Tony Hagen is senior managing editor for The Center for Biosimilars

Providers and health care institutions are going to need a lot more real-world data on how patients respond to various biosimilars and switches between biosimilars and reference products, according to a varied panel of private practice, academic hospital, and group purchasing organization experts in a discussion at the Community Oncology Alliance virtual Community Oncology Conference 2021.

“If we can solve the issue of real-world evidence and data and supply that, I think that will support the use of biosimilars moving forward,” said Sandeep Parsad, PharmD, MBA, BCOP, assistant director of pharmacy at University of Chicago Medicine (UCM).

Providers are going to need convincing, particularly as the choices among biosimilars become more numerous, the panel said. In the oncology space, biosimilars as therapeutic drugs are fairly new, although in supportive care these have been used much longer. And it is often stated that oncologists, especially, become more circumspect in the disease setting about the choice of agents, preferring to go with a well-established originator brand that both they and the patient may have come to trust. To encourage more switching to biosimilars, more evidence is going to be the tool for that, said E. Randolph “Randy” Broun, MD, a blood and marrow transplant specialist with Oncology Hematology Care (OHC), of Cincinnati, Ohio.

“I think data are really lacking in this area. Physicians are going to want data to understand that these truly are biosimilars that are interchangeable and they’re not shortchanging their patients by doing this, even under pressure from payers,” he said.

There’s an important distinction to be made, he said. At his practice, at least, biosimilars are a concept that physicians are very familiar with and they now use these agents in many settings and are comfortable with them. But their confidence in biosimilars can be strained when multiple versions of a single reference product start to appear and they are tasked with making the right choices for their patients.

“Once we have 8 different Herceptins (trastuzumab), are they all the same? Is it reasonable to simply pull a different one off the shelf for a patient who got something different 3 months ago? That will be a barrier, I believe. And you’re only going to solve that with a lot of data that are very convincing that these things are perfectly interchangeable,” Broun said.

Cardinal Health has recognized the value in using biosimilars, as their discounts, particularly when many are available on the market, can be significant, and became proactive with its participating physician practices to cultivate an understanding of these agents that would translate into greater use, according to Sonia T. Oskouei, PharmD, BCMAS, DPLA, vice president of Biosimilars for Cardinal Health.

Parsad said the same goes for her institution. “We took a very purposeful approach to meeting with physicians and nursing staff to talk about the regulatory requirements for approval and demonstrate how biosimilars are similar to reference products, how they have a high standard for safety and quality,” she said.

When it approves a biosimilar, the FDA certifies that it is as safe and effective as the original biologic, and that it has been rigorously evaluated, but the FDA doesn’t give it automatic interchangeable status, meaning pharmacists would be free to substitute the biosimilar with a reference product without informing the physician. Additional requirements are needed for that. It has been hard to explain to physicians that that shouldn’t stop them from prescribing biosimilars, Parsad said. “We felt that was a bit of a bump for us. This is what I’ve heard as well with other colleagues around the country, that physicians do prefer that they are informed when there is a decision whether we should switch or not from the reference product to the biosimilar. But I feel like it went fairly smoothly once there was this very open dialogue.”

It was more of a challenge to develop policies about switching from reference products to biosimilars and in what instances this should occur, she said. A lot of issues arose, such as whether patients should be asked for fresh consent before they are prescribed a biosimilar after having been on a reference product, and if a patient’s condition is stable on a reference product, is it really wise to “rock the boat” and prescribe a biosimilar? And further, following a new diagnosis of metastatic disease, should patients be started on a biosimilar instead of the reference product?

“We had to really work through this saying this is something that we believe as an organization. We believe in the literature, we believe in the data, and we would like to move forward. So, we’ve gotten past that hump,” Parsad said. 

All that said, UCM still wants to see more real-world evidence that shows biosimilars can stand the test of time outside of clinical trials performed in limited numbers of patients for the purposes of FDA approval, she said.

Oskouei agreed. “The conversation has definitely evolved with a desire for more real world evidence and studies around biosimilar to biosimilar switching. With 5 trastuzumab biosimilars on the market now for example, and more in the pipeline, this dynamic is becoming something that providers must navigate.”

At OHC, providers are now using biosimilars in practically 100% of situations when it comes to trastuzumab, rituximab, and supportive care products, such as growth factors for the control of neutropenia in patients treated with chemotherapy products, Broun said. But the practice has found it more manageable to administer a single brand of biosimilar overall except in instances where payers demand something different. “Actually, the ones that give us the most trouble as far as the payers are concerned are the growth factors. Every insurance company seems to have their favorite [pegfilgrastim], and so we stock 3 or 4 of those and we have to sort of interchange them.” 

