Tony Hagen is senior managing editor for The Center for Biosimilars

With its sights set on launching a high-concentration, citrate-free formulation of adalimumab in the European Union this year, Celltrion Healthcare presented positive 1-year results confirming equivalence of the biosimilar (CT-P17, Yuflyma) in patients with rheumatoid arthritis (RA) at EULAR 2021.

Celltrion hopes to gain a share of the lucrative market for high-concentration, citrate-free adalimumab (Humira; AbbVie), which has been displacing sales of lower-concentration adalimumab since 

. The Incheon, Republic of Korea, company would be the first to launch a biosimilar formulation of the high-concentration 100-mg/mL adalimumab product.

“We anticipate launching Yuflyma in 7 European countries, including Germany and France, in the third quarter of 2021 and in 3 additional European countries, including Italy, in the fourth quarter,” Celltrion told The Center for Biosimilars

No date for a US launch has been established so far; however, access to the US market is tightly controlled by the originator company’s extensive patent portfolio on adalimumab, and lower-concentration formulations are not expected to debut in the United States until 2023.

The randomized, double-blind, phase 3 trial for Yuflyma presented at EULAR, the annual European Congress of Rheumatology, met primary and secondary end points for efficacy, pharmacokinetics, safety, and immunogenicity, demonstrating outcomes comparable to reference adalimumab in patients (N = 648) with moderate to severe RA despite methotrexate treatment.

Patients were randomized 1:1 to receive a 40-mg dose of the biosimilar or reference adalimumab every 2 weeks through week 24. At week 26, patients were randomized again to treatment maintenance on the biosimilar (n = 303) or reference product (n = 153), or a switch from reference adalimumab to Yuflyma (n = 151). This round of treatment continued through week 48.

Demonstration of equivalent efficacy and comparable safety of CT-P17 to EU-sourced adalimumab in this study supports the ongoing clinical evaluation of CT-P17 as an adalimumab biosimilar.

For patients receiving maintenance therapy and those switched from reference adalimumab to Yuflyma up to week 52, the investigators reported comparable efficacy in terms of American College of Rheumatology–defined response rates for reduction in joint swelling and tenderness.

Similarly, drug concentrations at the lowest point prior to redosing (C

) also were comparable in all 3 treatment groups. Observed mean C

 levels fell within parameters reported for reference adalimumab (5-8 mcg/mL).

Safety profiles for patients receiving Yuflyma also were comparable. The most common treatment-emergent adverse event (TEAE) was neutropenia. Injection site reactions, hypersensitivity/allergic reactions, and infections also were similar to established TEAEs for reference adalimumab.

The investigators said antidrug antibody (ADA) and neutralising antibody (NAb) results also were equivalent among patient cohorts. ADA/Nabs were 28.4%/24.8%, 27.0%/24.3%, and 28.3%/26.3% in patients maintained on Yuflyma or reference adalimumab or switched to Yuflyma, respectively.

“Demonstration of equivalent efficacy and comparable safety of CT-P17 to EU-sourced adalimumab in this study supports the ongoing clinical evaluation of CT-P17 as an adalimumab biosimilar,” said Jonathan Kay, MD, a professor at the University of Massachusetts Medical School and the trial's principal investigator. 

In tandem with the trial results presentation, Celltrion stated that the European Commission has granted marketing authorization for the company’s infliximab biosimilar (Remsima) for use without intravenous (IV) infusion for new and existing patients with RA. Remsima received a positive recommendation for approval from the European Medicines Agency (EMA) as subcutaneous therapy without IV loading in adults with RA in March 2021.

Alvotech, a Reykjavik, Iceland–based company, also has developed a 100-mg/mL low-volume formulation of adalimumab (AVT02) but is facing legal action from AbbVie, which has made patent infringement 

 on its AVT02 marketing applications in September 2021 and late 2021, respectively. Alvotech has responded to the AbbVie litigation with a 

 seeking to invalidate Humira patents the company says are unjustified.

Articles

EULAR

Celltrion announces the launch timing for its much anticipated high-concentration formulation of adalimumab and presents trial data supporting equivalence to the reference product.

Celltrion Supports High-Concentration Adalimumab Biosimilar Launch With Phase 3 Trial Data

It is often said that legislators and patient advocates hope the biosimilars market will evolve as successfully as the generic market has, providing for robust competition and price declines that improve access. But a drug industry expert who spoke at the Association for Accessible Medicines' Access! meeting said generic and specialty drug markets, which include biosimilars, are evolving in very different ways.

