Tony Hagen is senior managing editor for The Center for Biosimilars

Tony Hagen

China is behind the United States and European Union in terms of biosimilars approved and marketed, but it dominates the Asia-Pacific (APAC) region and potentially could eclipse US and EU rates of biosimilar adoption, according to Quentin Horgan, senior analyst with GlobalData, who 

 on future biosimilar trends at CPhL North America.

China has at least 20 biosimilars on the market currently. The first one to gain approval was a rituximab biosimilar (HLX01; 2019) developed by Shanghai Henlius Biotech. “China saw a further 11 biosimilar approvals between 2019 and 2020, and 2 further approvals as of the first half of 2021,” Horgan said.

China’s positive environment for biosimilars was helped by changes at the country’s National Medical Products Administration, which released the first guidelines for biosimilar development in 2015, 10 years after the European Union, and removed barriers and lowered the cost of biosimilar research and development, Horgan said.

Regulatory policy is critical for biosimilar development and adoption, Horgan said. In the European Union, “The lack of an open and required interchangeable designation means that the moment a biosimilar appears on the market it can be substituted for the reference biologic very easily. This is very different from the United States, where the requirement of an [automatic] interchangeable designation limits the biosimilar’s uptake and makes it harder for pharmacies and payers to substitute.” He said this has caused payers to put biosimilars on lower, nonpreferred tiers.

Shanghai Henlius and Innovent Biologics are the leading biosimilar marketers in China currently, followed by Zhejiang Hisun Pharmaceutical, Sunshine Guojian Pharmaceutical Shanghai, and Qilu Pharmaceutical, he said.

The type of biosimilar products available in China reflect the therapeutic areas for which biosimilars have generally been approved globally, from oncology and immunology—at the top of the list—to musculoskeletal and hematological, toxicology, and, at the bottom of the list, ophthalmology.

Globally, antibodies are the major biosimilar type, representing a 53% share; followed by protein-based biosimilars, 32%; and peptides, 8%.

“The success of adalimumab biosimilars is driving antibody development,” Horgan said. “There are currently 68 adalimumab biosimilars marketed or in development.”

The APAC region accounts for 55% of biosimilar development, Horgan said. China, with a 41% share of APAC biosimilar development, is ahead of India (26%), South Korea (15%), Taiwan (8%), and Japan and Hong Kong (4% each). These figures give China and India a combined 77% share of the APAC market, Horgan said.

This dominance by APAC can be linked to the region’s traditional acceptance of generic drugs, which has made biosimilar uptake easier, he said. Biosimilar use also has been driven by “the need for cheaper pharmaceuticals within these less-economically-developed nations.”

The lack of an open and required interchangeable designation [in the European Union] means that the moment a biosimilar appears on the market it can be substituted for the reference biologic very easily.

Japan is not expected to become a strong, market-driven biosimilar developer because the Japanese harbor a “skepticism of unknown brands” of medicine, he said.

On a global scale, North America holds a 17% share of biosimilar development; and the European Union, 21%. South and Central America have 4%, and the Middle East and Africa, 3%, Horgan said.

Although the global biosimilar pipeline and sales are strong, Horgan said, in the context of other major pharmaceutical trends, biosimilars don’t rank very high. In a 2020 industry survey of emerging trends, they rated a 3.3 out of 5. Highest on the list were immuno-oncology drug development (3.9), personalized/precision medicine (3.9), remote patient monitoring (3.8), real-world evidence (3.8), and telemedicine (3.6).

Ping Cao, senior vice president of Business Development at Shanghai Henlius, about the company's development interests and market perspective. Pfizer, based in New York, was until recently a local player in the Chinese biosimilars market, but this year it withdrew from a substantial 

 there. Awash in revenues from its success with the Pfizer-BioNTech COVID-19 vaccine, the company has taken a 

Articles

Shanghai Henlius Biotech, Innovent Biologics, and other Chinese biopharmaceutical makers are leading the wave of Asia-Pacific (APAC) biosimilar development, according to a GlobalData analyst. 

Analyst: China Leads APAC Region for Biosimilar Development, Marketing

Biosimilars can reduce the costs of cancer care in the United States, which according to one 

 are expected to reach $246 billion by 2030, up 34% from $183 billion in 2015. But providers’ confidence in these lower-cost agents needs stronger support, Albert Kim, vice president of the Commercial Division at Samsung Bioepis, explained in a recent blog.