It would be nice if payers were more lenient about the choice of biosimilars, panelists said. For example, Parsad noted that the administrative work that goes into payer authorizations could be used on something more beneficial, such as patient education and support. “We’re dealing with it as best we can, but it’s unfortunate,” she said.

These issues resemble growing pains for a relatively new option in medicine that is already proving its value, said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center in Louisiana, who served as panel moderator. “The US market is still in its infancy. We just need to let it mature. Biosimilars have been, at least for our organization, a great way to help provide some cost savings to the system and to the patient.”

Articles

Community Oncology Alliance

Next-stage biosimlar acceptance will stand on the strength and availability of real-world data as more of these biologics are launched, a Community Oncology Alliance (COA) conference panel said.

COA Panel Says Confidence Rests on Real-World Data

Are we there yet with biosimilars? That’s often the back-seat perspective, but this negativism is really based on “fiction” and biosimilars are rapidly gaining ground, according to Ted Okon, MBA, executive director of the Community Oncology Alliance, which advocates on behalf of community-based, nonhospital oncology clinics.

Misconceptions about biosimilars are numerous, Okon said, listing them at the recent Festival of Biologics 2021 biosimilars conference:

Physicians won’t prescribe them because they’re not as efficacious as originator products or the doctors make more money on the most expensive products

Biosimilar naming suffixes and CMS coding for them are stifling growth

Biologics are “natural monopolies” that shut out biosimilars

There have been repeated calls from the Drug Pricing Lab at Memorial Sloan Kettering Cancer Center in New York to regulate the prices of originator drugs rather than trying to make biosimilar competition do the work of trimming the soaring costs of biologics, but Okon said there’s no justification for even considering throwing in the towel on biosimilars. “I think this is just not based in fact, it’s not workable, and it’s complete fiction,” he said.

Peter Bach, MD, MAPP, and Mark R. Trusheim, MSc, 

 requiring “that biologic drug manufacturers lower their prices to affordable yet still profitable levels when their market exclusivity expires.”

Okon in his talk said that proposed policy was “price fixing” under a disguise. “I just want to say that price fixing has never worked in the long-term history of humanity,” Okon said.

Such theories and “fictions” about biosimilars distract from the true facts of the case, Okon said. “The biosimilar market is growing. Yes, it’s taking a while, but it’s growing.” Although the United States is behind Europe in terms of biosimilars approved and launched, the FDA continues to add more approvals each year—29 since 2014—and 73 additional biosimilar candidates are in clinical trials and/or under FDA review, Okon said.

Physicians continue to prescribe more biosimilars, and price competition is improving. “At COA we have a biosimilars committee, and they are committed to the growth of biosimilars. There is price competition and the market could be stronger and produce more savings,” he said.

Hospital Incentives Undermine Biosimilar Progress

However, one place that biosimilars could be absorbed and appear to be snubbed instead is in the hospital community, where financial incentives are heavily weighted in favor of biologic reference products, which means biosimilars in many cases are not even considered, Okon said. He quoted from a January 2021 report from Bernstein, the financial advisory firm, which used a recent federal drug price disclosure mandate to probe what insurers are paying hospitals for the use of reference biologics.

For example, UT Southwestern Medical Center receives $17,241 from Cigna for administering a dose of the Neulasta originator brand of pegfilgrastim, whereas Aetna pays UT Southwestern $6474 per dose. Humana pays Wake Forest Baptist Medical Center $4370 for a dose of the Prolia originator brand of denosumab, whereas United Healthcare pays Wake Forest $2209, according to the Bernstein report. As these data show, because compensation levels can sometimes be high, 30% to 43% of hospitals only carry the innovator products, Okon said 

Okon said the average markups over average selling prices on biologics are 250% although the markups are often much higher, as indicated by the Bernstein information, especially if the drugs are acquired through the 340B drug price subsidy program, which is intended to improve access to drugs for patients. Providing a scenario, Okon said it’s possible for a hospital to be paid almost $8000 for a drug whose wholesale cost is $4500, with the payer being charged over $8000 and the patient paying over $2000 out of pocket.

“You can see, especially with 340B, it makes drugs very, very economically attractive, and as a result, biosimilars are not attractive to use.”

Citing information from IQVIA, Okon said the US market for biosimilars stands at $4 billion annually. Okon called that “amazing growth.”

Growth trajectories for filgrastim biosimilars have been slow but market share growth curves for more recent biosimilars for other products, including bevacizumab, trastuzumab, epoetin, and rituximab, have been very steep, Okon noted. Similarly, price declines due to biosimilar competition are becoming steeper, too.

“It’s very, very interesting. It just took more competition,” he said.

There are culprits holding back the growth of biosimilars, he added. These include patent battles and restrictive deals that favor innovator products. Pharmacy benefit managers and payers are responsible for the latter, he said.