The high costs of specialty drugs have caused payers and pharmacy benefit managers (PBMs) to develop distribution systems that afford high levels of control over patient behavior and access to these medications. “The PBMs will say to their plan sponsors—the insurers—‘Hey, if you limit the number of specialty pharmacies, limit the number of entities that can dispense this, we can keep an eye on the patient, make sure they’re doing the right thing,’” said Adam Fein, PhD, CEO of the Drug Channels Institute.

“One of the risks they have is a bad policy coming through, not because there’s some sort of bad intent but because there’s just a lack of understanding of what’s happening. 

As a result, manufacturers may end up launching their specialty drugs into limited networks of specialty pharmacies, typically mail order pharmacies, as opposed to the tens of thousands of retail pharmacies that might be involved in the distribution of generic brands.

Another issue affecting distribution of biosimilars is the dependence on rebates, which manufacturers offer as incentives for use of their product over 1 or more rivals. Narrow specialty drug networks and rebates are going to present unique challenges for biosimilar competition over the next few years as the number of biosimilars increases, Fein said.

“There’s a battle for control of the specialty patient," he said. "Biosimilar manufacturers are going to be dealing with payers who now control the dispensing and distribution channels for specialty drugs on the pharmacy side, and that’s going to create a challenge."

Biosimilars are certified by the FDA to be as safe and efficacious as their originator biologics. Once biosimilars start being approved as interchangeable to originators, meaning substitutable for originators without physician approval, the issue of access will become more complex, Fein said.

He cited the example of the 6 FDA-approved adalimumab (Humira) biosimilars scheduled to launch in 2023 in the United States. “One, and possibly 2, of these Humira biosimilars may be interchangeable for specific indications. It’s not clear what that’s going to mean and how the payers are going to play that game, how companies will come to market, how they’re going to price their products, and how the PBMs are going to maximize their own profits to save money for their clients,” he said.

“It’s really going to be a very exciting time for the study of biosimilars and probably a very challenging time if you’re living it,” Fein told the Access! audience, which included a contingent of generic and biosimilar company executives.

There will also be what Fein described as “public policy risk,” because the pace and complexity of the specialty drug market is often far ahead of the working understanding that legislators have, based on his experience. “One of the risks is a bad policy coming through, not because there’s some sort of bad intent but because there’s just a lack of understanding of what’s happening. So, I see that as potentially very problematic for this industry and, frankly, most parts of the pharmaceutical industry and pharmaceutical channel.”

We've reached peak generic penetration. If my math is correct, we’re not going to grow by another 50 percentage points.

If the evolution on the biosimilar side is hazy, so is what has happened on the generic side. Fein said that 5 years ago he could not have predicted the extreme “vertical” consolidation in the pharmaceutical industry or how this would have affected the management of generic drug distribution.

Mergers among industry titans have completely reshaped the way business is done, he said. “These companies are not just horizontally consolidating, with one company buying another company like it. We’ve now seen a dramatic trend toward vertical consolidation. The largest PBMs have integrated with the largest health insurers, which have also become merged with the largest specialty pharmacies and, in many cases, are moving into providing health care services.”

This means that at any level in one of these pharmaceutical totem poles, an entity cannot focus, as before, on maximizing its own profits but must consider the needs of the other members in the chain.

“There’s not a lot of consolidation left to go. There’ll be a few more deals, but we’re getting to a point where it’s going to be hard to consolidate this much further,“ Fein predicted.

Another important consideration is that generics now represent 90% of prescriptions filled, up from 40% 20 years ago, Fein said. He called this state of affairs “peak generic penetration. If my math is correct, we’re not going to grow by another 50 percentage points.”

Government has become the largest payer of all. “More than 40% of all prescriptions in 2019 were paid by Medicare or Medicaid or another government program. This will grow with the aging population. Medicaid expanded enrollment during the pandemic by about 10% to 12%,” Fein said.

Many commercial entities are responsible for the management of government payer programs, and the implication is that their influence will shape these programs, he said. “These are the companies that are controlling access to pharmaceuticals, that are controlling benefit designs that are essentially part of the system. So, keep in mind that if the government does extend its role in health care, you can be pretty sure [this activity] is going to be mediated by the companies that are already the significant contractors for the government in managing health care and, particularly, prescription drugs and generics and biosimilars.”

