, adding the novel anti-human epidermal growth factor receptor 2 (HER2) antibody HLX22 to the trastuzumab biosimilar 

 (Hercessi; Shanghai Henlius Biotech) and oxaliplatin and capecitabine (XELOX) chemotherapy prolonged progression-free survival (PFS) in patients with previously untreated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction (G/GEJ) adenocarcinoma over 14 months of follow-up.

According to the investigators, G/GEJ cancer is often diagnosed at the advanced stage and has poor prognosis, and more effective treatments are needed. HER2-positive disease makes up approximately 12% and 23% of gastric cancer cases. Although previous research established that trastuzumab plus chemotherapy significantly improved overall survival (OS) compared with chemotherapy alone, the authors said that median overall survival “is still limited” with the addition of trastuzumab.

HLX22 is a monoclonal antibody targeting HER2. According to the authors, although HLX22 binds to the same domain of HER2 as trastuzumab, it acts on a different epitope, allowing the 2 to bind HER2 simultaneously. A phase 1 study of HLX22 monotherapy found antitumor activity against HER2-overexpressing advanced solid tumors after failure of or intolerance to standard therapies.

The current study randomized patients to receive HLX02 and XELOX plus placebo (n = 18), or HLX02 and XELOX plus 15 mg/kg HLX22 (n = 17), or 25 mg/kg HLX22 (n = 18) every 3 weeks. The primary endpoints were PFS and objective response rate (ORR) as assessed by an independent radiological review committee (IRRC). Baseline characteristics were “well balanced” between groups, the authors said.

The investigators reported median PFS was prolonged in both HLX22 groups. In the 25 mg/kg HLX22 group, median PFS was 15.1 months compared to 8.2 months in the placebo group (HR, 0.5; 95% CI, 0.17-0.27). In the 15 mg/kg HLX22 group, median PFS was not reached (HR, 0.1; 95% CI, 0.04-0.52 compared with placebo).

Confirmed ORR by IRRC was comparable between groups, the authors said, at 78% in the higher-dose HLX22 group, 82% in the lower-dose HLX22 group, and 89% in the placebo group. At week 48, ORR was higher in the 2 HLX22 groups (39% and 59%) compared to the placebo group (17%), “indicating that patients had more sustained tumor response when HLX22 was added to the treatment regimen,” the authors wrote. Disease control rates were 83% in the higher-dose HLX22 group, 94% in the lower-dose group, and 89% in the placebo group.

At the time of analysis, 15 patients (28%) had died, and median overall survival (OS) was not reached in any of the 3 treatment groups. Twelve-month OS rates were 82% in the higher-dose HLX22 group, 82% in the lower-dose HLX22 group, and 67% in the placebo group.

Almost all patients, more than 90%, experienced at least 1 treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 72% of patients in the higher-dose HLX22 group, 41% in the lower dose group, and 44% in the placebo group.The most frequent TEAEs were decreased platelet count and decreased neutrophil count. Serious TEAEs were reported in 44%, 24%, and 28% of patients in the 3 groups.

Adverse events leading to treatment interruptions occurred more frequently in the higher-dose HLX22 group (67% of patients) compared to the lower dose (24%) and placebo (17%) groups. Adverse events of special interest (AESIs) occurred in 33%, 65%, and 17% of the higher-dose, lower-dose, and placebo groups, and these included infusion reactions, prolonged RR interval, and left ventricular dysfunction. There were no serious AESIs.

The authors concluded that adding the anti-HER2 antibody HLX22 to the trastuzumab biosimilar HLX02 and XELOX chemotherapy prolonged PFS and enhanced antitumor response as first-line treatment for HER2-positive gastric cancer, with manageable safety, providing evidence for clinical benefits of dual HER2 blockade in this patient population. They added that PFS and overall survival (OS) from this study with a longer duration will be reported in a future publication.

Li N, Qiu M, Zhang Y, et al. A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer. 

. 2024;5(10):1255-1265.e2. doi:10.1016/j.medj.2024.06.004

In a phase 2 study, the addition of HLX22, an anti-HER2 antibody, to HLX02 biosimilar and XELOX (oxaliplatin and capecitabine) chemotherapy extended progression-free survival (PFS) in untreated HER2-positive advanced gastric cancer patients.