Although there are problems that prevent biosimilars from getting to patients, the following actions could help to improve access and lower prices, Okon said:

Prioritize and streamline the FDA approval process for biosimilars

Eliminate rebate waivers for biologics, including biosimilars

Provide 340B drug discounts to patients, not hospitals

“The bottom line is this: the biosimilar market in the United States is growing and it’s producing savings,” Okon said. “Could it be growing more? Yes. Could it be growing faster? Yes. Could it be producing more savings? Yes. But the solution is not price regulating the market. That will destroy not only the biosimilars but also the biologics market.”

Festival of Biologics

Calls for price regulation and lopsided incentives are threats to biosimilar progress, Community Oncology Alliance (COA) Executive Director Ted Okon argues.

COA's Okon Takes Aim at Biosimilar Misconceptions

Shanghai Henlius Biotech is one of many companies in China working to crack open the market there to biosimilar competition. However, Henlius stands out so far for some notable achievements, such as bringing the first biosimilar (rituximab) to market in China and achieving significantly rapid market penetration in the product's first several months of life. 

The company has bigger ambitions to achieve dominance not only in China but also on the world biosimilar stage, Ping Cao, company vice president of business development, explained at the recent Festival of Biologics USA meeting. 

Henlius was formed in 2010 and filed its first biosimilar investigational new drug application (HLX01, rituximab) with the Chinese National Medical Products Administration (NMPA) in 2011. The company opened its first Good Manufacturing Practices–certified factory in 2016, and HLX01 was approved in China in 2019, becoming the first biosimilar approved in China.

In July 2020, the company saw its trastuzumab biosimilar (HLX02, Zercepac) approved in the European Union. The same drug was approved a month later in China, and in December of 2020, Henlius succeeded in getting an adalimumab biosimilar (HLX03) approved in China, also.

The company decided that its first several biosimilars would be oncology products because of the relatively huge market for oncology treatment in China. That meant the company saw huge potential in rituximab, trastuzumab, and bevacizumab biosimilars. The company anticipates an FDA filing for its bevacizumab biosimilar (HLX04) in 2021.

It also anticipated strong growth for its adalimumab biosimilar, referencing the blockbuster Humira, which Cao said still has a relatively small share of the market for autoimmune diseases in China. “Autoimmune disease actually has a huge unmet need in China,” she said. Humira’s 2019 sales share in China vs its global penetration rate was 0.2%, and the estimated access rate (to adalimumab) in China in 2020 was 1.3% of patients vs a potential market of 6.7 million patients.

Global marketing of its biosimilars is an important element of the company’s growth strategy , but Henlius also wants to develop biobetters, drugs that are based on originator products but deliver better efficacy, improved safety, or other enhancements. Developing new biologics and combination therapies also is a targeted area for growth at Henlius, Cao said. 

Its second wave of biosimilar contenders may target the cetuximab (Erbitux, rectal and head and neck cancer), ramucirumab (Cyramza, solid tumors), pertuzumab (Perjeta, breast cancer), and denosumab (Prolia/Xgeva, bone loss) markets. Henlius has biosimilars of these drugs in phase 1 development currently.

The company is seeking a rheumatoid arthritis indication for its rituximab biosimilar and, if successful, this indication would make HLX01 a bio-innovative medicine because the reference product, MabThera, has not yet been approved for this indication, Cao said. China’s NMPA has accepted a new drug application for HLX01.

Under its current indications, HLX01 was a record breaker, taking 50% of market share for new patients treated within 5 months of launch in China and surpassing market share of the originator product, MabThera, after 14 months on market, Cao said.

Although the cetuximab product candidate remains in early stage trials, Henlius has already granted commercialization rights in China to Shanghai Jingze. The company has multiple nonbiosimilar product candidates in early-stage development and antibody drug combinations in mid- to late-stage development for cancer treatment.

HLX02 (trastuzumab) was the first China-made biosimilar to gain approval in Europe, Cao said. “It has been launched in the United Kingdom, Germany, Portugal, and Spain, and used in tier 1 hospitals of Europe,” she said.

Henlius is working to increase the scale of its manufacturing operations to support its global ambitions for sales growth. It has 2 plants currently: one in Xuhui and a second in Songjian, with a total installed production capacity of 44,000 L. Both of these factories were fitted out and made operational within the past 3 years.

In Sonjiang, Henlius has a third plant in development, which Cao said when complete would rank among the largest biologics production facilities in Asia for size. This plant following phase 1 of development would have 36,000 L of production capacity, which would be increased to 45,000 L later on. Henlius currently has a manufacturing staff of 758 employees, Cao said. “For biologics, the important thing is to reduce manufacturing costs. We have our own proprietary technology to enable this mission.”

