimilar market.  

The company is based in Jersey City, New Jersey, but Organon revenues are expected to derive mainly (80%) from sources outside the United States. No single product is expected to represent more than 11% of its total revenue. Its portfolio consists of more than 60 medicines and products.

"Organon, as a standalone company, will be better positioned to realize its potential and to have a meaningful impact, particularly in women’s health,” said Rob Davis, president, Merck.

Pfizer doubles down on its pledge to fight rebates, and Organon executives discuss the growth potential of this planned Merck spinoff. 

Pfizer and Organon Provide a Glimpse of Biosimilars Strategy

Permitting automatic substitution of biosimilars for originator brand biologics at the pharmacy counter is often talked about as a potential money saver. Some integrated health care networks already direct pharmacists to intervene on prescriptions to ensure that biosimilars are substituted for higher-cost originator agents. But although the FDA has approved 29 biosimilars, none have interchangeable designations.

That appears likely to change soon. Boehringer Ingelheim recently expressed confidence that results from its phase 3 VOLTAIRE-3 study of the adalimumab biosimilar Cyltezo (BI695501) meet the FDA’s criteria for an interchangeable biologic designation. Cyltezo was approved as a biosimilar in 2017, but owing to the FDA’s unique approval system for biologics, it must pass through a different set of hoops to qualify for interchangeable status.

Similarly, Viatris, a company recently formed by the merger of Mylan with Pfizer’s Upjohn division, is seeking FDA approval for biosimilar and interchangeable designations for the insulin glargine product Semglee. This agent launched in August 2020 in the United States, just not as a biosimilar. It is considered a biosimilar in the European Union, however, where it has been available since March 2018.

So, what does it take for a biosimilar to be approved as interchangeable in the United States? To have its adalimumab biosimilar considered interchangeable to just the 40-mg/0.8-mL formulation of the reference product (Humira), Boehringer Ingelheim had to do a separate study that involved patients switching multiple times from reference drug to biosimilar and back again (

“An interchangeable biosimilar is a separate additional regulatory designation on top of the high FDA standards for a biosimilar,” Thomas Seck, senior vice president of Medicine and Regulatory Affairs at Boehringer Ingelheim, told The Center for Biosimilars

“In addition to meeting the requirements of biosimilarity, an interchangeable biosimilar must first have a highly similar profile and the same clinical result as the reference product in any given patient. Then it must additionally demonstrate that the risk in terms of safety or diminished efficacy of switching with the reference product is not greater than staying on the reference product,” he said.

Interchangeability studies that switch patients between reference product and biosimilar multiple times can help elucidate whether outcomes will be different for a given biosimilar compared with the reference product. These studies can build up physician confidence that patients who are switched to the biosimilar will not be subjected to different pharmacokinetics, immunogenicity, safety, or efficacy than they would if they remained on the reference product.

Interchangeability designations from the FDA would not override state laws on biosimilar substitution. In fact, many states have passed legislation protecting a physician’s right to retain authority over biosimilar use. Some biosimilar proponents might argue that there should be no opposition to automatic substitution following an FDA decision that a biosimilar is as safe and efficacious as a reference product with no clinically meaningful differences, coupled with a switching study to back up interchangeability.

However, state legislatures often see things differently.

“Regulating biologics raises new issues for both state and federal policymakers. Because of their complexity, biologic drugs are much more difficult to replicate than the chemically produced generics for other drugs. The cell lines used and modifications in the manufacturing process affect biologic medicines. As a result, truly identical [biosimilar] versions are currently virtually impossible to produce,” the National Conference of State Legislatures 

. “Once patents expire for the existing brand name biologic drugs, biosimilar medicines can be produced, which is an occurrence that raises regulatory issues in the states.”

of this hesitancy to unleash biosimilars at the state level can be found in Connecticut, where legislators recently attempted to amend the law to require private payers and Medicaid to cover originator biologics, not biosimilars, unless providers specify in writing or by electronic means that biosimilars are to be used.

In the European Union, the European Medicines Agency leaves it up to member countries whether to allow automatic substitution of biosimilars. In France, 

 of biosimilars for reference products has long been encouraged and permitted in cases where the physician has not expressly directed otherwise. 

For Boehringer Ingelheim, the standards for biosimilar regulatory approval and, on top of that, interchangeability, are a point of contention. The pharmaceutical company hopes to get the FDA to agree that clinically inactive ingredients included in a biologic formulation should not be a factor in whether an approved biosimilar can be used in different concentrations.

