Tony Hagen is senior managing editor for The Center for Biosimilars

Articles

Investigators evaluated trial spending and reasons for biologics license application failures. 

Study: Biosimilar vs Originator Spending on Comparative Efficacy Trials

Regulatory and launch news on rheumatology biosimilars for adalimumab and infliximab was plentiful in February 2021.

Biosimilars Rheumatology Roundup

Biosimilars Quiz: Which years have brought AbbVie the highest revenues for adalimumab?

Biocon and Viatris edge closer to EU marketing authorization for a bevacizumab biosimilar, among other biosimilar business developments.

News Briefs: Samsung Bioepis, Cipla, Biocon Report Progress

The National Comprehensive Cancer Network (NCCN) recommended providers contact their legislators to counteract single-biosimilar payer policies. 

NCCN Issues Guidelines for Biosimilar Use

Biosimilars Canada, a national trade association representing biosimilar developers and other industry stakeholders, has reelected Michel Robidoux, the president and general manager of Sandoz Canada, 

In a statement announcing his reappointment, Robidoux praised the biosimilar switching policies implemented by British Columbia and Alberta in 2019. These policies require that patients with chronic conditions be transitioned to certain biosimilars under the oversight of their physician. The programs have achieved savings that proponents have said could be reinvested in health care to broaden access not only to biologics but also other therapies and services.

“Biosimilar medicines have an important role in supporting health care sustainability and patient care,” Robidoux said. “The implementation of biosimilar switching policies could save the Canadian health care system hundreds of millions of dollars.” Citing a 2020 

 by the Ontario Drug Policy Research Network, the statement said that annual savings of $425.6 million for provincial drug plans is possible in Canada by switching patients from 3 of the top-selling reference biologics: Humira (adalimumab), Enbrel (etanercept), and Remicade (infliximab). “A similar magnitude of savings would be available for employer-sponsored benefit plans,” it said.

Biosimilars Canada is affiliated with the European trade group International Generic and Biosimilar Medicines Association and is a division of the Canadian Generic Pharmaceutical Association. The group also reelected Mike Woolcock to serve as vice chair of the board. Woolcock is a senior vice president at Apobiologix. Other companies represented by Biosimilars Canada include Auropharma, Fresenius Kabi, Pharmascience, Taro, Teva, and Viatris.

For an update on biosimilar savings in British Columbia from the perspective of Pacific Blue Cross, click 

Robidoux's reelection comes as biosimilars get a lift from automatic switching policies in British Columbia and Alberta. 

Biosimilars Canada Reappoints Robidoux as Chair

In 2019, British Columbia (BC) became the first Canadian province to announce and implement a biosimilars switching initiative. Soon after, 3 other provinces developed their own plans to draw on biosimilars for health care savings. BC’s initiative introduced a mandatory switching policy from reference products to a select list of biosimilars. Each phase of the initiative is given a transition period, allowing physicians time to prepare patients for biosimilars before BC PharmaCare, the public health program, officially stops covering the reference products. The province recently concluded in its third phase, officially using etanercept, infliximab, rituximab, and insulin glargine biosimilars as the primary medications to treat a number of rheumatic conditions, such as ankylosing spondylitis and rheumatoid arthritis.

Pacific Blue Cross, one of the health plan providers in BC, has already seen success in aligning plan sponsors and members with the initiative, generating $27 million in savings by converting 99% of their plans. We sat down with Anar Dossa, director of Pharmacy Services at Pacific Blue Cross and leader of biosimilar transitions for the company’s benefits plan clients and members, to discuss company projections and challenges that have come with implementing the initiative.

To learn more about phase 3 of the BC Biosimilars Initiative, click 

To learn more about recent biosimilar launches in Canada, click 

To learn more about biosimilar switches in Canada, click 

To learn more about other Canadian province’s biosimilar plans, click 

To learn more about Pacific Blue Cross’s success with the program, click 

Podcasts

Anar Dossa, director of Pharmacy Services at Pacific Blue Cross, discusses the company's involvement with British Columbia's biosimilars switching program.

Anar Dossa Discusses Success and Savings With British Columbia’s Biosimilars Initiative

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

The foundations for generics and biosimilars were laid in the enactment of several key pieces of legislation. In 1962, the Kefauver-Harris Amendments required proof of a product’s safety and efficacy, and they mandated that drugs released between 1938 and 1962 be reviewed for safety. In the late 1960s, the FDA developed the abbreviated new drug application for approval of generic drugs. The Drug Price Competition and Patent Term Restoration Act of 1984 (aka Hatch-Waxman) allowed the FDA to approve applications to market generic versions of brand-name drugs that were released after 1962 without repeating efficacy and safety studies; it also gave manufacturers of originator drugs 5 years of exclusivity for new products that contain previously unapproved chemical entities.