Achieving PFS in Advanced Gastric Cancer With HLX02 Biosimilar, Chemotherapy

Deana Ferreri, PhD

The evolution of biosimilars so far in the United States has revealed one thing for certain: Generalizations cannot be made about biosimilar market dynamics across different therapeutic areas. Although therapeutic oncology biosimilars gained significant market share in the year after they became available, adoption of infliximab biosimilars in rheumatology over the past few years has been sluggish at best. As products in other therapeutic areas make their way through the development pipeline, questions remain about how quickly uptake will occur. One therapeutic area to watch in the coming year is ophthalmology.

Ophthalmology biosimilars, specifically anti–vascular endothelial growth factor (VEGF) agents, are poised to compete with some of the most commonly used therapies for neovascular (eg, wet) age-related macular degeneration (AMD). With Samsung/Biogen’s FDA filing for SB11 (a ranibizumab biosimilar) in November 2020, and with several more candidates in the pipeline, biosimilars are about to make an impact on the ophthalmology market.

AMD is the leading cause of irreversible visual impairment in people aged 60 and older and is projected to affect over 288 million people globally by 2040 as the population ages. It is an eye disease that affects the macula (the central area of the retina), resulting in the loss of sharp central vision. Without central vision, people are unable to carry out critical daily activities such as reading, driving, and recognizing faces, which can lead to an overall decline in quality of life. In addition to lowering quality of life, AMD is associated with significant economic and treatment burdens for patients, as current management strategies include frequent monitoring and recurrent intravitreal injections with anti-VEGF agents. It is estimated that the US annual economic burden from direct health care costs due to AMD is $4.6 billion.

Three of the most common treatment options for AMD include anti-VEGF agents: ranibizumab (Lucentis), aflibercept (Eylea), and bevacizumab (Avastin, off-label).

 Bevacizumab has been used off-label for several years by being repackaged by compounding facilities for intravitreal administration.

 Both Lucentis and Eylea have multiple biosimilar candidates in development by various manufacturers, but there are no approved biosimilars for these agents. In the case of Avastin, biosimilars are already approved and available on the market, but the role of bevacizumab biosimilars in ophthalmology is unclear. Known utilization has been for on-label oncology indications.

To gain early insight into levels of awareness and perspectives on the role of biosimilars in ophthalmology, Cardinal Health conducted research via a series of survey questions with community-based retina specialists (N = 37) from across the country. Interim results of the survey revealed significant opportunities to help prepare the market for the entrance of ophthalmology biosimilars. When asked about their familiarity with biosimilars, 31% of physician respondents (29 total responses) said they are not very familiar with biosimilars, and more than half (55%) said they have read research about them but are not familiar with the specifics, such as manufacturing, approval processes, and clinical trial design. However, the majority of respondents (83%) perceive biosimilars as fitting into the treatment armamentarium to help keep drug costs down (29 total responses), and more than half of respondents said they would consider using a ranibizumab biosimilar or aflibercept biosimilar once they become available.

When asked what their primary concern with prescribing ophthalmologic biosimilars would be, 43% responded they would be uncomfortable from a clinical standpoint and 35% responded with payer coverage concerns. These responses serve as critical reminders that, when it comes to driving biosimilar adoption, it is important to provide proactive education to all key stakeholders, including providers, practice administrators, payers, and patients. For example, payers, and strategies such as step-therapy, will play a significant role in the ability to adopt ophthalmology biosimilars. Therefore, early payer engagement and education are critical to support clinically and financially sound formulary decisions that are best for patients and practices. Topics including the regulatory approval pathway and clinical trials structure and terms, such as extrapolation and interchangeability, are important in developing stakeholder familiarity and confidence in biosimilars. In fact, the vast majority of provider survey respondents said they would like to receive more educational information about the safety, efficacy, and performance of biosimilars (

Although the trajectory for ophthalmology biosimilars in the United States is still unknown, there are key lessons that can be applied from current and past experiences to better prepare the market for the launch of the first ophthalmology biosimilar. Education should be at the forefront of this drive. As the country prepares for the market entrance of the first ophthalmology biosimilar, the time to focus on educational efforts is now. Biosimilars are poised to bring significant cost savings to help mitigate the financial burden associated with the management of AMD, and in order to realize the full benefits of these agents, providers, payers, and patients must be well equipped to evaluate and adopt them as soon as they hit the market.