The company has its own sales team in China and is looking for partners in the rest of the world. The China sales team numbered 400 full-time employees at the close of 2020 and is projected to reach 1000 full-time workers by the end of 2021. Henlius has established relationships with 2700 upper grade hospitals and 30,000 oncologists in China, Cao said.

Shanghai Henlius Biotech began as a 2-person enterprise in 2010 and now has multiple oncology products in development and 3 biosimilars on the market. An executive discusses its business trajectory.

Shanghai Henlius Biotech Maps Out Its Biosimilars Future

It’s not easy to break into the insulin market, and for that reason the public should not expect a flood of insulin biosimilars producers, said a panel of experts on biologics manufacturing at the Festival of Biologics USA.

Insulin is a biologic that is very difficult to consistently produce at high purity in large volumes that would be necessary for distribution, and very few manufacturers have the resources to perfect this process and convince regulators that they can get it right, the panelists said.

Further, the United States is an intensely litigious country for biologics producers, and would-be biosimilar contenders may encounter a barrage of legal opposition from entrenched producers, they said. In the United States, Eli Lilly, Novo Nordisk, and Sanofi produce and distribute an estimated 90% of the insulin.

This relative monopoly has given rise to extraordinary inflation in the cost of insulin products. A report from Mayo Clinic in 2020 observed an 

 in the cost of a vial of Humalog (insulin lispro, Eli Lilly) between 1999 and 2019 ($21 vs $332, respectively).

The United States has attempted to clear a pathway for the introduction of insulin biosimilars. In 2020, the 

351(k) Biologics License Application process

 under the Public Health Service Act became available for insulins and growth hormones, allowing these products to be approved as biosimilars. 

There are no biosimilar insulins so far, although in mid-2020, Biocon and Mylan succeeded in getting an insulin glargine (Semglee) approved under the generic 505(b)(2) New Drug Application pathway and are seeking to have it designated a biosimilar. The panel discussion at Festival of Biologics USA included the participation of 

 vice president and head of Global Regulatory Affairs for Biocon.

Many companies have attempted to bring rival insulin products through the review process in Europe and have failed because the pharmacokinetics of these products are extremely difficult to match precisely with originator products, Ramanan said. “That’s barrier number 1. Barrier number 2 is we need to have economies of scale, and that requires a large capital investment, and not many companies have that to combine with the science. This limits the number of players that are coming in beyond the ones that are truly committed.”

Biocon is one of the success stories, having insulin products approved in more than 60 countries. “It took us a very long time, but now we have that institutional knowledge,” Ramanan said.

 an expert on pharmaceutical marketing who serves as a professor and chair of Brac University in Dhaka, Bangladesh, agreed that manufacturers have difficulty meeting the regulatory expectations for quality. “Regulators are encouraging companies to invest in continuous processing, so that would mean they have the technical mastery over the process. This is easier to say than to do,” she said.

Process validation is another source of regulatory rejections of insulin product applications, she said. Process validation refers to efforts to confirm that drug product of a standard quality can reliably be produced consistently over time.

Insulins are not complex drugs and, in fact, involve a simple amino acid sequence, Ramanan noted. “However, it is not easy to produce insulins of high purity at extremely large scale. That is what scientific capabilities require.” This makes producing insulin biosimilars a challenge, and it’s another reason why the market is not flooded with competitor products, Ramanan said. 

“It’s a production manufacturing challenge at scale. The world consumes many times more insulin than monoclonal antibodies,” which are the standard form of biosimilars commonly available in the United States, said 

 panel moderator and managing director of SBLehrer, an expert on biosimilar commercialization.

The insulin producer competition in the United States remains scanty, and for this reason, prices are unlikely to come down anytime soon, Ramanan said. Another structural problem in the marketplace is the heavy patenting that originator companies do to protect themselves against competition. “It prevents competition and it keeps the price higher for decades,” Kabir said. Multiple versions of insulin products are needed to really tamp down the price curve, she said.

“Due to the litigious nature of the US market, even before a company finishes a clinical study, there is litigation already ongoing,” said panelist 

ice president of Global Regulatory Affairs for Gan & Lee Pharmaceuticals USA

. Therefore, a company needs significant resources to endure these battles and finally get its product to market.

Despite the expansion of the 351(k) licensing pathway, US regulatory efforts to enlarge the insulin product pipeline have been “lagging,” Dave said. “The decision-making right now is really in the hands of the pharmacy benefit managers in the United States.”

Taking all structural conditions into account, Dave said he anticipates that only a “limited” number of companies will develop insulin biosimilars.