On the generics side, with peak consolidation, there will be a diminishing number of ways to eke out a profit, to achieve efficiencies that improve margins, Fein said. “The pharmacies will have to work harder and harder to make money dispensing prescriptions. That’s not just a reimbursement challenge. That’s simply an issue of there are only so many dollars they can make when the prescription is $20 or $30.”

A key development amid these industry changes is a snowballing trend toward the use of discount drug cards, such as GoodRx provides. Owing to the rise of generics and the government’s encouragement of generic competition, there has been steep deflation in the cost of small molecule drugs, such that costs of these drugs for many families may never reach coverage thresholds (beyond out-of-pocket costs), whether government or commercial. The average family deductible is $4500, Fein said.

Some consumers may find that they can obtain drugs for less using discount cards than if they rely on their insurance plans, Fein said. This is what's driving even covered consumers to flock to these discount cards. 

Increasingly, health care consumers are using discount cards rather than their health plan coverage for prescriptions, whether it has a prescription benefit or not. That means families and companies are sometimes paying premiums for prescription coverage needlessly. Fein said 36% of people who have commercial insurance use GoodRx instead, and this doesn’t include the many other discount card services available.

In 2016, the retail value of prescriptions GoodRx handled was $700 million in terms of consumer out-of-pocket costs, and that has grown so that this year it will be around $4.5 billion out of pocket, Fein said.

AAM Biosimilars Council Conference

Biosimilar manufacturers may encounter roadblocks in the months and years ahead, and generics manufacturers will find they've hit a ceiling, according to Adam Fein, PhD, CEO of the Drug Channels Institute.

Pharmacy Economist Describes Fork in the Road for Generics and Biosimilars

Investigators reporting on insulin availability in the Philippines said affordability and access are inadequate for many in the Southeast Asia country and recommended measures for improvement, including:

Bargaining with manufacturers for lower prices

Authors of the study, presented at 2021 ISPOR Virtual, said “insulins were affordable in the public sector, but access was affected by low availability.” Private-sector patients faced higher costs compounded by limited competition. Policy and regulatory reviews to improve insulin availability would help, investigators said.

Insulin pricing, availability, and affordability were reviewed in 6 regions of the Philippines following the imposition of a January 2019 value-added tax exemption policy. Insulin prices were compared with international reference prices (IRPs) and affordability was based on the number of days’ wages needed for the “lowest-paid unskilled government worker” to purchase a monthly supply of insulin (10 mL, 100 IU/mL).

The public sector was defined as public hospitals and medicine outlets; and the private sector, private hospitals and retail pharmacies. Mean availability of insulin originator products and biosimilars was 2.8% and 50.0%, respectively, in the public sector and 63.9% and 61.1% in the private sector.

LPG metaformin was the only insulin that met the World Health Organization target of 80% availability in both sectors, and originator versions of most insulins and biosimilars, along with analogue insulins, were not available in the public sector, except for human short-acting and analogue long-acting insulins (2.8% availability in both cases).

All insulin products included in the study were imported, and 3 companies (Eli Lilly, Sanofi-Aventis, Novo Nordisk) accounted for 65% of those products, authors wrote. Vials were the most common form of insulin available (55%), followed by prefilled pens (41.7%) and cartridges (3.2%). Vials were in general cheaper than pens and cartridges, and biosimilars were cheaper than originator products, according to findings.

Insulin in the private sector was 1.05 to 3.66 times more costly than IRPs; in the public sector, prices were uniformly less costly than the IRP. “Purchasing 10 mL of human and analogue insulin in the private sector would need 2 to 4 days’ and 4 to 8 days’ wages, respectively,” the authors wrote.

Although affordability was based on wages of the lowest-paid government workers, the authors noted that “a significant portion of the population earns less than the lowest-paid government worker.”

Virtual ISPOR

There is low insulin availability in the Philippines and investigators recommend policy and regulatory reviews. 

Study Evaluates Insulin Availability in the Philippines

More education about the value of biosimilars for doctors, nurses, and especially patients could help significantly with getting more of these agents into circulation and achieving savings that, in turn, could be plowed into health care system improvements. This observation came from a recent Medicines for Europe expert panel discussion on biosimilar use in Europe.

“Whenever I speak about biosimilars, the prior knowledge of patients makes them believe that I’m giving them something cheaper that is not the same quality, and they will look at me in a way that says, ‘Are you certain you really want to give me that stuff?’” said Matti Aapro, MD, president of the European Cancer Organization. “I think education is extremely important.”

