Tony Hagen is senior managing editor for The Center for Biosimilars

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.

Articles

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

Virtual ISPOR

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.

Regulators Look Back on 15 Years of Biosimilars in Europe

Boehringer Ingelheim believes it is on its way toward gaining perhaps the first interchangeable designation for a biosimilar, based on 

, a phase 3 randomized study that compared pharmacokinetic properties for the adalimumab reference product (Humira, RP; 40 mg/0.8 mL) with those of the adalimumab biosimilar Cyltezo (BI 695501) in patients with moderate-to-severe chronic plaque psoriasis.

Patients received RP continuously or switched between the biosimilar and RP, and investigators concluded that patients who were switched multiple times between RP and Cyltezo experienced similar clinical outcomes in terms of pharmacokinetics, efficacy, immunogenicity, and safety.

“This study is, to our knowledge, the first to report outcomes that meet the US FDA’s criteria for interchangeable biologic designation,” investigators stated in findings presented at the American Academy of Dermatology 2021 virtual meeting this month.

There are 29 FDA approved biosimilars but none of them has an interchangeable designation, meaning that, depending on individual state laws, pharmacists could fill prescriptions with biosimilars rather than the originator product without approval from the prescribing physician. It is generally assumed that the lack of interchangeable designations is a chief impediment to patient and physician confidence in biosimilars, which are FDA approved as being “highly similar” to originator brands, and just as safe and efficacious, with no clinically meaningful differences.

For an interchangeable designation from the FDA, a biosimilar is “expected to produce the same clinical result as the reference product in any given patient” and “not present greater risks in terms of safety or diminished efficacy from alternating or switching between the interchangeable candidate and reference product,” Boehringer Ingelheim noted, quoting from FDA guidelines.

Cyltezo was approved in 2017 and is scheduled for launch on July 1, 2023, based on a settlement with AbbVie. Boehringer Ingelheim anticipates an FDA decision on the application for interchangeability in the fourth quarter of 2021.

In VOLTAIRE-X, investigators evaluated area under the curve (AUC), or drug concentration over time in the bloodstream; Cmax, or peak concentration after administration of the first dose; presence of anti-drug antibodies (ADAs), a measure of immunogenicity and the body’s response to adalimumab; and presence of neutralizing antibodies (nAbs), which can diminish or boost biosimilar effectiveness.

They randomized 238 patients to the switching (n = 118) or continuous treatment (n = 120) arms. In the switching and continuous treatment cohorts, the adjusted mean AUC was 2025.83 μg.h/mL vs 1925.90 μg.h/mL, respectively (ratio of adjusted means, 105.19%; 90.2% CI, 96.58-114.64).

Adjusted mean Cmax was 7.08 μg.h/mL and 7.00 μg.h/mL in the switching and continuous arms, respectively (ratio of adjusted means, 101.14%; 90.2% CI, 93.26-109.70). Investigators concluded the 90.2% CIs for AUC and Cmax were within the acceptable bioequivalence boundaries of 80% to 125%.

In the evaluation for immunogenicity, investigators found that at week 32 similar proportions of patients had developed ADAs in the switching vs continuous treatment arms (90.2% vs 94.5%, respectively), and nAb results were similar also between the 2 arms (41.1% and 41.8%, respectively).

In the switching vs continuous treatment arms, the proportions of patients who achieved a psoriasis area and severity index (PASI) score of 75 (75% or better showing improvement over baseline PASI scores) were also similar: 84.7% vs 79.0%, respectively (90% CI, –2.45%-13.96%).

The proportions of patients with physician global assessment (PGA) scores ≤1 at week 32 were also similar between the switching and continuous treatment arms: 70.3% vs 64.7%. The PGA is 5- to 6-point measure for disease severity.

On safety, investigators noted that following randomization, the percentages of patients who experienced at least 1 treatment emergent adverse event (TEAE) were similar in both arms (56.8% and 62.5%, respectively). A slightly higher percentage of patients experienced drug-related TEAEs in the continuous treatment arm (18.3% vs 11.9%).