“It is important that prescribers understand how biosimilars work and why they are safe to use and are able to tell what value biosimilars bring from the patient’s perspective,” he wrote.

Samsung Bioepis has developed multiple biosimilars that are now approved and marketed, including Byooviz (SB11), a ranibizumab biosimilar referencing Lucentis that was approved by the European Commission in August 2021. Byooviz is the first biosimilar for ranibizumab, used in the treatment of macular degeneration and other ophthalmic diseases.

“Biosimilars are a practical solution to the current health care system in terms of providing physicians and patients more ‘choice’ of medicines that have the comparable quality, efficacy, and safety as the reference medicine, potentially saving millions of dollars for health care systems and practices,” Kim wrote.

He is a strong advocate of the policies adopted by Kaiser Permanente, whose payer-provider integrated network has enabled it to promote the use of biosimilars and disseminate reliable information about these agents.

For example, following its approval in 2016, the biosimilar Inflectra (infliximab) had achieved just a 3.2% market share in the United States by 2019. Kaiser Permanente, however, achieved far greater success in getting physicians to use this product. Their usage rate by 2019 was 80%.

Kaiser Permanente attributes this success to multiple reasons:

Building prescriber confidence in its formulary by relying on evidence-based choices and expert opinion

Providing unbiased information about biosimilars rather than allowing physicians to rely on pharmaceutical industry sales representatives

Taking the reimbursement factor out of providers’ decisions about which drugs to use

Working closely with providers, care teams, and patients on treatment decisions

Sharing “biosimilar success stories” to generate appreciation for these products

Kim agrees. “As more hospital networks are looking to transition toward value-based care model, it would be beneficial to have more practices share their success stories with biosimilar implementation and the practical solutions to overcoming operational challenges so that other institutions feel more at ease when they start considering biosimilar implementation, including clinical assessment, electronic medical records integration, economic assessment, and most importantly, ensuring provider utilization and comfort and patient education,” he wrote.

Kaiser Permanente was quick to adopt some biosimilars and slower with others. The payer endorsed the use of Zarxio, a filgrastim biosimilar to Neupogen, roughly 9 months after Zarxio was approved by the FDA. It waited a year before adopting Inflectra, following that biosimilar’s approval in April 2016. And it was close to 2 years after the approval of Mvasi, a bevacizumab biosimilar referencing Avastin, that Kaiser Permanente adopted use of this product. Similarly, Kaiser Permanente adopted Truxima, a rituximab biosimilar, a year after its approval in November 2018.

Kaiser Permanente contends that improvement is needed in incentives for biosimilar adoption and uptake. 

“Converting patients from reference products and overcoming other operational barriers to using biosimilars can be resource intensive. Policy makers may need to provide temporary support to encourage providers to take these steps until a greater level of expertise with biosimilars is achieved,” the company said in a 

Payment issues also need resolution, the company states. “Potentially insufficient or perverse payment incentives that encourage providers and health plans to prefer more expensive reference biologics over biosimilars should be examined and addressed.”

The Center for Biosimilars® covered the Byooviz 

 by the European Commission. Ocular diseases and biosimilars have been a contentious issue lately between payers and eye disease specialists. Ranibizumab was specifically approved for these indications, but the use of bevacizumab biosimilars in these settings is 

Kaiser Permanente got biosimilars into circulation by building physician confidence, a strategy that a Samsung Bioepis executive says should be employed more widely.

Samsung Bioepis Executive Comments on Kaiser Permanente’s Biosimilar Success

Policy developments, business milestones, and physician-led efforts to shape biosimilar absorption made August 2021 an active time for these lower-cost biologics. The following is a roundup of these events.

One of the leading stories was an attempt by the 

 (AAO) to counter payer policies that favor bevacizumab biosimilars for ophthalmic uses. Avastin is the originator bevacizumab brand and has been used off-label for years for intravitreal injections to address eye disease, such as macular degeneration.

There’s a large amount of clinical evidence in support of Avastin use in these settings and very little if any for the bevacizumab biosimilars Zirabev and Mvasi. The Center for Biosimilars

 discussed the AAO’s reasons for opposing use of these biosimilars in an 

 clinical spokesperson and past president of the AAO.