Pennington KL, DeAngelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. 

. 2016;3:34. doi:10.1186/s40662-016-0063-5

Holekamp NM. Review of neovascular age-related macular degeneration treatment options. 

. 2019;25(1suppl 10):S172-S181. www.ajmc.com/view/review-of-neovascular-agerelated-macular-degeneration-treatment-options

Cardinal Health. 2020. Cardinal Health survey of US retinal specialists. Internal report. Unpublished.

Samsung Bioepis has filed for FDA approval for a ranibizumab biosimilar candidate (SB11), and more ophthalmology biosimilars are in the pipeline. 

Opinion: Is the Ophthalmology Market Ready to Embrace Biosimilars?

Sonia T. Oskouei, PharmD, BCMAS, DPLA, is vice president of Biosimilars for Cardinal Health.

Sonia T. Oskouei, PharmD, BCMAS, DPLA

Joshua Ney, PhD, JD, is a shareholder in Brinks Gilson & Lione’s Ann Arbor office. Ney represents pharmaceutical clients in patent litigation and prosecution matters, which includes counseling clients on the interplay between regulatory and patent strategy. His experience spans a range of pharmaceutical modalities and therapeutic applications.

Joshua Ney, PhD, JD

Amanda Forys, MSPH, is a senior director at Xcenda, a part of AmerisourceBergen, on the Reimbursement Strategy Insights consulting team. Her experience includes reimbursement policy analytics, with emphases on Medicare and commercial coverage and payment policy. Her work has covered a wide range of topics, including economic and policy modeling and analysis around biosimilars, innovative payment models, chronic disease management, federal budgetary impact models, and Medicare payment systems. 

Amanda Forys, MSPH

For years, biosimilar developers have lamented the lack of patent transparency around reference biologics. The Purple Book Continuity Act (PBCA), enacted in December 2020 

, directs FDA for the first time to publicly list certain patent information in the “Purple Book,” a database of approved biological products.

The PBCA is a welcome first step, but many in the biosimilar industry argue that Congress needs to do more to illuminate the patent landscapes for approved biologic products. Disclosure of reference product patents comes too late and is too incomplete to meaningfully guide business decisions. Developers of follow-on biologics need greater disclosure in order to make well-informed decisions about which products to pursue, with the ultimate goal of encouraging more development and earlier entry of follow-on biologics.

Pharmaceutical companies seeking to develop small molecule generic drugs have long looked to a different database maintained by the FDA, the “Orange Book,” for patent information. Here, sponsors of small molecule drugs are required by the Hatch-Waxman Act to list patents they own or license that cover those drugs. Generic developers can thus rely on the Orange Book to provide the universe of patents that an originator might assert during prelaunch litigation and thereby gauge their litigation exposure in considering whether to pursue a generic pharmaceutical. This increased certainty allows generic manufacturers to proactively prepare for litigation, thereby increasing their chances of a clear path to launch.

Until the PBCA’s enactment, follow-on biologic developers had no such clarity and had to rely on their own due diligence in assessing which patents they might face in litigation. The FDA’s Purple Book listed approved biologics but provided no patent information. The PBCA now provides at least 

 degree of patent disclosure. Under the new law, a reference product sponsor (RPS) must provide the FDA with a list of the patents and associated expiration dates that it discloses under 42 USC § 262(l)(3)(A) and 262(l)(7) as part of the patent dance, a series of disclosures required under the Biologics Price Competition and Innovation Act (BPCIA).

Although some patent transparency is better than none, many biosimilar companies argue that the PBCA nevertheless falls short in several important respects. First, the PBCA does little for companies seeking to expedite development of follow-on biologics. The RPS must only provide information on its patents to the FDA for listing in the Purple Book after it engages in the patent dance with a follow-on developer. Therefore, rather than encouraging companies to move quickly to develop follow-on products, the PBCA only helps those developers who wait for others to forge ahead without the benefit of patent transparency. Contrast this with the Orange Book, which delivers the patent information to all developers, including first-movers who push to get their products to market faster.