Even if the problem of too few competitors can be solved, there isn’t much hope for price reduction. The benefit for patients and health care systems from having insulin biosimilars will not be as dramatic as has occurred for generic drugs, where deep discounts have been achieved, Dave said.

Biosimilars involve costly biologics manufacturing, and biosimilar developers will not be willing to enter market at deep discounts to the originator products. Combining the scarcity of players in the market and the unwillingness to discount products, the problems of low competition and high prices are very likely to persist, he said.

For an article about legislation introduced to grant automatic interchangeability for insulins, click 

Insulin is not a complex drug, but churning it out in massive quantities at high levels of purity is one of the main hurdles inhibiting biosimilar competition, panelists said. 

Panel: Insulin Biosimilar Competition May Be Scant at Best

It is tough enough to get manufacturers to take the plunge and develop biosimilars for even-lucrative drugs that address major diseases, so what are the chances of seeing biosimilars developed for orphan drugs? Very slim, said a panel of experts who spoke at the Festival of Biologics USA conference.

Orphan drugs address conditions that affect relatively small patient populations, and it is difficult to recruit patient populations large enough for clinical trials needed to prove that experimental drugs are going to be efficacious. The expense of development and the small patient base for these agents translate into very high prices, which it is why it is desirable to have lower-cost biosimilar versions.

But with orphan drugs, biosimilar developers face almost the same set of difficulties that originators do. “When you’re talking about biosimilars, this can be considered even more challenging,” said 

 executive director of Global Biosimilars Regulatory Affairs and Regulatory and Research and Development Policy at Amgen.

Biosimilar companies need samples of originator drugs so they can develop their own versions of these agents, but with orphan drugs, access to drug samples is heavily controlled, she said. After that come the clinical trials, and, again, recruiting patients is difficult and time consuming. Patients may not want to participate in clinical trials with a biosimilar candidate if they know that their rare condition is already in stable condition on the originator drug, which further narrows the already small pool of available trial candidates, Christl said.

It may therefore be helpful if regulators are flexible in their demands for evidence used to support orphan drug development and willing to consider alternative means of demonstrating bioequivalence between biosimilar candidates and reference products. “But where should you look for flexibilities from the regulatory and scientific side?” Christl asked. “Can you conduct studies, maybe, in healthy individuals?”

Regulatory approvals that are more reliant on molecular characterization than clinical trials might also be possible, she said. Along the way, it’s important to ensure that patients and providers are confident in the process used to establish biosimilarity. “We need to find ways that are right, from a scientific perspective, to answer the question, to maintain the confidence in those regulatory pathways and what regulators are doing when they’re approving a biosimilar,” she said.

Whatever happens, standards for approving biosimilars cannot be lowered for the sake of making it easier to have affordable medicines, said panelist 

 who served 8 years with the FDA, most recently as acting deputy director of Therapeutic Biologics and Biosimilars. “The FDA has an approval standard, and any product it approves has met that standard. There may be different pathways to that same end point. It may be that one product is approved based on more analytical data—tighter analytical data—and a different pharmacodynamic end point.”

The desire for less costly versions of originator drugs for orphan diseases is just as strong in Europe, said 

director of Biosimilar Policy and Science for Medicines for Europe, an industry group for generics and biosimilars producers. “The price tags are really high, so it’s a problem for patients and for health care systems if there is no prospect of competition ever.”

“In the orphan space in Europe, we are up for a very big overhaul of the regulation and legislation around this. I’m expecting that there will be quite a substantial amount of discussion, not only scientific, but bringing the science and the regulatory processes to serve that purpose and meet those objectives,” she said.

In Europe there have been incentives and other support granted to encourage the development of even originator drugs for orphan diseases, and the question is whether biosimilars will emerge for orphan drugs without the same incentives that were offered to originator companies, Maréchal-Jamil said. “Less than 11% of those orphan biologics have biosimilar candidates in development at the moment, so that gives a little bit of a perspective on the difficulty for biosimilar developers to overcome the risks that are set in front of us at the moment.”

For coverage on the regulatory environment for biosimilars from Festival of Biologics USA, click 

Potential developers of orphan drug biosimilars face daunting challenges to get these drugs approved and onto market, said a panel of experts. 

Are Orphan Drug Biosimilars Too Costly and Difficult to Produce?

In the court of expert opinion, clinical efficacy studies for evaluating biosimilar equivalence to reference products increasingly stand in a gray area. Many experts agree they are not sensitive enough in comparison with other tests to provide convincing evidence of biosimilarity, but regulators in the United States and Europe still hold onto their right to require these tests for biosimilar approval. The United Kingdom’s recent decision not to require these tests, therefore, is “revolutionary,” said 

 who leads Regulatory Affairs Policy at Sandoz and spoke at the Festival of Biologics USA conference.