Following the AAO’s protest of these payer policies, 

 that it would no longer prefer bevacizumab biosimilars for eye conditions.

 changes to give preferred status to biosimilars and remove some biosimilars from the preferred list. The moves reflect the changeable nature of pricing arrangements in the pharmaceutical industry.

 surveyed its membership, it put together 

 on biosimilar use. The guidance was conservative about biosimilar switching and substitution at the pharmacy counter and called for physician and patient involvement in decisions about whether biosimilars are used.

Guidance from physician groups is important to help build trust and understanding in the use of biosimilars, said 2 

 on the value of biosimilar education. Misconceptions are slowing the uptake of these products and can be overcome in many ways, they explained, listing recommendations.

 is reportedly considering an adjustment in biosimilar coding that would change individual biosimilar reimbursement to reimbursement based on average prices for a group of biosimilars and their reference products. The move has not been announced officially but reports of the policy change have been circulating in Washington, DC. The Community Oncology Alliance has expressed 

 that such a change would cause prices to drop sharply and force biosimilar companies out of the marketplace.

 asking HHS and CMS to formulate policies to combat high drug prices and drug price inflation, a group of patient advocates asked HHS to consider a 

 for Medicare Part B patients, which they estimated would save seniors as much as $3 billion in out-of-pocket costs.

 on drug price reforms by August 23, 2021, but if it was produced, it wasn’t made public.

is a big player in the biosimilar market and highlights its revenue progress with these agents in every earnings statement. The Center for Biosimilars

 executive director of Marketing and the Global Biosimilars commercial lead for Amgen, about marketplace trends. Some biosimilars are seeing significant uptake and Pettit expressed confidence that the future will bring more biosimilar approvals and savings.

 described a slight easing off in the upward march of 

 in 2020. The finding was based on an assessment of health plan spending. The slowdown most likely had to do with delayed or deferred diagnostic care during the COVID-19 pandemic, increased biosimilar use, and the availability of more generic products, Artemetrx said.

The COVID-19 vaccine game isn’t just for large players, according to 

 a biosimilars development consultant, professor, and entrepreneur. In a 

, Niazi explained that the availability of development information freely provided by COVID-19 vaccine developers, coupled with speedy regulatory approval avenues, makes it possible for smaller companies to step in and clean up.

During the month of August, biosimilar companies partnered with one another in the effort to bring more of these products to market or released information about important milestones in biosimilar development and commercialization.

 provided information about their ranibizumab biosimilar candidate, and 

 set their sights on commercializing an ustekinumab biosimilar. 

 scored an important European Medicines Agency approval to begin marketing the first 

These and other important biosimilars stories reflect the dynamic nature of the biosimilars market during August 2021, and with people returning from summer vacations and getting back to work, the news is likely to move at an even faster pace in September.

Policy developments, business milestones, and physician-led efforts to shape biosimilar absorption made August 2021 an active time for these lower-cost biologics. 

Biosimilars Roundup: Policy and Business Developments Signify a Busy August

Biosimilar uptake would be more successful and swifter if efforts were made to educate patients and providers about them, wrote Sonia T. Oskouei, vice president of Biosimilars for Cardinal Health, and Andrew R. Kusmierczyk, supervisor of Chemistry, Manufacturing, and Controls at Cardinal, in a 

“In order to overcome any potential hesitation with biosimilars from a scientific or clinical standpoint, education will need to be at the forefront,” they said. 

According to the review, the top reasons physicians and patients resist using biosimilars include:

 – This is the tendency of a biologic to provoke an immune reaction that could change the clinical profile of the drug, although “the risk of immunogenicity with switching to a biosimilar has not been shown to be any greater than switching between 2 batches of any [originator] biologic,” the authors said. More evidence would be helpful in addressing provider concerns about immunogenicity.

 – In its approval pathway, the FDA stresses physicochemical characterization of the biosimilar molecule, or “analytical studies,” and underweights clinical efficacy trials, which are less helpful in validating biologic equivalence. Physicians, traditionally reliant on clinical studies, need to be educated on the scientific rigor behind the analytical rationale.