Originator drug companies were opposed to the idea of generic drugs and declared that these copycat drugs would cause havoc to health care. The protests were unsuccessful, and many of these manufacturers ultimately made generic drugs as well, although generics were less profitable for them.

Now, 37 years after Hatch-Waxman, despite widespread use of generic drugs, the controversy continues about their safety and efficacy, particularly in prescribers’ minds. In 2010, the Biologics Price Competition and Innovation Act (BPCIA) was signed into law, and we saw history repeating itself as originator companies objected to biologics, as they had once objected to generics. However, this time, they found a sympathetic audience because the stakes were much higher. The most common argument presented was that biological drugs do not have a fixed structure, and manufacturing process controls are pivotal to assuring safety and efficacy. Because only innovator producers are privy to these controls, they contended, it is impossible to create a safe and effective copy of a biological drug.

AbbVie protested to the FDA in a citizen petition that the BPCIA constitutes an unlawful taking of private property under the Fifth Amendment because each biologics license application (BLA) contains trade secrets and confidential commercial or financial information, and the “approval of a biosimilar necessarily relies on and uses the trade secrets that the innovator sponsor submitted in support of the BLA.”1 The petition was denied by the FDA.

Many more petitions demanded that within biosimilar product labeling should be a declaration acknowledging that a biosimilar is different from the reference product. Extended lobbying efforts, as well, were aimed at getting state legislatures to preemptively ban interchangeable biosimilars. When originator companies realized that biosimilars were not going away, however, they got aboard the train, just as they did for the generic drugs. Big-name companies with many original biologics became the largest producers of biosimilars. Of 29 biosimilars so far approved by the FDA, all but a few are owned by the larger pharmaceutical companies. It might be assumed that the distrust sowed against biosimilars’ safety and efficacy by major pharmaceutical manufacturers would have dissipated, but it did not. Patients were reluctant to use these agents. And the same companies that once revolted against biosimilars adopted a new mantra: “Only we know how to make biosimilars because only we know how to make biological drugs.”

Physicians get information about new drugs from medical journals, continuing education meetings, and, most important, from visits by medical reps who are employed by the pharmaceutical industry. Physicians are good at what they do, but they are not scientists. They are well able to understand the results of a published clinical study, but most would be lost in the jungle of protein structure and immunogenicity profiling that is critical for biosimilar approval. Overall, the message received by physicians was simple: “Do not risk your patients.” The FDA did a lot to educate every stakeholder, including the physicians, but that was not enough to fully counter the bias created against biosimilars.

Over my career, I have conducted many advisory board meetings with stakeholders to introduce biosimilars. In 2019, I was hired by an originator company to educate physicians about biosimilars. To one group of about 500 primary care physicians, I presented a high school–level science lecture on biosimilars, with graphics, to reduce the jargon and complexity. Before my talk, I asked them to take a survey that included 2 questions: (1) Do you trust the safety and efficacy of biosimilars? and (2) Do you trust the FDA? Most physicians did not believe that biosimilars are safe, despite the FDA labeling that biosimilars in comparison with originator drugs have “no clinically meaningful difference” In response, I asked why they believed the FDA would not be truthful about biosimilars. The typical response was that, every year, many drugs are recalled and many companies are given citations for lack of current good manufacturing practice compliance. I had difficulty connecting these issues with the biosimilar issue, but the responses helped me understand the provider mindset: The FDA cannot assess the safety of biological drugs because if you do not know what you are looking for, how would you know you are not finding it?

Later, I gave these physicians another survey that asked these questions: (1) Would you prescribe a biosimilar to a patient if the insurance will not pay for the originator product? and (2) Would you trust biosimilars from smaller companies, now that the innovator companies are also making biosimilars? To the first question, the answer was an overwhelming yes. And to the second question, it was overwhelmingly no. I did not get a chance to continue my arguments. Still, in a social gathering over lunch, many physicians agreed that they did not have the time to understand the scientific nuances I presented in my talk. In brief, physicians remain misinformed or ill-informed about the FDA’s role in assuring the safety and efficacy of drugs, and originator companies perpetuate the confusion by asserting it is only a published clinical trial of efficacy that matters.

One physician was very frank. Her hospital has a policy of using biosimilars where available, and prescribers can get approval for an innovator biologic only by filling out a 10-page form. That killed the revolt against biosimilars quickly, she said.

So, where do we go from here to make physicians believe in biosimilars? The first responsibility goes to the FDA. Often, physicians do not scroll the pages of FDA websites or watch FDA YouTube videos. My suggestion to FDA Acting Commissioner Janet Woodcock, MD, is that she send a direct communication to physicians (a paper letter, not an email) to assure them that when the FDA approves a biosimilar, that is a golden seal of “no clinically meaningful difference.”