Second, the patent disclosures that an RPS makes pursuant to the patent dance might not include, as the Orange Book does, all of the patents owned or licensed by the RPS that cover its product. Instead, the Purple Book will only list patents that the RPS alleges covers a specific follow-on product. It is entirely possible that the RPS might have a different set of patents that it would assert against another follow-on product. But under the PBCA, that different set of patents would not be listed in the Purple Book, until and unless they are included in another (l)(3)(A) list against a different follow-on developer.

This concern is not merely theoretical. A survey of previous BPCIA litigation shows that RPSs can and do assert different patents against different defendants. For example, the RPS of trastuzumab, Genentech, brought suit against 4 different follow-on developers. Against both 

, Genentech disclosed the same 40 patents. When 

 filed, Genentech disclosed 37. And when Genentech brought suit against 

, it disclosed 21 patents. Some of the patents asserted against Amgen and Samsung Bioepis were neither disclosed nor asserted in the Celltrion and Pfizer cases. Thus, which patents get listed in the Purple Book may depend upon which developers file an abbreviated biologics license application (aBLA). 

Extensive patent portfolios—sometimes called “patent thickets”—compound this problem. With larger patent portfolios, it is more likely that the RPS will have patents that have not been asserted or disclosed in previous suits. It will thus take more aBLA filings, resulting in more (l)(3)(A) lists, to expose the full extent of larger thickets.

On top of this, more patents qualify for prelaunch litigation under the BPCIA, where RPSs can assert patents covering manufacturing processes. Because manufacturing patents can be asserted prelaunch under the BPCIA but not under Hatch-Waxman, the Purple Book should have comparatively greater patent disclosure requirements than the Orange Book.

Proactive disclosure of manufacturing patents would also give follow-on developers the opportunity to design around patents during the early phases of product development. For example, 

Humira is the subject of some 154 patents and Rituxan is covered by at least 80

The large number of patents that tend to cover biologics (relative to small molecule drugs) weighs in favor of more transparency. Yet, even with the passage of the PBCA, the Purple Book will provide less patent information than the Orange Book. And while follow-on developers can depend upon earlier waves of litigation to identify some portion of an RPS’s patent portfolio, a great deal of diligence is often required to identify the universe of relevant patents with reasonable certainty.

The PBCA has also been criticized because, even after an RPS engages with the first follow-on developer to begin the patent dance for a given biologic, that engagement might not yield a patent listing in the Purple Book under the PBCA. The parties could reach a settlement before the RPS provides its Section 262(l)(3)(A) patent list. Or, the FDA may decline to request retroactive disclosure of patents from previous biosimilar litigations.

It is true that these patents—and those to be listed in the Purple Book going forward—can be found by leafing through public court dockets. But asserted patents routinely make up only a subset of the entire portfolio. Whether it be in the Purple Book or in a court filing, those disclosures are insufficient to bring meaningful transparency to follow-on developers.

In any event, the PBCA means that some patents will soon be coming to the Purple Book. Although the FDA is not required to make patent data available in the Purple Book until June, the obligation to communicate lists under Sections 262(l)(3)(A) and (l)(7) to the FDA is already in effect. Thus, the patent disclosures from biosimilars litigation initiated in 2021 may be among the first posted to the Purple Book.

 on November 19, 2020, that the FDA had accepted its application for a biosimilar of Humira. And on April 27, 2021, AbbVie, the RPS, 

. Although Alvotech agreed to only 4 patents for prelaunch litigation, AbbVie disclosed 62 patents which it could potentially assert in the Section (l)(3)(A) list. As of December 27, 2020, the PBCA requires that the RPS communicate any list under Sections 262(l)(3)(A) or (l)(7) to the FDA within 30 days of sending it to the aBLA applicant. Presumably these 62 patents will be provided to FDA for inclusion in the Purple Book.

The PBCA will bring some nominal level of transparency and notice for follow-on developers. But many in the biosimilar industry argue that it falls far short of what is needed. The PBCA provides no patent disclosure to the first filer of an aBLA, which must rely on its own diligence to identify patents that may be asserted. Nor does the PBCA require RPSs to proactively identify patents which cover a given biologic, as they must do for small molecule drugs in the Orange Book.

It may be true that numerous manufacturing patents might apply to a given product or its biosimilar depending upon the methods of manufacture. But the same cannot be said of patents which cover the active substance or those which cover a method of use. If proactive disclosure of such patents were compulsory, the Purple Book would begin to provide a level of transparency and utility on par with the Orange Book.