– Biosimilar developers usually obtain approval for just 1 indication of an originator biologic, and after that the FDA is OK with doctors using biosimilars for all approved indications of an originator. “Studies have revealed greater provider hesitation with biosimilar utilization in indications that were granted via extrapolation,” the report stated. Giving physicians more training on critical quality attributes that justify biosimilar approval would alleviate these concerns.

– Biosimilar developers can obtain interchangeability designations for their products, allowing pharmacists to make biosimilar substitutions without physician intervention. “Interchangeability is a regulatory designation, not a clinical one,” the report noted. Education can reinforce the concept that there are no clinical differences between biosimilars and interchangeables.

The report said education can be a powerful factor in getting physicians to employ biosimilars, noting the difference over time in survey responses from gastroenterologists in Europe who were asked to describe their confidence in biosimilars.

In a 2013 study, the majority reported little or no confidence in these agents. Yet, following an extensive EU effort to increase biosimilar knowledge, a 2015 survey revealed “drastic changes” in gastroenterologist attitudes: “47% of respondents felt either totally or very confident with biosimilars in 2015 compared with only 13% in 2013,” the report stated.

“Moreover, the 2015 survey revealed more than a 50% reduction in safety concerns with immunogenicity associated with biosimilars,” Oskouei and Kusmierczyk wrote.

Market adoption of infliximab biosimilars in the European Union also picked up, giving these agents a 50% share of the infliximab market (vs the originator biologic) by 2017, they said.

In the United States, the signs are that understanding and acceptance of biosimilars among rheumatologists has improved significantly. 

A 2016 survey of US physicians (N = 102) who were mainly rheumatologists indicated that just 38% described themselves as “extremely familiar with the FDA’s definition of biosimilars,” which is that a biosimilar is “highly similar to and has no clinically meaningful difference from an existing FDA-approved reference product.” 

A study of rheumatologists in 2019 (N = 320) found that 83% were “very familiar” with the FDA’s biosimilars definition. However, just 34% said they were likely or very likely to switch patients not doing well on the reference product to a biosimilar, which suggests that “a not-insignificant number of US rheumatologists still have knowledge gaps on the concept of biosimilarity,” Oskouei and Kusmierczyk said.

On the patient side, efforts need to be made to overcome the “nocebo effect,” they said. Patients often have never heard about biosimilars and, of those, not all would be confident about using one even if recommended by their physician. 

When patients lacking confidence are treated with biosimilars, there is a documented potential for treatment to fail, and this is described as the nocebo effect. “The magnitude of this effect is not fully understood and could vary with disease state, but several recent studies on infliximab and etanercept biosimilars suggest an effect on the magnitude of 1 in 8 patients,” they wrote.

Negative outcomes from use of biosimilars can feed negative perceptions about them and add to physician and patient hesitancy to use these agents—another reason why efforts have to be made to overcome nocebo through education. 

“The importance of patient education to mitigating the effect has been recognized and researchers are beginning to be able to measure its impact,” Oskouei and Kusmierczyk said.

Overall, in the struggle to boost acceptance via education, data can play a major role. “Data are always the best argument and continued evidence development is rightfully at the top of the list of action items,” they wrote.

– These would help to convince providers about the value of biosimilars and would also work by playing on the leverage that comes from peer confidence. By following good standards, physicians would achieve better outcomes and thereby improve their faith in these products.

 – Data indicate that younger health care providers are less familiar with biosimilars and less likely to prescribe them, so biosimilar education programs during medical training could improve usage. Further, teaching the general public about biosimilars could prepare them to be more accepting of biosimilars if they become patients.

 – Messaging tools with appropriate language can be effective in addressing patients’ concerns.

 – Nurses have been shown to be very influential when it comes to educating and reassuring patients about biosimilars.

Misperceptions of biosimilars contribute to low acceptance of these products. Two Cardinal Health researchers discuss barriers to understanding and the importance of biosimilar education. 

Report: Physician-Patient Education Can Improve Biosimilar Acceptance

Guangzhou, China-based Bio-Thera Solutions has 

 with UK-based Hikma Pharmaceuticals for the commercialization of a proposed ustekinumab biosimilar (BAT2206) for the treatment of chronic inflammation.

BAT2206 references Stelara, which was developed by Janssen Biotech. In the United States, Stelara is approved for the treatment of psoriasis, psoriatic arthritis, Crohn disease, ulcerative colitis, and plaque psoriasis.