Second, payers can do their part to increase biosimilar use by establishing reimbursement policies that favor biosimilars, a sure-fire means of getting lower-cost biosimilars into play. I have also met with CMS leaders and suggested a legislative change to enable CMS to create a biologics substitution list that is based on cost with no other differentiation between a biosimilar and a reference product. This has already been tried in Europe; it works and will work in the United States.

Third, biosimilar developers should monitor misleading or anticompetitive public statements made about biosimilars and report these to the FDA and Federal Trade Commission. Innovator companies have been admonished for such actions by regulators before. Merely reaching out to physicians to explain the advantages of biosimilars may not be enough if entities opposed to biosimilars continue to disparage these agents.

With proper, unhindered education about the value of biosimilars, these cost-saving agents can become as significant a force in improving access to health care as generics have before them.

Regulations.gov. Citizen petition from AbbVie, Inc. FDA. Published June 3, 2015. Accessed February 16, 2021. https://www.regulations.gov/document?D=FDA-2015-P-2000-0001

Biosimilars have come a long way, and their path has mirrored that of generics—fraught with obstacles. Still, a stronger embrace is needed from physicians and payers. 

Opinion: A Short History of Biosimilars

Trastuzumab biosimilars are available in intravenous (IV) but not subcutaneous (SC) form, and although the SC form of originator trastuzumab is often preferred, IV biosimilars may offer the better deal from the standpoints of cost and convenience, investigators concluded in a recent review of trastuzumab options.

“It is therefore important for health care providers to consider the potential benefits of IV trastuzumab biosimilars (eg, lack of need for additional injections) and whether they outweigh the benefits associated with SC administration, as well as to consider patient preferences,” the authors wrote. The review outlined the current options available for trastuzumab therapy to aid decision-making by health care providers.

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), is used to treat HER2-positive breast cancer and metastatic gastric cancer. According to the authors, combined with chemotherapy, biologics including trastuzumab “have emerged as paradigm-shifting treatments for patients with HER2-positive breast cancer, significantly improving patient outcomes and survival rates.”

The IV formulation of trastuzumab was approved by the FDA in 1998. An SC formulation was approved (for HER2-positive breast cancer only) by the European Medicines Agency in 2013 and FDA in 2019.

The reviewers noted a drawback of trastuzumab, as with other biologics, is its high cost. Since patent expirations in the European Union and United States, multiple trastuzumab biosimilars have been approved in these 2 regions, all formulated for IV use only. The patent on the SC formulation is set to expire in 2030 in the United States, precluding the availability of biosimilars using the SC route of administration for almost a decade.

Comparable pharmacological and clinical parameters

The authors noted that several studies have investigated the dose of SC trastuzumab required to produce similar pharmacokinetic parameters and serum trough concentrations to the IV formulation and that several studies have compared the efficacy and safety of IV vs SC trastuzumab. Collectively, according to the authors, these studies demonstrate that the IV and SC formulations have “generally comparable pharmacological and clinical profiles” in patients with HER2-positive breast cancer.

However, they acknowledged some questions do remain. The authors said the effect of body weight on the efficacy of each of the 2 formulations might “require additional evaluation.” Additionally, they noted that one study found twice as many patients taking the SC formulation compared with the IV form (6.8% vs 3.4%) developed antidrug antibodies. They also cited 2 trials that evaluated switching between the formulations. In one trial, adverse events (AEs) were similar in patients switched from SC to IV or IV to SC adjuvant therapy for HER2-positive early breast cancer. In a similar study of patients with metastatic breast cancer, there were more AEs in patients during the SC treatment compared with the IV treatment (67.6% vs 44.1%).

Each formulation may offer “unique advantages to patients depending on their individual needs,” the reviewers wrote. They noted the potential for pain at the injection site associated with the SC formulation, due to the large (5 mL) injection volume, and recommended health care providers discuss this with their patients.

The authors suggested that for patients receiving trastuzumab as monotherapy, SC administration could be a time-saving option in that it requires only 2 to 5 minutes vs 30 to 90 minutes for IV administration.

They concluded that as an adjuvant therapy, the SC formulation probably does not present an advantage in time or convenience to the patient, because trastuzumab would likely be combined with another IV therapy, and in many cases, the patient would have a central venous port in place. Therefore, IV administration could be more convenient for these patients, avoiding an additional injection. Contrary to this practicality, the patients in the 2 formulation-switching studies the authors cited overwhelmingly preferred SC administration (88.9% and 85.9%) over IV administration.