“Under the FDA’s interpretation of ‘strength,’ any currently approved [lower-concentration] adalimumab biosimilar (including Cyltezo) cannot be considered biosimilar or interchangeable to the same dose of Humira’s high-concentration formulation,” according to Seck. “This  interpretation affects all the currently approved biosimilar versions of Humira and has the potential for wider implications to other biologics and biosimilar and/or interchangeable competition.”

 with the FDA appealing for a change in the interpretation of strength of formulation. A wording change in the company’s favor would be a significant win for the biosimilars community because AbbVie, the maker of the originator adalimumab product (Humira), has captured over 60% of the market for adalimumab in the European Union with its high-concentration, 100-mg/mL dosage form, according to IQVIA. In the United States, the respective percentage for high concentration adalimumab is 70%. And when it comes to displacement of just the 40 mg concentration formulation of adalimumab, the high concentration takeover 

Yuflyma Becomes First High Concentration Challenger

Celltrion Healthcare, in February 2021, received 

 to market a similar concentration biosimilar version (Yuflyma), but that was the first competitor product to gain access to the high-concentration market. Humira was first approved in a 40-mg/0.8-mL strength in 2002, and the FDA approved additional strengths and concentrations over the years. The higher-concentration formulation was first marketed in July 2018. 

“We continue to work closely with the FDA, industry peers, payers, health care providers, and patient advocates, engaging in a transparent and public discussion of the issues we have raised, and Boehringer Ingelheim believes that correction of the interpretation of ‘strength’ by the FDA may increase access to more affordable biosimilar and interchangeable biological products approved via the 351(k) pathway,” Seck told The Center for Biosimilars

The anatomy of an interchangeability switching study. 

The Difference Between an Interchangeable Biosimilar and One That Isn't

Sandoz said it will initiate enrollment of patients in a confirmatory phase 3 efficacy and safety study (

) for an aflibercept biosimilar candidate. Aflibercept is used for improving visual acuity in patients with neovascular age-related (wet) macular degeneration (nAMD), diabetic macular oedema, macular oedema secondary to retinal vein occlusion, and other neovascular retinal diseases.

There are no aflibercept biosimilars on the US or EU markets. Multiple competitors are working to be among the first to tap into the market dominated by Bayer (Leverkusen, Germany) and Regeneron Pharmaceuticals (Tarrytown, New York) for the originator product (Eylea), which had US net product sales of $4.95 billion in 2020 vs $4.64 billion the previous year.

Those include Alteogen, a Republic of Korea company, that in March 2021 said it had successfully completed a 

 of an aflibercept biosimilar. In August 2020, Formycon and Bioeq, both Germany-based, initiated a 

Florian Bieber, global head of Biopharmaceuticals Development at Sandoz, noted that “nAMD accounts for 10% of all age-related macular degeneration cases, but is responsible for 90% of AMD-related blindness.” Aflibercept inhibits ocular vascular endothelial growth factor–A, which promotes the growth of abnormal blood vessels in the choroid or pigmented layer of the eyeball between the outer layer of the eyeball (sclera) and the retina.

MYLIGHT investigators hope to confirm that the biosimilar candidate has equivalent efficacy and comparable safety to Eylea.

The study is a randomized, double-blind, parallel 2-arm trial with a projected enrollment of 460 patients in 20 countries. The biosimilar candidate will be tested in patients with wet age-related macular degeneration because that is one of the most common disease types for patients who use aflibercept and because the findings can be extrapolated to other indications.

Patients with nAMD will be randomized to receive either the biosimilar candidate or the reference product for 48 weeks. The mean change in best corrected visual acuity score from baseline to week 8 will serve as the primary end point.

Sandoz is heavily invested in biosimilars. The company has 3 supportive care oncology biosimilars and 1 blood cancer biosimilar that doubles as an immunology drug. The company has 3 other immunology biosimilars and an endocrinology drug, for a total of 8 biosimilars on the market. Sandoz also has a denosumab biosimilar in phase 3 development, along with various other development-stage biosimilar candidates.

There are multiple contenders now in the race to bring the first aflibercept (Eylea) biosimilar to market in the United States and European Union.

Sandoz to Start Phase 3 Trial of Aflibercept Biosimilar

Are pharmaceutical companies truly investing their profits in innovative products that extend the capabilities of medicine, or are they spending that money on fending off the competition so that their originator brand products enjoy longer periods of exclusivity?