Hikma would have rights for US commercialization of BAT2206 and first rights to negotiate marketing in the European Union. “This partnership provides us with a unique opportunity to enter the biosimilar market in the United States,” said Siggi Olafsson, CEO of Hikma.

In July 2021, Bio-Thera announced the first dosing of a patient in a phase 3 clinical study for BAT2206. The randomized, double-blind, parallel controlled study will compare the efficacy and safety of BAT2206 with Stelara in patients with moderate-to-severe psoriasis. Projected enrollment is 472 individuals in the United States and European Union.

Ustekinumab is a monoclonal antibody that suppresses the action of cytokines (interleukin 12/23) that contribute to the body’s inflammatory response.

Bio-Thera is developing biosimilars for bevacizumab (Avastin) and tocilizumab (Actemra), for the treatment of certain cancers and rheumatoid arthritis (RA), respectively. These pipeline products have completed phase 3 trials. The company is also developing golimumab (Simponi; RA), mepolizumab (Nucala; asthma), and dupilumab (Dupixent; asthma, eczema) biosimilars.

Hikma was founded in Jordan in 1978 and now has various FDA-inspected manufacturing sites globally. The company recently acquired Roxane Laboratories in Columbus, Ohio, in a move to build its non-injectables business.

Bio-Thera Solutions has found a partner to help with US distribution of its proposed ustekinumab biosimilar, which entered phase 3 trial development this summer.

Bio-Thera and Hikma Partner to Commercialize an Ustekinumab Biosimilar

Two India-based companies said they have formed a partnership to develop biosimilars for respiratory disease. Their goal is to sell these biosimilars in global markets.

Cipla, based in Mumbai, and Kemwell Biopharma, of Bengaluru, will pair their complementary strengths in product development, clinical development, regulatory filings, manufacturing, and commercialization to develop the biosimilars pipeline, they said.

“This development reinforces our strength as leaders in respiratory therapy and is in line with our aspiration of global lung leadership,” Umag Vohra, managing director and CEO of Cipla, said in a statement.

Cipla is a lung disease specialist with products on the international markets for asthma, chronic obstructive pulmonary disease, allergic rhinitis, and other conditions. The company also produces medicines across multiple other therapeutic categories, including diabetes, women’s health, and tuberculosis.

Besides India, the company has facilities in Africa and North America. The company’s plant in Durban, South Africa, was recently vandalized and looted during the political violence over the jailing of former president Jacob Zuma, but has since reopened.

Kemwell is a contract biologics development and manufacturing company. Kemwell boasts facilities designed in collaboration with German expertise and has partnered with Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer, according to its website. Kemwell has manufacturing plants in Sweden. 

For companies in the developing world, it is important to reassure international clients and markets that facilities and products meet 

Cipla, a medicines developer and retailer, and Kemwell Biopharma, a contract manufacturer, intend to produce biosimilars for lung disorders.

Cipla and Kemwell Collaborate on Lung Disease Biosimilars

Whether payers put biosimilars on formulary, vs originator products, depends in large part on the respective deals they strike with manufacturers over payment. In some cases, biosimilars may be the better deal; in others, originator products.

 for July 2021 helps to illustrate the shifting sands of payer preferences.

A few changes reflect better value obtainable from biosimilars. For treatment of certain cancers, the bevacizumab originator Avastin is now non grata and has been replaced on the CVS formulary by the biosimilar Zirabev.

Similarly, the originator trastuzumab Herceptin has been replaced by the biosimilars Kanjinti and Trazimera.

The formulary also reflects that sometimes one biosimilar will outdo another as far as pricing.

The revised CVS list of options allows the rituximab biosimilar Ruxience in place of Riabni and Truxima, both of which were formerly biosimilar rituximab options and have been removed. The originator rituximab is Rituxan.

The originator insulin glargine Lantus was previously the CVS preferred drug in its class for long-acting diabetes medication; however, this has been replaced by Basaglar and Levemir (insulin detemir).

Basaglar is not officially a biosimilar, as it was not approved under the Public Health Service Act, which encompasses the formal biosimilar pathway legislation. But Basaglar is a “follow-on,” which is a class of copy biologics that may meet the requirements for biosimilarity but have not been approved as such.