The authors cited 2 time-and-motion studies, 1 in the United Kingdom and 1 in Belgium. Both found higher costs associated with IV treatment compared with SC treatment. Based on the United Kingdom study, the authors estimated that over a full treatment course (18 cycles), SC trastuzumab would cost approximately $2826 less per patient. The authors noted limitations in both studies; in particular, they did not consider the cost of insertion, maintenance, and potential complications associated with IV catheters.

The authors argued that the discussion of cost savings associated with the SC administration route compared with the IV route “have predominantly overlooked the possible cost benefits of IV trastuzumab biosimilars.” However, patent expirations for the trastuzumab reference product were recent (European Union, 2014; United States, 2019), and therefore, they wrote, this limits “a comprehensive assessment of economic benefits.”

A budget impact analysis the authors cited estimated potential cost savings associated with trastuzumab biosimilars in 28 European countries, estimating cost savings between $1.1 billion and $2.74 billion during the first 5 years, and an additional 55,000 to 116,000 patients able to access trastuzumab therapy.

Trastuzumab biosimilars could improve access by giving physicians a lower-cost option to prescribe. According to the authors’ review of the literature, health care providers may be hesitant to prescribe biologics, despite their efficacy, because of their high cost. They cited a 2014 survey that found “nearly half of oncologists would increase the prescription of anti-HER2 biologics across multiple settings if a lower-cost biosimilar was available.”

The reviewers viewed IV trastuzumab biosimilars as having more potential for cost savings compared with the SC formulation of the reference product. “Given the general reduction in cost associated with the introduction of a biosimilar to the market, it is unlikely that the reduced administration costs associated with the SC formulation of trastuzumab will outweigh the lower cost of IV biosimilars,” they wrote.

Waller CF, Möbius J, Fuentes-Alburo A. Intravenous and subcutaneous formulations of trastuzumab, and trastuzumab biosimilars: implications for clinical practice. 

. Published online February 16, 2021. doi:10.1038/s41416-020-01255-z

In a review of trastuzumab treatment options, reviewers concluded subcutaneous (SC) vs intravenous (IV) options may be more costly and sometimes less practical. 

Study: Trastuzumab Biosimilar IV Offers Better Value Than Reference SC

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

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

Number 5: Coherus BioSciences reported that the FDA has 

 its biologics license application (BLA) for an adalimumab biosimilar (CHS-1420), but did not specify the formulation concentration.

Number 4: Frontline use of rituximab biosimilars plus chemotherapy in patients with follicular lymphoma (FL) is 

 than a regimen of obinutuzumab (Gazyva) plus chemotherapy, investigators reported, based on a decision-analytic modeling study.

Number 3: Fresenius Kabi, a Germany-based biopharmaceutical company with global operations, mapped out an ambitious biosimilar launch program as it released 

Number 2: Fresenius Kabi has launched an adalimumab injectable biosimilar (Idacio) in Canada. The launch is the 

 launch in a week, right after Sandoz’ launch of Hyrimoz.

Number 1: Gary H. Lyman, MD, PhD, provides an 

 on overcoming the challenges of discussing biosimilars with patients.

To read all of these articles and more, visit 

Videos

The Top 5 Biosimilar Articles for the Week of February 22

Coherus BioSciences said its pegfilgrastim biosimilar Udenyca now commands a 21% share of the overall US market for this agent and a “nearly 50%” share of the prefilled syringe segment. Company executives said they hope to begin chipping away at the market for Amgen’s Neulasta Onpro, a wearable pegfilgrastim injector kit, if the pandemic eases and conditions return to normal.

 Udenyca sales of $476 million for 2020 vs $359 million for 2019. In addition, Udenyca sales for the fourth quarter of 2020 were $110 million, down from $124 million in the comparable 2019 quarter. Coherus attributed the decline to COVID-19–related issues and anticipated that full-year 2021 Udenyca sales would be lower than in 2020, also because of COVID-19.

“Certainly, COVID-19 made 2020 a difficult year for Udenyca, impacting our ability to grow market share as planned in the face of new competitive entrants,” Dennis M. Lanfear, president and CEO, said during an earnings 

The bottom line, said Chris Thompson, executive vice president of sales, is that Coherus must hold the line on average sales price 

for Udenyca to maintain a robust profit margin, although some price decline is anticipated. "The most challenging variable for us to forecast and the one over which we have the least control is, of course, price. That said, our goal is to remain disciplined, as we have been, in our long-term management of ASP while also remaining competitive. We would expect our competitors to operate in this rational manner as well."

The company is anticipating upward growth in Udenyca sales to resume in the second quarter of 2021, as conditions return to normal and the COVID-19 advantage starts to fade for Onpro, which has enabled patients to receive pegfilgrastim injections at home, sparing them the risk of infection from a trip to the clinic—although the injector kit is less reliable that clinic injections. “We expect that, as COVID-19 recedes, we will resume market share growth, largely coming at the expense of the Neulasta Onpro,” Lanfear said.