The news about the pharmacovigilance is that there is ‘no news,’ or nothing [untoward] has happened. 

The panelists suggested moving education about biosimilars into early training for health care professionals, such as doctors and nurses, many of whom can influence how patients perceive biosimilars.

“As we know in biosimilars, the switching process is very important for patients to take biosimilars up, because we sometimes see the nocebo effect with patients and they go back to the innovator product, and this could be prevented if you educate your patients the right way, and it’s not just the nurse’s job. It’s about aligning every health care professional to make this happen,” said Johan De Munter, president of the European Oncology Nursing Society and assistant nurse manager in the University Hospital Ghent Cancer Center, Belgium.

Digestive Cancers Europe (DiCE) has done extensive project work to promote the use of biosimilars in colorectal and gastric cancers, and these efforts have involved participation from pharmacy, clinical, industry, and nursing, said Zorana Maravic, acting DiCE CEO. She’s observed  that patients become more supportive of biosimilar use if you let them know that the savings from these often lower-cost agents can be spent to broaden and improve their care and care facilities.

There should be a setting of health care system priorities that says if the drugs are equivalent, you use the cheapest one.

“If you say to a patient a biosimilar saves money for the health care system, this doesn’t mean anything to them; but if you say biosimilars save money and, in turn, facilities can be improved or patients will have an additional nurse or support from a nutritionist or psychologist, this is something tangible for them,” Maravic said.

She recalled an educational meeting with a group of patients that transformed their attitudes toward these agents. “That was really a magical experience, because we were in a room together with 8 or 9 patients, and we organized the session during an afternoon where, I have to say, patients in the beginning were skeptical about biosimilars because, you know, ‘They’re similar but not equal.’

“That was their perception, and then the experts presented the science and the safety and the role of the European Medicines Agency [in approving biosimilars]. And all that information really changed their perspective, and those 8 or 9 patients are now really advocates for biosimilars,” she said.

Europe is ahead of the United States in biosimilar use and has closely studied the pharmacologic effects of biosimilars. European regulators have made good use of this growing body of evidence to help convince a skeptical public that biosimilars as safe and efficacious as their reference products, said Maja Sercic, policy and science manager for Medicines for Europe.

“The news about the pharmacovigilance is that there is ‘no news,’ or nothing [untoward] has happened. So, I think this is such an important piece of information, that biosimilars are actually safe and there were no complications in the last 15 years. So, regulators share this clinical experience. I think that is really the key, and I think it can really comfort the whole community,” Sercic said.

A big theme with the panel was the existing inefficiencies in health care, which they said are quite large in some instances and in serious need of attention. “We think it’s really important to look at the health care budgets overall. Too often—for us and for everybody—it’s difficult to find the data. We don’t know how the money is invested in every hospital, according to the outcomes that happen, so there are a lot of inefficiencies, and it’s important to stop wasting the money,” Maravic said. “I think that biosimilars can contribute to, if not making some surpluses, definitely in decreasing the budget deficit.”

Waste may involve inefficiencies at the practice level, such as preparing drug for patients who do not show up for their appointments, Aapro said.

The savings from biosimilars can be deployed strategically to cut down on overall requirements for care, Maravic said. “Currently we have a budget for prevention, we have a budget for treatment, and we can use the savings from biosimilars and deploy this into screening. We could save money because a lot of cancers would be detected at an earlier stage.”

It costs $4881 on average to treat a patient with stage I colorectal cancer, whereas stage IV disease requires treatment that costs $48,800. Currently just 14% of the population in the European Union has access to screening, and this just shows the value of earlier screening, Maravic said.

Adding to this, Sercic said that optimal use of biosimilars for just 3 molecules routinely used in cancer could save up to $2.9 billion in Europe. “I think that’s a huge value. And I’m not sure if my perception personally is that not everyone is aware how great the potential actually is.”

The panelists suggested a range of core objectives that, if implemented, would get biosimilars used more often and foster trickle-down savings and health care quality improvements:

“There should be no discussion. There should be a setting of health care system priorities that says if the drugs are equivalent, you use the cheapest one,” Aapro said.

“We should reinvest the biosimilar savings locally in a transparent and tangible way, because then everybody would be able to recognize the value of biosimilars,” Maravic said. 