Nevertheless, there is reason for hope for the biosimilar industry: Congress has indicated a willingness to revisit which patents are listed in the Purple Book. The PBCA requires that, in 3 years’ time, the FDA take public comments on the type of patent information that should be included in the Purple Book. The FDA will then report this information to Congress along with its own recommendations.

If and when Congress revisits the issue, it might impose proactive patent disclosure requirements that would facilitate informed decision-making by follow-on developers and thus stimulate the development of more biosimilars for the US market.

Intellectual property attorneys from Axinn discuss the limitations of the Purple Book patent disclosure requirements and the burden these impose on biosimilar developers.

Opinion: Purple Book Patent Listings Are Only a First Step

Stacie Ropka, JD, PhD, is a partner at Axinn. Her practice focuses on intellectual property litigation, due diligence, and client counseling, with an emphasis on the life sciences. Ropka’s experience includes extensive counseling for product development efforts relating to biologics and reconstructive biomaterials, including products that utilize adult stem cells. Prior to attending law school, she held a faculty position at SUNY Upstate Medical University, and she also spent many years as a research scientist in the fields of neurology, virology, and immunology.

Stacie Ropka, JD, PhD

*This article was originally published by the 

Amgen has released the fourth edition of its 

, which addresses key challenges that need to be overcome for the widespread uptake of biosimilars in the US market.  

“As the biosimilar market grows in the US, all stakeholders will assess this new category of medicines with a focus on driving value-based healthcare, which includes delivering quality of care, effectively managing cost and achieving intended patient outcomes,” the authors of the report wrote. Most surprisingly, for Medicare patients who are still in the coverage gap, a biosimilar product could cost the patient more out-of-pocket than the originator drug. This is because biosimilars are lumped together with generics in Medicare reimbursement policy.  

Other challenges facing biosimilars include disputes about the interpretation of certain provisions of the Biologics Price Competition and Innovation Act (BPCIA). Litigation has become a common occurrence for many biosimilar applicants. In fact, a single infringement lawsuit by the reference product could delay a product launch, or a biosimilar applicant may decide to launch at-risk, according to the report.  

At-risk launches mean that patent ownership issues remain unresolved, even as the products are being dispensed. These launches may result in the withdrawal of a product from the market and/or royalties for the reference product sponsor at the end of the lawsuit. Three of the 4 FDA-approved biosimilars are currently involved in lawsuits as of January 2017. Two of the biosimilars on the US market were launched at risk, according to the report.  

Six more products have active fillings with the FDA that are expected to be acted on in 2017.  Issues that payers and other formulary decision-makers should take into consideration when evaluating a biosimilar are product considerations, manufacturer considerations, and operational considerations. Product considerations include extrapolation; curative treatment versus supportive care; product dosing; delivery device, formulation, and handling; and distribution channels. Manufacturer considerations are supply chain reliability and patient support programs. Lastly, operational considerations include pharmacovigilance, pricing and contracting, reimbursement, and information technology.  

Both patients and physicians have expressed unfamiliarity in whether a biosimilar can be used in all the same indications as the reference product. A 2016 survey by the Biosimilars Forum found that only 12% of respondents reported being completely comfortable with the concept of extrapolation. Post-marketing surveillance and data from observational studies may help address concerns around extrapolation, according to the report. In the United States, the first 4 approved biosimilars received approval for all available indications; however, some indications may be initially excluded from an approved biosimilar’s label because of established exclusivity periods by the FDA.  

The use of biosimilars in certain clinical settings is also important to consider. In oncology, utilization of biosimilars may depend on whether the drug is administered for supportive use or with curative intent.   Biosimilars could be available in several forms, and physicians, pharmacists, nurses, patients, and caregivers need to be aware of differences in indications, corresponding doses, and dosage forms between the branded reference product and the biosimilar.

 “Longer-term, what happens as more biosimilars for the same reference product become available?” the authors wrote. “What if each one has its own particular packaging that differs from that of the reference product? The question then becomes more complex: how may differences can a market accommodate and how many ‘highly similar’ products will have nonclinical differences that need to be noted and tracked in electronic systems?”  