Lanfear also discussed pipeline projects to bring other biosimilars to market. He noted that the FDA has accepted the company’s biologics license application (BLA) for an adalimumab biosimilar (CHS-1420), referencing Humira and indicated for rheumatologic and gastrointestinal disorders. The FDA has set a December 2021 decision date for the BLA.

“After years of double-digit price increases with Humira, there is clearly significant pent-up demand” for a lower-cost biosimilar. There are multiple approved adalimumab biosimilars, but none of these will be available before 2023. Recently, Vizient predicted a 7.5% increase in the price of Humira before biosimilars do reach the market.

“There will be a payer-driven dynamic, and they are heavily incentivized, too, for switching from the brand to biosimilars,” Lanfear said. He added Coherus aims to achieve a 10% share of the US market for adalimumab.

Coherus is partnering with Bioeq on development of a ranibizumab biosimilar, referencing Lucentis. The drug is used for the treatment of macular degeneration. A 2021 midyear FDA application submission is planned.

The company also has a bevacizumab biosimilar in development (IBI-305), referencing Avastin and indicated for the treatment of various types of cancer. This project is in conjunction with Innovent. A pharmacokinetics study is underway.

Additionally, company executives expressed optimism for a recently announced partnership with Junshi Biosciences of Shanghai, China, to commercialize toripalimab, an anticancer PD-1 antibody, in the United States and Canada. Toripalimab is indicated for second-line treatment of unresectable or metastatic melanoma in China. Coherus 

 to commercialize this product and obtain options to market 2 potential other agents in the United States and Canada.

Sales of the pegfilgrastim oncology support biosimilar Udenyca fell off in late 2020, but Coherus doesn't see orginator company Amgen's advantage lasting much longer. 

Coherus BioSciences Squares Off Against Neulasta Onpro

Fresenius Kabi, a Bad Homburg, Germany-based biopharmaceutical company with global operations, mapped out an ambitious biosimilar launch program as it released 

data that showed a 4% decline in net income ($2.2 billion) and 2% growth in sales ($44.0 billion) for 2020.

The company expressed confidence in its potential to make biosimilars an exceptional driver of income in the near future, although company executives described “unprecedented challenges” over the past year of the coronavirus disease 2019 (COVID-19) pandemic that affected performance.

“I am convinced these times will reward corporates who can draw resilience from their large critical infrastructure and well-proven business models,” said Stephan Sturm, CEO, in an investor presentation.

Fresenius has an adalimumab biosimilar that has been launched in 22 countries, most recently 

. In the second quarter of 2021, the product will be launched in Australia; and in the third quarter, Brazil. A US launch is planned in 2023.

The company said its biologics license application for a pegfilgrastim biosimilar was accepted by the FDA and European Medicines Association in May 2020. In those markets, the product is intended to launch in a prefilled syringe in the third quarter of 2021. In 2022, Fresenius hopes to launch a pegfilgrastim on-body injector, a device that has enabled the originator company, Amgen, to capture significant 

“Even though the prefilled syringe launch is important, the planned on-body device market entry is financially significantly more meaningful for us,” Sturm said.

The company has previously announced plans to bring a tocilizumab biosimilar to market, and the anticipated launch date is 2023 in the US and EU markets for subcutaneous and intravenous versions of this. The tocilizumab biosimilar would reference Actemra, for the treatment of rheumatoid arthritis. “The financially more meaningful market for us is the subcutaneous dosage form, since we are currently assuming to lead the competition here,” Sturm said.

Autoimmune biosimilars and an oncology biosimilar are slated for launch in 2024 and 2025, respectively, in the US and EU markets, although further description was not provided in the investor presentation.

Whereas biosimilars are an increasingly important part of Fresenius’ growth strategy, the company has a broad portfolio of therapeutic products in oncology, diabetes, critical care, liver and renal insufficiency, among others.

The Germany-based company with global operations plans to ramp up its biosimilars portfolio through 2025. 