Interestingly, Semglee, which the FDA approved this summer as a biosimilar to and interchangeable to Lantus, is not on the CVS formulary list, either as a replacement or former preferred product.

Semglee was originally approved under the nonbiosimilar 505(b)(2) regulatory pathway, in June 2020. Its makers applied for interchangeable status, which they 

, as this offered the product improved positioning for market acceptance.

Further, Lantus has been dropped from the CVS formulary before and has found its way back on, demonstrating that there’s always room for renegotiation between payers, pharmacy benefit managers (PBMs), and manufacturers.

In its updated formulary, CVS has replaced a number of granulocyte-colony stimulating factors, for the control of neutropenia in patients undergoing chemotherapy, with a single biosimilar: Ziextenzo (pegfilgrastim).

The products that got removed from formulary? They were a mixture of originator products and biosimilars. They included Amgen’s originators Neulasta and the Neulasta wearable injection device, Onpro, along with the biosimilars Fulphila and Udenyca.

Udenyca is the flagship biosimilar product for Coherus BioSciences and held a 19% share of the pegfilgrastim market during the second quarter of 2021, down 1 percentage point from the previous quarter. However, revenues for Udenyca were up 6% to $88 million, which goes to show that market share, sales volume, and pricing do not always move in tandem.

The formulary revisions demonstrate that CVS doesn’t dismiss originator products “with prejudice,” meaning permanently, nor does it follow any consistent pattern with biosimilars, although a look at the inner workings of the contracting process and the bottom line attached to each product might be revealing. Unfortunately, that’s proprietary information.

“CVS Health’s PBM relies on a range of strategies to drive towards the lowest net prescription drug cost for our clients and members, including generating more competition through biosimilars,” said Phillip J. Blando, spokesman for CVS, in response to an inquiry from The Center for Biosimilars

. “These strategies helped us keep the rate of growth in prescription drug costs for our clients to less than 3% in 2020.”

In the United States, there are now 30 approved biosimilars, of which 21 are on the market, and this increasing number allows companies such as CVS to play biosimilars off originator products in the effort to squeeze concessions from manufacturers and achieve the lowest-cost deal. Further, there are cost differences between biosimilars that may influence the PBM’s choice of one biosimilar vs another.

of biosimilar approvals in the United States and European Union. 

CVS Caremark has reordered its list of preferred therapeutics, adjusting the emphasis on biosimilars, and demonstrating that preferential status can change at any time. 

CVS Juggles Biosimilar Options on Its Formulary

Guidance from the International Psoriasis Council (IPC) on biosimilars emphasizes a cautious approach to switching patients from reference products (RPs) to biosimilars and retention of physician control when it comes to substitution.

 recommends that switching from RPs to biosimilars in psoriasis should be done only with patient knowledge and agreement.

The IPC notes the FDA’s strong emphasis on pharmacokinetic (PK) and pharmacodynamic (PD) aspects of biosimilars and its tendency to place less value on clinical studies in the determination of biosimilarity, compared with the development of RPs. However, the IPC guidance indicates the group wants clinical evaluations to continue to play a significant role in verifying the safety and efficacy of biologics, including biosimilars.

“Clinical testing for regulatory approval must be conducted in a patient population sensitive enough for the detection of differences in efficacy or safety between the biosimilar and reference products,” authors of the guidance wrote.

The IPC convened a panel of experts (N = 23) on psoriasis and polled them for consensus on a myriad of biosimilar issues, including switching, extrapolation (using biosimilars off label), and physician-patient agreement. The responses were unanimous or near unanimous for almost all topics.

They failed to achieve consensus on the following 2 statements:

Multiple switches between various biosimilars and reference biologics is not the preferred option but is acceptable

Switching between different biosimilars should be performed with caution, until more evidence is generated supporting this practice

“These results indicate that single or multiple switching between biosimilars in patients with psoriasis is still open to argument in the councilors’ opinions,” the IPC wrote.

“Switching clinically stable patients from originator biologics to their biosimilar
alternatives still raises some concerns, although according to the available clinical trials and literature reviews, a single switch from an originator to a biosimilar is not associated with any significant risk or loss of efficacy,” the guidance states.