Menter A, McCabe D, Lang B, et al. Phase III, randomized trial comparing clinical outcomes between patients with moderate-to-severe chronic plaque psoriasis receiving adalimumab reference product continuously versus those who switched between BI 695501 and adalimumab RP. Presented at: American Academy of Dermatology 2021; April 23-25, 2021. 

American Academy of Dermatology

The results of Voltaire-X could persuade the FDA to authorize automatic substitution of the adalimumab biosimilar Cyltezo for its reference product (Humira), investigators believe. 

Cyltezo Is a Contender for First Interchangeable to Humira, Boehringer Ingelheim Says

An ongoing real-world observational study of bevacizumab biosimilar (Mvasi) vs originator (Avastin) has demonstrated comparable safety and effectiveness for a cohort of patients with metastatic colorectal cancer (mCRC) treated in a US integrated health care system (Kaiser Permanente), according to a poster presentation at the Academy of Managed Care Pharmacy (AMCP) 2021 meeting. 

Patients were enrolled in the study based on initiation of biosimilar bevacizumab between July 1, 2019 and March 30, 2020 (n = 232) or initiation of bevacizumab reference product between July 1, 2015 and June 30, 2018 (n = 1128).

The primary end point was overall survival (OS) and mortality, and secondary end points were treatment persistence, defined as the total number of doses received, time between first and last dose, and the proportion of patients who switched to the reference product. Other secondary end points were the incidence of serious adverse events (SAEs) and hospitalizations and emergency department visits of any type.

Investigators said OS for the bevacizumab biosimilar cohort (82.8%) was noninferior to that of the reference product group (81.7%), based on a 4% margin of acceptability. They said that between the 2 groups, there were no significant differences in treatment persistence, SAEs, or hospitalizations and emergency department visits.

They said the study successfully captured real-world outcomes for patients treated with bevacizumab biosimilar immediately after the product was launched. They also said a strength of the study was its use of a large historical control group. Limitations of the study included that it was observational, which is not considered as reliable as a clinical study, and that it had a relatively short follow-up period, investigators said.

Pham C, Chiu T, Ekinci E, et al. Real-world evaluation of biosimilar bevacizumab-awwb versus bevacizumab in patients with metastatic colorectal cancer in a U.S. integrated healthcare delivery system. Presented at: AMCP 2021; April 12-16, 2021. Accessed April 23, 2021. https://amcpannual2021.pathable.co/organizations/7nYnTLzA3j3JZpccw#/?limit=10&sortByFields[0]=isPinned&sortByFields[1]=lastActivityAt&sortByOrders[0]=-1&sortByOrders[1]=-1&uid=pAcLoMw6BXog7ypr6

AMCP: Academy of Managed Care Pharmacy

Investigators tapped health system data to conduct an observational, real-world comparison of bevacizumab (Mvasi) vs the reference product (Avastin). 

Kaiser Permanente Study Demonstrates Equivalence for Mvasi

It’s going to be an issue for accessibility of medicine if competing companies won’t produce biosimilars of drugs that aren't as lucrative as biosimilars of blockbuster medicines, a panel of European experts said at the Medicines for Europe Biosimilar Medicines Virtual Summit 2021.

“It’s well known that development costs of biosimilars are very high compared with the development costs of generics,” said moderator Adrian van den Hoven, director general of Medicines for Europe. “Are we, in Europe, going toward a market where biosimilars will be up only against very big blockbuster biologics, whereas the smaller, more medium-size biologics won’t be worthwhile?” he asked.

In Denmark, the market for biosimilars is small (population 6 million), and yet there has been robust interest from biosimilars developers. Health authorities have to be careful not to get into a situation where prices are too low that companies might withdraw their bids to supply biosimilars, said Dorthe Bartels, senior strategic advisory at Amgros, the national procurement organization for Denmark. 

However, she said, a positive sign is that in China many companies are developing biosimilars for a broad range of biologics that are not limited to the most lucrative of biologics. 

Given the high cost of developing biosimilars, manufacturers might have minimum sales revenues requirements, which could preclude them from producing biosimilars for relatively minor indications, said Phillip van Wilder, a professor at Université Libre de Bruxelles School of Public Health in Belgium. This issue is connected to the problem of sustainability of biosimilars and needs to be part of the general discussion, “because it’s something where resilience is necessary,” he said.