Fresenius Kabi Maps Out Biosimilar Strategy

Frontline use of rituximab biosimilars plus chemotherapy in patients with follicular lymphoma (FL) is more costly than a regimen of obinutuzumab (Gazyva) plus chemotherapy, investigators reported, based on a decision-analytic modeling 

The study was conducted by assuming biosimilar rituximab agents were used in place of reference rituximab in the GALLIUM trial, which evaluated originator rituximab (Rituxan) vs obinutuzumab, both in conjunction with chemotherapy in the upfront setting. Rituximab is an older therapy, approved for first-line treatment of FL in 1997, and obinutuzumab was approved for advanced untreated FL in 2017.

provided evidence for longer progression-free survival (PFS) for patients with untreated, advanced FL who received the obinutuzumab regimen (G+chemo) vs the rituximab regimen, although grade 3-5 adverse events were more numerous with obinutuzumab. The 3-year PFS results from GALLIUM were 80.0% vs 73.3% for patients on G+chemo vs the rituximab regimen, respectively (HR 0.66; CI, 0.51-0.85; 

Investigators used GALLIUM as a model to evaluate potential savings and improvement in quality adjusted life years (QALY) for the rituximab biosimilars Truxima (Ra+chemo) and Ruxience (Rp+chemo). In the context of QALYs gained and cost savings that accrued from delayed disease progression, G+chemo proved to be the more cost-effective treatment, they said.

The model suggested that G+chemo would result in longer PFS and overall survival vs the rituximab biosimilar–based regimens 

. Although the overall cost of rituximab-biosimilar plus chemo options was less than for G+chemo, the incremental cost effectiveness ratio (ICER) for G+chemo was within commonly accepted thresholds for cost-effectiveness.

“Our results from the model indicate that G+chemo continues to offer good economic value, including improved patient outcomes, compared with R+chemo or equivalents based on rituximab biosimilars, and that value-based policy decisions should consider G+chemo as standard of care for patients with untreated FL,” the authors wrote.

A chief factor driving the cost-effectiveness outcome for G+chemo in GALLIUM was the “significant and clinically meaningful difference in PFS,” which the authors noted contributed to the additional QALYs deriving from use of this regimen.

Second, although the incremental costs of G+chemo vs Ra+chemo ($26,978) and Rp+chemo ($21,562) were higher, these differences were not high enough to undermine willingness to pay for the higher cost treatment, based on QALY thresholds. By contrast, in the original GALLIUM trial, the ICER for G+chemo vs the originator rituximab product plus chemo was $2300.

In addition, a cost savings of $7050 was attributed to the delay in disease progression afforded by G+chemo regimen.

Spencer SJ, Guzauskas GF, Felizzi F, et al. Cost-effectiveness of obinutuzumab versus rituximab biosimilars for previously untreated follicular lymphoma. 

. Published online February 17, 2021. doi:10.18553/jmcp.2021.20424.

Although a more costly medicine, obinutuzumab proved more cost-effective over the long run than rituximab biosimilars in follicular lymphoma.

Rituximab Biosimilar Regimen Fails Cost-Effectiveness Test in FL

Communicating the essentials of biosimilars to patients requires background knowledge and the right approach. These lower-cost agents have the potential to save money and improve access to care, but this can be of no avail if patients don’t get the information they need the way they want it.

Gary H. Lyman, MD, MPH, is an oncologist, hematologist, and public health researcher who has long been an advocate for biosimilars and, indeed, has developed guidelines in support of using these biologics for the treatment of cancer. In a recent interview, he shared his insights on conducting the patient-provider conversation about biosimilars and how physicians can prepare themselves to succeed with this encounter.

Lyman is co-director of the Hutchinson Institute for Cancer Outcomes Research in Seattle, Washington; a full member of the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center; and a professor of medicine and medical oncology at the University of Washington. 

CfB: What’s missing from the patient-physician biosimilar conversation, and what are the essentials of communicating a patient’s biosimilar options successfully?

 I’m speaking primarily from an oncology perspective, but I’ve been involved with biosimilars from day 1. It’s important to focus on education and convince patients and providers about the enhanced regulatory process for molecular characterization, both structurally and functionally, of these agents. It’s far more sophisticated than it was 20 years ago when the first biologics were approved based largely on clinical comparative trial data. The FDA, and I’m in support of this, feels that there is sufficient depth of clinical data for demonstrating efficacy and safety once you fully characterize the molecule and its structural [and] functional characteristics and critical quality parameters. There are now dozens of these that the FDA is using to classify these biosimilars as highly similar to the originators.

Biosimilars get approved with data on pharmacokinetics, pharmacodynamics, and immunogenicity, and these trials are often done in patients with disease, but also in healthy volunteers, because at least in the oncology space, problems may not be as apparent in an immunocompromised patient who has been on chemotherapy or radiation therapy. Clinical comparative data are used to fill in any gaps of remaining uncertainty about the safety and efficacy of these agents to demonstrate that they are essentially the same as the originator molecules.

When talking with the patient, the challenge is to communicate a lot of this comfort with the regulatory process and the integration of biosimilars into treatment guidelines. ASCO has recently published an updated guideline in early stage breast cancer and [human epidermal growth factor receptor 2]–positive breast cancer that basically said the 5 approved trastuzumab biosimilars in the United States can be used equally or alternatively to the originator [Herceptin] without any concern about loss of efficacy and safety.