The IPC guidance called for careful patient monitoring “using a registry and long-term observational studies” to add to the library of evidence and inform on the safety of multiple switches.

Consensus was achieved for 36 of the remaining statements put to the group.

Clinical trial designs should incorporate at least 2 switches between the biosimilar candidate and the RP (96%), they said. And use of biosimilars in diseases for which they were not directly approved (extrapolation) was also considered acceptable (83%), although the IPC suggests some regulatory guidance is important for extrapolation.

They expressed support for switching patients who are “stable” on RPs to biosimilars, provided there is physician and patient agreement (87%), and initiating biosimilar treatment in biologic-naive patients with psoriasis also is acceptable with physician-patient agreement (96%).

Pharmacy Counter Substitution of Biosimilars

When it comes to substituting biosimilars for RPs, the IPC guidance is conservative:

Clinicians should be notified and should provide approval prior to any originator or biosimilar drug substitution being made 

Clinicians should be given explicit authority to override any suggested substitutions 

Substitution would be conducted at the pharmacy counter, meaning a pharmacist would intervene to some degree and dispense a biosimilar instead of an RP. Some institutions have developed substitution policies to save money on use of biologics. Interchangeable status, an FDA designation that requires switching studies, would make it possible for substitution to be carried out more broadly; however, just 1 biosimilar, an insulin glargine (Semglee), has qualified for interchangeable status so far.

of an in-house biosimilar substitution program and reported significant savings. 

The guidance stresses that biosimilars should be clearly identifiable and given names that facilitate recognition and tracking and, further, these names should not differ country to country. For example, biosimilar developers sometimes market the same products under different brand names in the United States vs the European Union.

However, biosimilar usage policies should be made locally, and dermatologists and dermatologists’ professional associations should be able to participate in the policy and regulatory decisions concerning use of biosimilars, the IPC guidance states.

Practice guidelines for biosimilars should be developed at a local level, which will differ across countries throughout the world

Copy Biologics That Do Not Qualify as Biosimilars

The IPC guidance expresses full support (100%) for avoidance of nonbiosimilar agents that may not meet standards for clinical equivalence to RPs. The group agreed that “biocopies,” “intended copies,” and “biomimic products” do not qualify as biosimilars and should not be used (100%).

Such copy products are prevalent in the developing world, where regulatory authorities may not have quality control standards that are appropriate for the production and development of these agents, biopharmaceutical companies may lack technological sophistication or resources to produce high-quality biologics, and biologics widely available in developed and industrialized countries may not be affordable to patients in developing countries.

The International Psoriasis Council (IPC) reaches consensus on switching, patient agreement, and biosimilar safety and efficacy qualification. The IPC guidance is conservative when it comes to substitution of these products.

IPC Guidance Is Issued on Safety of Biosimilar Switching in Psoriasis

Recently, biosimilar developers have sought to obtain “interchangeable” status for their products so that pharmacists can dispense them without first consulting the prescribing physicians.

But demonstrating that biosimilars are interchangeable with reference products (RPs) requires that developers perform studies that ensure that the same clinical outcomes are achieved whether patients switch back and forth between RP and biosimilar multiple times or remain on RP throughout.

, investigators said the optimal number of switches that must be performed is 3 to reliably conclude that outcomes would be the same. This means patients would start out on RP, switch to the biosimilar, switch back to RP, then switch back to the biosimilar again.

“At least 3 switches appeared necessary to optimize the detection of potential [pharmacokinetic] PK differences,” investigators wrote. They also evaluated the merits of a single switch and 5 switches, concluding 1 was inadequate and 5 would be more than necessary. 

 on switching, which calls for 2 periods of patient exposure to both the biosimilar and RP 

Investigators also concluded that the development of antidrug antibodies (ADAs) is significant in determining clinical equivalence of switching vs nonswitching, as is “area under the curve” (AUC), or extent of exposure to a drug and its clearance from the body.

“Our simulation work illustrates that a range of factors should be carefully considered when designing a switching study for the assessment of interchangeability between 2 biological products,” authors of the study wrote.

The difference between a biosimilar and an interchangeable can be confusing. For biosimilar approval, a manufacturer must demonstrate that its product has no clinically meaningful safety or efficacy differences from RP. For an interchangeable designation, a manufacturer must show that the product “can be expected to produce the same clinical result as the [RP] in any given patient,” and for this a switching study is necessary.