“This is the way the future will look, so we will see more complex biologicals, which can be developed as biosimilars, without the need for these very large efficacy studies, and the evidence to ensure the safety and effectiveness of biosimilars will be collected by other means,” such as pharmacokinetic studies, Schiestl said.

Such regulatory changes can significantly improve the landscape for biosimilar development and acceptance, panelists at the conference agreed, but too much divergence between national policies can be a hindrance, as it adds complexity, said 

Biosimilar Policy and Science for Medicines for Europe, an industry group for generics and biosimilars producers. “Complexity is never really linked to access or availability in the end. That is just an additional hurdle.”

But it’s important to note that biosimilar approvals are based on the “totality of evidence,” and although the data that regulators will require may be voluminous and diverse, it is certainly not “one size fits all,” panelists said. In other words, US and European regulators are willing to be flexible in their requirements for individual biosimilar applications.

“I think we’re going to see the FDA and the European Medicines Agency be more open, and hopefully that will influence other regulators about what types of data and studies are really necessary to demonstrate biosimilarity," said 

Christl previously headed up the therapeutic biologics division at the FDA, and drawing on that experience, she said the FDA has tended not to provide micro-level, rigid guidance about biosimilar approval requirements simply because it makes sense to stay flexible so that it’s possible to adapt to changing needs and situations.

“You can target the data you need to look at—are there clinically meaningful differences between the products?—and look across the spectrum of different scientific studies, whether they are in the analytical space, looking at functional data or pharmacodynamic end points, vs those traditional clinical end points. I expect that the FDA is going to keep moving forward with that same type of approach,” she said.

Perceptions about what data are essential for biosimilar characterization may change, but ultimately one of the hurdles that must be crossed is the acceptance factor among providers and patients. They’re the ones who need to be convinced, ultimately, that biosimilars are safe and efficacious, so the requirements for regulatory review have to be tailored, somewhat, in that regard, said 

 who served 8 years with the FDA, most recently as acting deputy director of Therapeutic Biologics and Biosimilars. 

“There’s a real push-and-pull that regulators are grappling with around these issues," she said. "On the one hand, there’s a desire, and I think appropriately, to have efficiencies wherever we can and to really harness the flexibility that’s built into the 351(k) biosimilars approval pathway, and to exercise that flexibility appropriately. On the other side of that coin is that we also have patients and health care providers who need to be driving uptake and utilization of these products for that piece of this puzzle to be successful.” Temkin is now in private practice with King & Spalding in Washington, DC.

Insulin products, which are now approved under the Biologics Price Competition and Innovation Act, could help open the door for simplification of regulatory requirements, such that gaining FDA approval for substituting these biosimilars with established brands will be put on an easier gradient, said 

 of Axinn, Veltrop & Harkrider. “I’m sincerely hoping that because insulin is so well understood and such a simple protein, the FDA will be able to work with those who are seeking an interchangeable designation so that the immunogenicity clinical trials, which seem to drive up the cost of development for follow-on biologics, will not be required.”

That, in fact, is the direction the FDA wants to go, Temkin said. “My understanding is that the elimination of that requirement will save many, many months and potentially millions and millions of dollars from the development of biosimilar and interchangeable insulins, which can hopefully catalyze some additional development of those products.”

Regulators want built-in flexibility, and that benefits biosimilar developers, but there can be a price for this amount of latitude, panelists said.

Biosimilar Experts Debate Divergence in Regulatory Standards

Early adoption of the trastuzumab biosimilar Kanjinti was high among patients with breast cancer whether or not they had prior use of the originator (Herceptin), investigators said in a poster presentation at the National Comprehensive Cancer Network (NCCN) Virtual Annual Conference 2021.

Investigators set out to measure how quickly patients with a breast cancer diagnosis were started on the biosimilar during the agent’s first year of availability. Kanjinti, an Amgen product, was launched in July 2019. They used Flatiron Health retrospective data to develop 2 patient cohorts: those with early breast cancer (eBC, n = 2149) and those with metastatic breast cancer (mBC, n = 799). Those cohorts were further subdivided into patients with prior reference product (RP) exposure and no RP exposure.

Investigators said that among trastuzumab-naïve patients, the median time from diagnosis of eBC to initiation of biosimilar trastuzumab was 34 days; the respective time for those with a diagnosis of mBC was 30 days.

Among patients with prior RP exposure, 81% of patients with eBC transitioned and 75% with mBC transitioned to the biosimilar within 28 days of the final administration of RP. “Use of [Kanjinti] was observed in both RP-naïve and prior RP-treated patients, with evidence showing comparable patient characteristics between the 2 groups,” investigators wrote (

The investigators found that the first providers began to employ the trastuzumab biosimilar soon after it was launched—within 4 and 12 days of market entry. In the United States, Kanjinti was the first trastuzumab biosimilar to be launched, although it was not the first trastuzumab biosimilar to be approved by the FDA. 