We have all that, and I communicate that to patients, along with my personal comfort with these biosimilars. But patients have many different levels of background and education, and the challenge is to communicate this information in a simple, nontechnical fashion. Many doctors don’t understand some of the terms, such as 

. Even if the doctor has a science background, communicating biosimilar information to patients in any kind of depth is going to be a big challenge. We’ve encouraged professional organizations and health systems to develop targeted educational materials, such as pamphlets, that summarize these points in lay language.

It’s also important to make clear that no major safety issues have been raised with biosimilars. There has been no withdrawal of agents from the market. We really need to reassure patients that the experience to date tells us that these are safe and efficacious. 

I do tell patients that biosimilars are approved with less clinical data than was used to approve the original agents, but those reference products were approved years ago when our technology was not nearly as good. Even so, there could be rare or delayed adverse events that emerge that you did not see in the limited clinical data used for biosimilar approval. I tell the patient, even if it seems unrelated to your treatment, let us know. We need to know if you’re having any unexpected symptoms or signs or concerns as time goes along.

Of course, the FDA is doing a lot of postmarketing surveillance of these agents. Each biosimilar is given a random 4-letter suffix that is used to track the performance of these products very closely. For Herceptin and the 5 approved biosimilars, you want to know which was given to the patient who developed a rash or some adverse event, and you can do that by being able to go back to the specific name and label given the biosimilar. But it’s traceable, and with the data capture, through patient-reported/physician-reported adverse events to the FDA, and just patients telling their doctor about problems, we hope that anything that’s slipped through inadvertently can be tracked and quickly pinned down if it has anything to do with the drug patients have received. Communicating all of this to the patient in a nontechnical fashion is a challenge.

One other issue is that biosimilars are biologic substances that cannot be reproduced exactly like a generic, and that’s one of the starting points I take with patients in communication. Biosimilars are not produced like generics in a test tube in the laboratory They’re produced in living systems like the originator biologic, and small differences will inevitably occur. And over time, there can be what we call drift in the structure and functional nature of these molecules.

Any small change in manufacturing, in the components that go into manufacturing these agents, could potentially change the molecular structure of these, although mostly this will not impact  the functionality or the toxicity of these agents. You cannot assume that automatically, so the FDA mandates that changes in components or processes of the biosimilars and originator products be reported and evaluated to make sure no critical aspect of the molecule has been changed. I think everybody’s very much attuned to making sure that we track these molecules, these biologic substances, over time to make sure they’re the same as the original.

It’s very difficult in a 15-minute office visit to communicate this level of information, and even physicians are not necessarily always comfortable explaining this, so I think having this information in nontechnical language, written out, simple and short, and then allowing patients an opportunity to look it over and ask any questions that they come up with is a really critical part of our communication, rather than just throwing out a whole lot of jargon very quickly, which causes them to glaze over. They may not want to ask questions or they won’t know what to ask.

CfB: Do you find that the literature that you’re provided for this purpose is adequate, clear, and helps to ease patients’ concerns?

We’ve developed some of our own, locally, and I know ASCO has, and I’m sure other professional organizations have done so, and they use outside observers, generally patient advocates or patients themselves to review it and validate the information or the conveyance of the information. I do think that, at least in many instances, due diligence has been done to make sure it’s comprehensive and understandable. That’s not to say it can’t be better.

I know that the Biosimilars Council and other organizations have worked on this as well. I think we all have the same goal: to make sure that patients fully understand about biosimilars and that they’re partners in this effort to improve access and reduce costs, but also to make sure safety and efficacy are maintained with these complex molecules. The information is available, but like anything else, it probably can continue to be improved over time—in particular, making sure that patients get their questions answered.

CfB: How are patients reacting? Are they throwing up their hands and saying, “Look, I just want to go with a brand drug. It’s so much easier”?

It can be a problem. As I said, patients come in all shapes and sizes and backgrounds. It ranges between 2 extremes, one being they don’t want to know anything. “Just tell me what to do, doc. Tell me what to take and I’ll do it. I don’t want to know too much about it.” At the other end, I’ve had patients come in with a whole laundry list of questions because they were told they were going to get a new drug. They come in and say, “Oh, you know, I need to know all this stuff.” Most patients want to know or at least be told. You may have to quiz them or ask a couple of targeted questions to make sure they’re comprehending, or just to reinforce.

Most patients are in that middle ground. They’re going to trust you. The most common question I get is, “Would you give this to your wife or your mother?” and I’m generally able to say “Absolutely. These are perfectly safe and effective.” You can’t put that into the pamphlet, but for most patients, if they have any questions, they’re probably going to be of that nature rather than the technical ones. They do want to know they’re not being sold a bill of goods and being given a drug purely because it’s cheaper. I and my colleagues feel the same way. We don’t want to use biosimilars just because they’re less expensive.