Representative Carolyn B. Maloney (D-NY), chairwoman of the House Committee on Oversight and Reform, takes the latter position. In recent 

 before the House Subcommittee on Antitrust, Commercial, and Administrative Law, Maloney contended that a review of 1.3 million pages of internal pharmaceutical documents—part of an investigation initiated by the late Representative Elijah Cummings (D-MD) into prescription drug prices—has convinced her that an undercurrent of anticompetitive behavior is denying Americans fair access to vital medicines.

“We rely on the pharmaceutical industry to develop critical new therapies, cures, and vaccines. In exchange, our system grants these companies the exclusive right to sell their products for a limited number of years without facing competition from lower-priced generic and biosimilar drugs,” she said in 

 on April 29, 2021. "Unfortunately, brand name drug companies have abused this system by engaging in blatantly anticompetitive strategies to extend their monopoly pricing for far longer than our system intended.:"

As a result, health care consumers in the United States are paying far higher prices for medications than their counterparts in other parts of the world, she noted.

“Our investigation found that pharmaceutical companies dedicate significant portions of their research budgets to coming up with new ways to suppress generic and biosimilar competition, rather than focusing on developing new therapies,” Maloney said.

One company that is repeatedly held up as a poster child for blocking competitor access to the market is AbbVie, which has successfully stalled biosimilar competition in the US adalimumab market until 2023, allowing the company to increase the price of its originator adalimumab product, Humira. The anti-inflammatory drug was first approved in the United States in 2002. 

AbbVie posted total first quarter 2021 Humira revenues of $4.87 billion, up 3.5% since the comparable first quarter of 2020, largely on the strength of US sales and price increases. In the United States, AbbVie raised the price of adalimumab 7.4% for 2021, according to health care research firm 

 in the United States were $3.9 billion, up 6.9% vs international Humira revenues of $960 million, which were down 8.3% due to biosimilar competition in those markets. Adalimumab biosimilars have been available in Europe since 2017.

AbbVie’s relatively large “thicket” of patents protecting Humira has long been a source of contention, and AbbVie CEO Richard Gonzalez in 

 before the Senate Committee on Finance argued that although the patents are an obstacle to competition, the company has struck “a reasonable balance” with competitor companies by allowing them to license the use of inventions and technologies that concern the manufacture of adalimumab prior to the expiration of some patent protections.

At the time of that testimony, there were 136 patents for Humira, and Gonzalez explained that the company had generously allowed competitors to bring biosimilar versions of adalimumab to market “literally 10 years before the last patent expires in that portfolio.” The first adalimumab biosimilars will enter the US market in 2023, according to patent settlements between AbbVie and the biosimilar developers. Gonzalez is expected to appear before the House Oversight Committee on May 18, 2021, for more testimony about the Humira franchise.

In her committee report, Maloney said the internal reports her investigative team examined showed that Amgen and Novartis delayed generic drug market entry by negotiating with potential competitors rather than seeing patent disputes through to a court ruling.

“Amgen internally estimated that it collected $202 million in extra sales of the kidney drug  Sensipar [cinacalcet] by delaying generic entry by just 10 weeks. Experts estimate that Novartis’ delay of generic competition for its cancer drug Gleevec [imatinib mesylate] cost the US market $700 million,” she said.

Maloney said a “product hopping” strategy by Teva Pharmaceuticals cost the US health care system $4.3 billion in “excess expenditures” when the company switched patients over to a higher dosage formulation (40 mg) of Copaxone (glatiramer acetate injection) just as the lower dosage (20 mg) formulation neared the end of exclusivity protection.

Among various maneuvers to support this product-hopping, “Teva even considered discontinuing its patient financial assistance program for 20-mg Copaxone to pressure patients to switch to the 40-mg version of the drug,” she alleged.

In the same hearing, Senator Amy Klobuchar (D-MN) noted that health care spending accounted for 17.7% of the US gross domestic product in 2019 and is projected to reach 19.7% by 2028 if curbs on drug price increases are not introduced.

“Nearly 20% of older adults report not taking their medicines as prescribed because of the cost,” she said.

Klobuchar said there is a need for Medicare Part D to be granted the ability to negotiate drug prices and that competition be promoted through importation of lower-priced drugs.

“The availability of generic drugs and biosimilars is critical to reducing drug costs. But branded drug companies have powerful financial incentives to delay the introduction of these more affordable alternatives to their own high-priced products,” she said.

Representative Carolyn B. Maloney, D-New York, questions the use of pharmaceutical profits to defend against biosimilar competition. 