“Experience and best practices among member states will need to be shared. It’s important to translate that experience into the different country settings. And the European Commission can serve as a platform for doing so,” Sercic said.

“Competition is something that has to be sustainable over the long term, so we need to make sure that we will always have a couple of players in the market to make sure this competition takes place,” she added.

Medicines for Europe  Biosimilar Medicines Conference

More transparency in how health care money is spent could improve utilization and efficiency, panelists said at the Medicines for Europe event.

Medicines for Europe Panel Targets Inefficiencies, Need for Education

In a study of infliximab originator vs biosimilar use, the choice of regimens was not significantly associated with treatment success at the 6-month cutoff after initiation, investigators said in findings presented at Virtual ISPOR 2021.

Patients (N = 2806) with rheumatoid arthritis who initiated or switched to infliximab originator (Remicade) or biosimilars (Inflectra, Renflexis) since December 2016 were included in the retrospective analysis. Data were retrieved from the American Rheumatology Network–Trio Health Rheumatology registry.

Investigators said 70% received originator product; 69%, Inflectra; and 31%, Renflexis. They said there were differences in demographic and baseline clinical characteristics between the reference product and biosimilar patients that were significant factors in treatment success, based on multivariable analysis.

According to the study findings, the reference product was used earlier in the treatment process than biosimilars, and a higher proportion of reference product patients were likely to be in remission or with low disease activity when treatment began (66% vs 43% for Inflectra and 43% for Renflexis) or at the 6-month cutoff (75% vs 60% for Inflectra and 56% for Renflexis).

Remicade patients had fewer prior synthetic disease-modifying antirheumatic drugs or biologic regimens (mean regimens, 1.4 vs 2.2 and 2 for Inflectra and Renflexis, respectively; 

Patients on the originator product were less likely to be covered by Medicaid (4% vs 8% for Inflectra and 24% for Renflexis). The originator product cohort also demonstrated a smaller improvement in clinical disease activity score by the 6-month point (–1.6 vs –4.9 for both Inflectra and Renflexis).

Variables that significantly affected outcomes were baseline disease activity, payer types, and use of glucocorticoids, but not the choice of a biologic drug. “Patients with high or moderate baseline disease activity on Medicaid as opposed to commercial insurance and those receiving glucocorticoids were less likely to achieve remission or low disease activity at 6 months post regiment initiation,” investigators said.

Helfgott S, Radtchenko J, Soloman N, et al. Outcomes with infliximab and its biosimilars in patients with rheumatoid arthritis: real-world experience in the US. Presented at: Virtual ISPOR 2021; May 17-20, 2021. Accessed May 21, 2021. https://www.ispor.org/conferences-education/conferences/past-conferences/ispor-2021

Adjusting for variables, investigators found little difference in disease outcomes for patients who switched to the infliximab originator vs biosimilars.

Infliximab Study Yields Evidence of Biosimilar Equivalence

Investigators in Quebec, Canada, say they have found significant costs associated with nonmedical switching (NMS) from originator products to biosimilars in patients with rheumatic conditions. The findings were presented at Virtual ISPOR 2021.

Although the direct costs of switching from an originator to a biosimilar are expected to be lower, given the relatively high costs of originator brands, switching is accompanied by costs of patient evaluations, lab tests and X-rays, additional time spent by health care professionals on education, documentation, hospitalization, emergency department use, workplace productivity loss, and other societal and health care resource utilizations (HCRCs) .

“The true economic impact of originator-to-biosimilar NMS requires the assessment of the difference in costs related to HCRU in addition to those related to the originator and biosimilar drugs themselves,” authors of the study wrote.

The emergence of the study has potential significance for Quebec as it has just announced intentions to 

 most patients from originator biologics to biosimilars with an anticipated savings of US $83 million by 2022. Although the study evaluated HCRU in patients with rheumatic disease, it did not disclose the originator and biosimilar agents included in the analysis.

The study was funded by AbbVie and conducted in part by researchers from AbbVie Canada and from Peripharm, a company that consults with AbbVie and receives AbbVie funding. AbbVie manufactures the adalimumab originator (Humira), indicated for the treatment of rheumatic diseases and ulcerative colitis, and has much at stake in the mandatory switch from originator biologics to biosimilars currently underway in Quebec and 3 other Canadian provinces.