CfB: Is there enough information out there to convince providers that biosimilars are safe and efficacious? Are you satisfied with the FDA’s decisions on biosimilars, outright?

I am satisfied with the process, and the sophistication of the preclinical work that’s done is just light-years ahead of where things were when we approved Herceptin, Rituxan, Avastin, and many other original drugs. It’s just night and day, so that really reassures me. But given all that, I still am a strong believer in postmarketing surveillance, and the FDA has taken some recommendations from us and others to use big data for that. They‘ve engaged with CancerLinQ, the ASCO big data system. They’re working with Flatiron and other commercial big data suppliers.

I don’t think we can ever assume that because a study of 300 patients didn’t show some rare, serious, long-term adverse event, that it wouldn’t emerge when you have tens or thousands of patients taking this—often patients with more comorbidities than were included in the pivotal trials. As much as I’m comfortable with the process and the need to use biosimilars the way we’ve embraced them, it’s important not to let our guard down, and I think that’s reassuring to patients as well, to be able to tell them there are continuing efforts to monitor these agents very closely. 

CfB: Should you be completely honest with patients and tell them whether they’re getting a biosimilar or an originator?

I think you should. If you’re changing a patient from what they were getting, it’s absolutely crucial, because if you don’t, a nurse will tell them, or they’ll know from the bag, the prescription label, or the color of the medication. Or they’ll get a bill that mentions the drug that they’re taking. Trust is gold when it comes to communicating with patients. Otherwise they won’t be confident in your care.

Even when you’re starting a patient off on a biosimilar, it’s still worth the effort to explain, along with a brochure that details the process. And you should tell them that they can call any time if they have more questions, because you’re very comfortable that the treatments they are getting are as good as anything available for their disease. With only rare exceptions, you should be open and honest and tell the patient what they’re getting. If it’s a biosimilar, you can tell them that without spending an hour doing it.

CfB: What can doctors do if they feel they need more preparation for the conversation with patients about biosimilars?

It’s 3 words: education, education, education. There are a lot of education materials out there, but it’s such a rapidly changing area. Many biosimilars have come along already, and we can expect more in 2021. Keeping up with that is not an easy task, just like all of medicine. We’re in a biologics revolution. Generally, with targeted small molecules or biologics, continuing education is just absolutely at the core of being an oncologist these days, and it’s true for biosimilars as well.

I’ve been privileged to chair an ASCO task force on biosimilars in educating oncologists on biosimilars, and we’re in the process of updating our original statement paper. I believe there’s a substantial segment of the professional community, including my oncology colleagues, who have not looked at the issue as deeply as I wish they had. And it’s understandable. The rate of change we are talking about here is not just biosimilars; it’s all of biologics itself—cancer, therapeutics, diagnostics, molecular testing, and so forth. I think we’re all kind of struggling with how do we attract that 50%, or maybe it’s even more, of oncologists who haven’t really dived in and fully educated themselves on biosimilars such that they can discuss them with comfort and reassurance to their patients.

Gary H. Lyman, MD, PhD, provides an expert overview on overcoming the challenges of discussing biosimilars with patients.  

Filling in the Blanks: The Patient-Provider Conversation About Biosimilars

Reference adalimumab (Humira), developed by AbbVie was approved by the FDA in December 2002 and quickly became a blockbuster drug used to treat 12 rheumatic and inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Biosimilar competition overseas has eroded much of AbbVie’s international market share. Humira’s patent thicket and settlements have shielded the drug from US market competition posed by biosimilars until 2023. Additionally, AbbVie developed and received approval for a high-concentration, citrate-free formulation, which has rapidly become the dominant form of adalimumab, posing an additional challenge to biosimilar competitors.

However, Celltrion Healthcare and Alvotech are positioning themselves to be the leaders in high-concentration, citrate-free adalimumab biosimilars, with Celltrion getting the greenlight Yuflyma in mid-February 2021 from the European Union to enter the market. With new versions of adalimumab on the horizon, what will this mean for the market and the biosimilars already marketed and in the US’ pipeline?

We sat down with Sarfaraz Niazi, PhD, an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, and founder of Karyo Biologics, Adello Biologics, and PharmSci, to discuss the implications for the adalimumab market and patients.

To learn more about Celltrion's EU approval, click 

To learn more about Alvotech’s high concentration adalimumab, click 

To learn more about high-concentration citrate-free adalimumab products, click 

We sat down with Sarfaraz Niazi, PhD, an adjunct professor and biosimilar industry expert, to discuss the potential impact high-concentration adalimumab products could have on the US market.