The first interchangeable biosimilar approved in the United States was an insulin glargine (Semglee; Mylan and Biocon Biologics), for which a switching study (INSTRIDE 3) that included the 3 recommended switches was performed. Interchangeability was 

Boehringer Ingelheim and Alvotech have each sought interchangeable status for proposed adalimumab biosimilars and have conducted switching studies. FDA decisions are pending.

There is an inherent marketing advantage in an interchangeable designation. There is also the potential for health care savings as more of these products are approved, authors of the study on optimal switching said.

“The continued rise of biosimilar product development programs and regulatory approvals in the past few years has offered a solution to address the high costs of these new biologic treatments, and the lower costs of biosimilars are easing an ever-increasing strain on national health care systems. Interchangeable products have the potential to further lower health care costs and improve efficiency in the prescription dispensing process,” they wrote.

The purpose of a switching study is to demonstrate that the risk of switching to a biosimilar or back again doesn’t increase the risk of diminished safety or efficacy vs remaining on the originator product. To establish this, an analysis of PK and pharmacodynamic (PD) changes is recommended by the FDA.

“Changes in PK and/or PD concentrations or exposures may be the result of ADA formation,” the authors wrote. In their virtual study, they randomized patients (N = 200) 1:1 to the switching or nonswitching arms, and 750 mg of the reference or test product were hypothetically administered each cycle (4 weeks or 28 days).

Investigators evaluated ADA incidence during the lead-in (baseline) period with the RP treatment and the additional ADA incidence resulting from switching between periods. The end points were AUC and maximum concentration (Cmax) values from PK sampling. Cmax is the highest concentration of a drug in the bloodstream following dosing. Investigators concluded “Cmax was less sensitive for assessing the impact of ADA on PK.”

Ji P, ren Y, Li L, et al. Impact of switching on pharmacokinetics of therapeutic biologics and interchangeability assessment—a simulation study. 

. Published online August 19, 2021. doi:10.1111/1954

For a column on the significance of interchangeability by Jeff Baldetti, MBA, of Cardinal Health, click 

How many switches between a biosimilar and reference product will be sufficient to demonstrate that the risk of transitioning is minimal? A virtual study verifies the strength of FDA guidance.

Investigators Test Reliability of Interchangeability Switching Studies

Rumors that HHS could calculate payment for biosimilars differently under a potential policy change have sparked concerns among providers and biosimilar developers.

If the rumors are correct, the Medicare Part B payment methodology for biosimilars would be overhauled for the second time in 4 years.

Currently, CMS bases payment for biosimilars on the average sales price (ASP) for the individual biosimilar and then adds an additional amount that represents 6% of the ASP for the reference product. This policy was 

 and was thought to encourage biosimilar use in the marketplace, leading to lower overall costs of biologics and expanded access for patients.

Under the rumored policy change, payment rates for biosimilars in a particular class of therapeutics, such as trastuzumabs, would be based on ASPs of the biosimilars and their reference products, meaning 1 ASP would be calculated to represent all products, and payment would be based on that.

With some products having lower individual ASPs and some having higher ASPs, basing reimbursement on a single ASP would wreak havoc and drag overall pricing down, contends Ted Okon, MBA, executive director of the Community Oncology Alliance (COA). If the goal is to achieve lower prices for biologics, this would accomplish that, but it would also destroy incentives for biosimilar companies to participate in the market, he said.

“On a short-term basis, you will artificially drop biosimilar pricing through the floor, but the problem with that is it kills the market, because no one’s going to turn around and invest in new products,” Okon predicted.

Data suggest that, in their sixth year in the United States, biosimilars are achieving significant market share and price discounts from originator products, which shows that these lower-cost agents are a success.

“Why would you want to change that?” Okon asked. “This is a time when you don’t want to screw around and, possibly, put a major dent in the biosimilar marketplace.”

Again, there has been no official announcement of such a policy change, although an August 18, 2021, report from 

a subscription-only news publication that claims to have inside information on federal government activities, stated that such a change is being contemplated and cited "a source who spoke to [HHS] department staff." 

Worries about what HHS will propose in its anticipated biologics pricing reform policy have been exacerbated by a rumored coding change. 