The study findings were reported in Canadian dollars and converted to US dollars for this article. According to results of the study, nonswitchers were associated with HCRU-related costs over a 6-month period of $435 vs $1036 for switchers. Nonswitchers were associated with societal costs over a 6-month period of $1024 vs $1509 for switchers. The total HCRU and societal costs were $1423 vs $2545 for nonswitchers vs switchers, the authors said.

“A patient undergoing an originator-to-biosimilar NMS will incur an additional $1087 over a 6-month period in comparison to patients who remain on the originator,” they said.

Investigators said the main drivers of the difference in costs between those who remained on originators vs those who switched were hospitalization and productivity loss, “with added costs of $465 and $297, respectively, for patients undergoing an originator to biosimilar NMS,” they said.

Other types of costs bear consideration, such as costs associated with adverse events and government costs of implementing an NMS policy, such as physician paid incentives. “It is possible that patients who undergo an originator-to-biosimilar NMS in Quebec are associated with greater costs than what is reported in the current study,” the authors said.

They drew their data from Quebec sources that included governmental publications. They also cited prior UK and Denmark studies of costs associated with nonmedical switching of patients from originator to biosimilar etanercept, a product that also is used for rheumatic diseases and competes with adalimumab.

In the UK study, investigators used a model based on prior data to estimate costs for hypothetical patients who switched from originator etanercept to 1 of 2 etanercept biosimilars (Benepali and Erelzi). Some were assumed to have switched back to the originator or from one biosimliar to the other. A nonresponder population was included, and it was assumed that some patients switched to other types of biologic agents.

 “considerable increases in resource use (procedures and visits) for switching vs nonswitching patients,” although annual per patient costs of Benepali and Erelzi were 92% and 90% of the costs of etanercept originator, respectively.

“Nonmedical switching can result in increased costs to health care payers because of increased healthcare resource use following switching; therefore, switching should be a medical decision based on clinical evidence, and driven by physician decision in collaboration with the patient. Further analyses of the impact of nonmedical switching of etanercept in different markets and over longer time periods are required,” the UK study authors wrote.

 (N = 1620) did a 1-year follow-up of a government-imposed switch of patients with rheumatic conditions from originator etanercept to biosimilar (Benepali). Investigators reported modest increases in use (8%) and costs (7%) of outpatient services after switching, “whereas costs of admissions (55%) and medication (5%) decreased.”

“We demonstrated no obvious changes in overall use and costs of health care services following switch from originator to biosimilar etanercept,” the authors wrote.

Mathurin K, Castonguay A, Parison D, et al. Economic impact of originator-to-biosimilar non-medical switching on health care resource utilization in rheumatic patients in Quebec, Canada. Presented at Virtual ISPOR 2021; May 17-20, 2021. Accessed May 19, 2021. https://www.ispor.org/conferences-education/conferences/upcoming-conferences/ispor-2021

A study funded by AbbVie finds support for maintaining patients on originator rheumatic agents, such as Humira (adalimumab), rather than switching to biosimilars.

AbbVie Study Highlights Switching Costs for Rheumatic Biosimilars

Investigators say they have confirmed the safety and efficacy equivalence of bevacizumab biosimilar Mvasi compared with its reference product (Avastin) in a real-world population of patients with advanced nonsquamous non–small cell lung cancer. The results were presented at Virtual ISPOR 2021.

Investigators studied outcomes in a population of adult patients within the Kaiser Permanente integrated health care network in Northern California and Southern California. Patients were initiated on the biosimilar (n = 58) between July 1, 2019, and March 30, 2020, or on the reference product (n = 295) between July 1, 2015, and June 30, 2018. The primary end point was overall survival (OS) and secondary end points were treatment persistence, serious adverse events (SAEs), and any-cause hospitalization and emergency department visits.

Investigators concluded that OS was not significantly different between the biosimilar and reference cohorts, and there also were no significant differences between cohorts for treatment persistence, SAEs, and hospitalization or emergency department use.

The 6-month OS was 72.1% for the biosimilar cohort and 79.0% for the reference product group (

The incidence of hemorrhaging was 3.5% vs 3.7% for patients in the biosimilar vs reference groups, respectively. The respective percentages for thromboembolism were 5.2% vs 3.7%; severe hypertension, 8.6% vs 12.5%; gastrointestinal perforation, 0.0% vs 0.3%; and congenital heart failure, 0.0% vs 1.4%.