Europe may be perceived as a place where biosimilars have in general been widely accepted, compared with the United States, and yet biosimilar success varies across EU member states. Panelists discussed the value of “top down” approaches to impose the use of biosimilars where market dynamics appear not to be working.

The European Union as a whole cannot force the use of biosimilars on member states, but it can influence biosimilar uptake via recommendations issued to countries that receive money from the European Union, van den Hoven said. “Many EU countries are now in the situation where they are receiving recommendations from the [European Commission], so should the commission be recommending or telling member states “you should have more biosimilar competition in your market?” he asked.

Bartels said that based on the Denmark experience, it might be better to use an education approach to communicate to stakeholders the gains that have been achieved by using biosimilars. For example, in Denmark, the country has achieved an initial 85% discount on the cost of originator adalimumab. “In the rheumatoid arthritis area, around 15% more patients have gained medicine, because we have introduced biosimilars, so maybe the story should be around the success of introducing biosimilars and the treatment for patients,” she said.

Have conversations with physicians and patients about switching to biosimilars and provide information that supports this education and influences behavior.

Use a top-down policy approach that provides a structure for biosimilar uptake.

Plan everything over time so everybody is prepared, because then you have people with you instead of against you. And you can do things regionally, nationally, or even in just one hospital.

Use a holistic approach that incorporates biosimilar company contracts (tenders), hospital finances, communication, and quotas.

A somewhat authoritarian policy that imposes biosimilar uptake could be of value in some Central Europe countries where biosimilar competition has not evolved as hoped, said panelist Tomas Tesar, an associate professor of pharmacy with Comenius University in Slovakia. There tends to be segmentation in these markets where originator biologics end up not competing head-to-head with biosimilars. “These are issues which could be solved by a top-down approach,” Tesar said.

Biosimilars have been approved as monotherapies for various indications, but more and more, pharmaceutical companies are developing combination medicines, and the panel viewed this as an opportunity to channel more biosimilar use, because these combinations of 2 or more drugs, which end up getting approved by regulators, could include 1 or more biosimilars from the get-go. The use of biosimilars has the potential to bring down the cost of these combination therapies. “We’ve seen in some countries, mainly in the United Kingdom, that expensive innovator compounds used in combination with biosimilar versions are cost-effective and are therefore accessible to the patients,” van den Hoven said.

This is happening in Denmark, Bartels said. Biosimilar use is written into applications for marketing of biologic combinations. “I think that’s actually the way forward. It will be cheaper for all of us.”

Combining innovator products with biosimilars as a concept appealed to other members of the panel. However, “we need to find a policy in which there is at least some competition in the market between various providers of the same products,” van Wilder said.

European countries have tender systems that allow drug companies to bid to obtain near exclusive license to supply drugs, although countries also work with multi-tender agreements that allow more than 1 supplier. In Denmark for adalimumab, although it is a small country, the tender was awarded to 2 bidders because of concerns that a single supplier might not be able to supply the whole market consistently. For now, that’s the only multi-supplier arrangement in Denmark, Bartels said, but it’s possible it might be tried with other drugs.

Europe has biosimilars approved for 17 different originator drugs, and another 30 innovator biologics are expected to lose market exclusivity over the next 10 to 15 years, according to IQVIA. Van den Hoven asked the group to speculate whether or not the next wave of biosimilars can be incorporated into practice with greater ease than the ones that came before.

Ireland is still on the beginning end of the biosimilar adoption curve, said Bernard Duggan, a chief pharmacist with Trinity Centre for Health Sciences at St James’ Hospital in Dublin. “We’ve come a long way in the last 2 years.” That experience likely could make uptake of the next series of biosimilars much swifter, he said. “I supposed we’ve learned a lot as we’ve gone through the process. It’s not one-size-fits-all. There will be slight nuances that need to be considered, but I think we have a framework here now that, if we’re called upon again, could be used to promote further uptake of other biosimilar medicines.”

The European Union is a diverse market with pockets of biosimilar resistance but also cost-saving triumphs, panelists said at the Biosimilar Medicines Virtual Summit 2021.

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