The study did not evaluate for reasons why patients previously treated with RP were transitioned to the biosimilar, owing to a lack of appropriate data, investigators said.

Jin R, Accortt NA, Sandschafer D, Lawrence T, Mahtani RL. Characteristics of breast cancer patients treated with trastuzumab-anns, a trastuzumab biosimilar, in a real-world setting. Poster presented at: NCCN Virtual Annual Conference 2021; March 18-22, 2021. Accessed March 18, 2021. https://www.nccn.org/professionals/meetings/annual_conference_2021.aspx

NCCN  Virtual Annual Conference

Investigators observed early adoption of the trastuzumab biosimilar Kanjinti in patients with early breast cancer and metastatic breast cancer. 

Study: Rapid Adoption Noted for Kanjinti During First Year of Availability

Oncology providers are, in general, highly sensitive to costs of biologics, so expanding payer coverage of these agents to include lower-cost options is likely to drive adoption of biosimilars in oncology, said Sonia T. Oskouei, PharmD, BCMAS, DPLA, vice president of Biosimilars at Cardinal Health.

“From our surveys we know that the top 2 reasons oncologists are likely to prescribe a biosimilar are if it provides costs savings to the patient or practice or if the insurance company mandates a switch,” Oskouei said at this year's Association of Community Cancer Centers (ACCC) 47th Annual Meeting & Cancer Center Business Summit. Her presentation covered motives and biases that influence the prescribing behavior of oncologists.

A 2017 Cardinal Health survey identified fear of monetary loss as the chief bias influencing physician decision making in oncology, with 23.9% of respondents in agreement. These same physicians identified a strong bias toward following established guidelines from such nationally recognized entities as the National Comprehensive Cancer Network and the American Society of Clinical Oncology (22.0%). Lack of clinical response and the predictability of outcomes were 2 other factors that oncologists identified (16.5%) as influencing their likelihood to prescribe biosimilars.

“The responses really haven’t changed that much since 2017. This is a consistent theme when it comes to biosimilar utilization—the correlation to cost savings,” Oskouei said.

Whereas physicians may gravitate toward biosimilar use to save money, value-based care programs, such as alternative payment models (Oncology Care Model, Oncology Care First, Merit-based Incentive Payment System) are accelerating that trend, she said. “Biosimilars are really valuable tools for providers practicing in the value-based care initiative. These are ways to allow cost savings and efficiencies in delivering high-value cancer care and expanding the use of biologic treatment.”

In fact, loss aversion is a very powerful motivator in the oncology sector. Asked in 2017 how often fear of not being reimbursed influences their prescribing habits, 37.1% of oncologists answered “very often," and 25.8%, “moderately often.”

“The fear of monetary loss has double the impact of any potential equivalent gains, studies have shown, so it makes sense that this would be a primary driver of potential bias,” Oskouei said.

Familiarity with biosimilars plays a large role in acceptance and use, she said. Oncologists were first introduced to biosimilars via supportive care products, which as indirect treatments for cancer present a lower-stakes risk for oncologists. Their positive experience with these products may have contributed to their acceptance of therapeutic oncology biosimilars, she said.

However, familiarity also may mean a dependence on peer experience with and willingness to adopt biosimilars. For example, in a 2017 survey, 64% of oncologists agreed that they expected to be early adopters of biosimilars, but 33% said they would wait for other academic and community leaders to adopt biosimilars before prescribing them themselves, and the remaining 4% said they would not use biosimilars unless mandated to do so by payers.

“They’re trying to develop that familiarity and see peers utilize biosimilars and build more confidence in the outcomes before adopting,” Oskouei said.

Oncologists’ confidence in biosimilars may be biased by the statements about them written by the FDA and other authorities, she added. For example, the statement “Biosimilars are not inferior to reference products in terms of safety and efficacy” is less convincing than “Biosimilars are as safe and effective as the reference products."

Indeed, the FDA has considered rephrasing biosimilar language to get around the bias that such cautious language induces.

Differences in the language used to present biosimilar is known as “framing,” and these differences have the potential to influence decisions about the use of these agents, Oskouei said. 

“A lot of educational efforts and programs have helped address the potential framing bias with biosimilars,” which has turned up in literature from not only the FDA but also health care industry sources, she said.

When it comes to biosimilar uptake, a lot depends on physician education, but other agents and drug developments also play a role. Originator manufacturers are continuously innovating, developing new formulations of existing treatments, new methods of delivery, and also new medicinal products entirely, Oskouei said.