In discussion, investigators said study strengths included the capture of real-world outcomes immediately following the launch of Mvasi; comprehensive access to electronic health records on patient history; treatment and outcomes; and use of Cox proportional-hazards modeling, which offers the advantage of simultaneous analysis of the effects of multiple risk factors on survival time.

Limitations of the study included its observational, or retrospective, design, short follow-up, and small sample size.

For related reading on Kaiser Permanente findings on Mvasi in patients with metastatic colorectal cancer, click 

Pham C, Ekinci E, Chiu T, et al. Real-world evaluation of biosimilar bevacizumab-awwb versus bevacizumab in patients with advanced non-squamous non-small cell lung cancer in a U.S. integrated healthcare delivery system. Presented at: Virtual ISPOR 2021; May 17-20, 2021. Accessed May 16, 2021. https://www.ispor.org/conferences-education/conferences/upcoming-conferences/ispor-2021

The retrospective, real-world study (N = 353) conducted within the Kaiser Permanente network followed the July 2019 launch of the bevacizumab biosimilar Mvasi.

Kaiser Permanente Investigators Confirm Mvasi Safety and Efficacy in Population With Nonsquamous NSCLC

Investigators in Germany said that a comparison of adalimumab biosimilar (Amgevita) vs originator (Humira) treatment for patients with rheumatoid arthritis (RA) has demonstrated significant cost savings both for earlier treatment overall and for use of the lower-cost biosimilar vs the originator product.

Findings were presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2021 virtual meeting, May 17-20, 2021.

RA is a chronic autoimmune condition associated with persistent joint inflammation, organ involvement, significant comorbidities, and “considerable adverse physical, economic, emotional, and social consequences,” authors of the study said. “The negative impact of RA can be cumulative over the course of a patient’s life.”

Investigators sought to weigh the economic effect of delaying the start of biologic treatment for RA and the potential savings from earlier treatment with adalimumab, which would be more feasible with the biosimilar than originator product because in Germany at current prices Amgevita is cheaper than Humira, investigators said.

They said that a 6-month delay in initiation of treatment with biologics was associated with cumulative incremental costs of $8177 per patient, which included loss of productivity. After 3 years, the cumulative costs of delayed treatment were more than $12,146 per patient; after 8 years, the cumulative costs were more than $24,291.

In addition, use of the biosimilar vs the originator product resulted in an overall lifetime reduction in costs (including drug costs, medical resource use, indirect costs, and monetized health outcomes) of $30,519 per patient, and this calculation is based on a 6-month delayed initiation of treatment for the more-costly originator product. This figure also represents a lifetime reduction in drug cost of $26,823 (Amgevita, $199,478; Humira, $226,303). Note that figures were converted from Euro values and rounded. 

“Excluding the monetary value of health outcomes, cost neutrality compared with later treatment with adalimumab at current originator pricing was estimate to be achieved treating 3 years earlier, assuming patients are eligible to receive biologic treatment at that time,” authors concluded.

Investigators said significant savings on hospitalization and productivity loss were possible by initiating treatment earlier in the disease cycle.

“The model demonstrated the value of biologic treatment for eligible patients with RA and that avoiding delays in the initiation of biologic treatment could be cost saving,” they said. “Treating patients earlier may result in better health outcomes in the long term.”

Further, they concluded, “The costs of treating eligible patients earlier with Amgevita at current pricing levels are expected to be offset by later cost savings.”

In the European Union, competing biosimilar forms of adalimumab have been approved for use since 2017. In 2018, non-US sales of Humira peaked at $6.25 billion and began a swift decline. They measured $4.3 billion in 2019 and $3.7 billion in 2020. For a list of approved adalimumab biosimilars in the European Union, click 

Porter J, Stuart P, Bartsch R, Lebioda A. cost-effectiveness analysis of adalimumab biosimilar compared to delayed biologic treatment initiation in patients with rheumatoid arthritis in Germany. Presented at: Virtual ISPOR 2021; May 17-20, 2021. Accessed May 16, 2021. https://www.ispor.org/conferences-education/conferences/upcoming-conferences/ispor-2021

Investigators evaluated both biosimilar vs originator savings and savings from earlier use of a lower-cost adalimumab biosimilar (Amgevita).

German Study Calculates Adalimumab Biosimilar Savings From Earlier Intervention

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

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

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

In 2017 the European Medicines Agency (EMA) instituted a 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

US, EU Regulators Discuss Tailoring Biosimilar Approvals

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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