“We can’t just look at the originator biologic and the biosimilars in silo when making treatment decisions, because there are continued advancements and novel dosage forms that can compete with biosimilar utilization. Conversely, there’s also the discussion around obsolescence when it comes to biosimilars and their originator biologics,” she said. “The key message is that it’s really going to continue to be a very dynamic market.”

Oskouei ST. Biosimilar adoption in oncology: how attitudes have changed and what’s ahead? Presented at: ACCC 47th Annual Meeting & Cancer Center Business Summit; March 1-5, 2021. Accessed March 5, 2021. https://www.accc-cancer.org/home/attend/accc-47th-annual-meeting-cancer-center-business-summit/agenda#undefined5

ACCC Annual Conference

Sonia T. Oskouei, PharmD, BCMAS, DPLA, vice president of Biosimilars at Cardinal Health, discusses motivating factors that affect use of biosimilars in oncology.

Oncologists' Cost Sensitivity May Drive Biosimilar Uptake

Biosimilars have become largely integrated within oncology therapeutic and supportive regimens, and surveys of oncologists indicate these professionals are increasingly comfortable with not only using these agents but substituting them for originator biologics, according to Sonia T. Oskouei, PharmD, BCMAS, DPLA, vice president of Biosimilars at Cardinal Health.

Biologics spending predominates over small-molecule drugs in oncology, antidiabetics, and immunology, so there is an outsized potential for biosimilar growth in those classes of drugs, Oskouei said at the Association of Community Cancer Centers (ACCC) 47th Annual Meeting & Cancer Center Business Summit, March 1-5, 2021.

Filgrastim biosimilars were introduced to the US market in September 2015 and have achieved a 90% share of the market for this agent, which is used to boost white blood cell count following chemotherapy, Oskouei said. Bevacizumab biosimilars entered the market in July 2019 and now command a 59% share of their respective market. Bevacizumab is used for treatment of ovarian, cervical, renal, non–small cell lung, and colorectal cancers, among others.

Trastuzumab, for breast, stomach, and esophageal cancers, entered the market in biosimilar form in July 2019; these biosimilars now have a 43% share of their respective market. The comparable date and market share for rituximab, for autoimmune diseases and cancer, are November 2019 and 48%, respectively, according to Oskouei.

“The vast majority of biosimilar experience in the United States is in the oncology space currently. Just in December we had a fourth pegfilgrastim biosimilar become available and in January 2021 we had a third rituximab bisosimilar” enter market, Oskouei said.

Pegfilgrastim biosimilars, with 31% market share in the United States, have achieved the lowest share among biosimilars in oncology, although this is partly attributable to the Neulasta Onpro, a reference manufacturer product that offers the convenience of home-based injections.

Surveys conducted by Cardinal Health have yielded insight into oncologists’ improving disposition toward and knowledge of biosimilars. Whereas just 30% of those surveyed in 2017 (n = 61) stated they were very familiar with biosimilars, 53% said they were very familiar with biosimilars in 2020 (n = 195).

The survey findings also suggest that providers are increasingly likely to prescribe biosimilars for their patients. Asked whether they would prescribe biosimilars for new patients, 53% answered yes in 2017 (n = 93) vs 67% in 2020 (n = 195). The same study suggested that those willing to prescribe biosimilars for patients who were successfully treated with reference biologics rose from 28% in 2017 to 70% in 2020. “We can see there’s been a big shift,” Oskouei said.

According to the 2020 survey, 86% of oncologists said they would prescribe biosimilars in indications acceptable for extrapolation, vs 57% in 2019. In 2020, just 5% said they would extrapolate only for supportive care biosimilars. Oskouei stated that was “a pretty significant jump.”

In the 2020 survey, 72% said they would feel comfortable with switching patients from one biosimilar to another for the same condition. “That, again, highlights the sense of comfort that has developed with the FDA approval process and the scientific rigor that goes behind extrapolation and approving biosimilars as highly similar to reference biologics,” Oskouei said.

For more coverage of this year's ACCC meeting, click 

Survey results show that oncologists are embracing biosimilars not just in supportive care but for therapeutic uses also. 

Cardinal Health: Oncologists’ Comfort With Biosimilars Is on the Increase

At the Association for Community Cancer Centers’ 47th Annual Meeting & Cancer Center Business Summit (AMCCBS), we spoke with Lalan Wilfong, MD, a medical oncologist/hematologist and executive vice president of Value Based Care and Quality Programs. At the AMCCBS Virtual 2021 meeting, Dr Wilfong spoke about improving patient outcomes in cancer. We talked with him about the challenges of integrating biosimilars in a large network of physicians and how that was accomplished.

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Lalan Wilfong, MD, an expert on value-based care, explains how Texas Oncology worked with physicians and payers to make biosimilars available for patients.

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