How a manufacturer chooses to employ delivery methods is also a challenge. The manufacturer’s choice of delivery device for a biologic drug can make a difference in the patient’s compliance and adherence. Some manufacturers have already chosen to use delivery devices that differ from the biosimilar’s reference product. Patients and healthcare professionals will require adequate education regarding the different devices and their proper use and handling, according to the report.  

Formulation is another potentially important point of differentiation, the report noted. Distributors and health care professionals who administer biosimilars need to know of and take precaution when dealing with differences between biosimilar storage, handling, and route of administration with the reference product. 

For biologics launched in recent years, specialty distribution has been used more frequently. The specialty channel could enhance the efficacy of biologics distribution, with respect to issues such as product storage, cost and delivery, product dating, and inventory management. Supply chain reliability is an important manufacturer consideration. Disruptions to drug supply is becoming a common occurrence, especially for oncology drugs, the authors noted. To avoid treatment delays, the report said it’s important to consider the robustness of the manufacturer’s supply chain when evaluating biosimilars. The manufacturer’s history of shortages and recalls related to quality concerns should also be considered, and an evaluation of their ability to maintain adequate production and stock to support the demand.  

In recent years, drug shortages have gained attention as a common occurrence due to their highly-specialized manufacturing process. Furthermore, sterile injectables account for a large percentage of these shortages. Although the number of new shortages have decreased overall since 2011, the number of ongoing shortages remains high. These shortages can cause serious logistical, ethical, and financial issues, and could potentially lead to a variety of other health and safety issues.  

“It’s horrible and incredibly challenging when you experience drug shortages,” a pharmacy director and editorial council member said in the report. “In oncology, for example, if there isn’t an alternative you have to look at intensive treatment versus curative or supportive and determine if any patients can discontinue treatment early.”  

Patient support programs are crucial for patients and can influence the behavior of physicians or serve as a point of differentiation between biosimilars. Biosimilar manufacturers will likely consider providing meaningful patient support services as part of their value proposition to meet the needs of patients and providers.  

Pharmacovigilance—tracking and monitoring of drug safety over time&mdash;is especially important for biologics and biosimilars to detect any emerging safety signals, the authors wrote. To help facilitate pharmacovigilance, the FDA released final guidance on nonproprietary naming of biologics in January of this year. Biologics can be covered under the medical benefit or the pharmacy benefit, according to the report. Self-administered medicines are typically covered under the pharmacy benefit, while injections of infusions that are supervised by a physician are typically paid for as medical benefits.

Key differences between the 2 payment systems, from the payer’s perspective, is that specialty drugs covered under the pharmacy benefit are reimbursed based on their national drug codes (NDCs). The NDC codes enable anyone to analyze the use of that medicine to track utilization and know the drug, manufacturer, strength, and package size.

Under the medical benefit, specialty drugs are commonly tracked and reimbursed using the Healthcare Common Procedure Coding System (HCPCS) codes, which identify the drug’s chemical name, but not the manufacturer, the strength, or package size. Biosimilar products that appear under the same HCPCS codes under Medicare Part B will be issued and assigned modifiers that help identify the manufacturer of the product and distinguish between biosimilar products that are made by different manufacturers. Through the modifiers, CMS will have the ability to track claims payment and develop a better understanding of the use of biosimilars in Medicare Part B.   

The expected trend in biosimilar utilization versus the originator product may be a proxy for biosimilar adoption, according to the report. To create a sustainable biosimilar market, an ongoing commitment to driving competition is required.  

“As 2016 drew to a close, there were 4 approved biosimilars and 6 active filings pending FDA review in 2017,” the authors wrote. “Simultaneously, US regulatory bodies committed necessary resources to support the review of biosimilar applications as they continue to form final guidance around the biosimilar path-to-market.  

“The events that unfold in 2017 may increase experience and understanding of biosimilars, which in turn could increase confidence and utilization of these medicines in the US. Limited exposure to biosimilars in the US has resulted in the cautious uptake of biosimilars and identified knowledge gaps impacting downstream user trust in these products.”  

A 2015 study in Europe, however, found that 40% of surveyed physicians had increased confidence in the use of biosimilars compared with 3 years ago. The study suggests that gains in clinical experience could help reduce hesitation regarding biosimilar use in the United States.  

Discussions carried out among health care professionals, administrators, regulators, manufacturers, and patient groups, regarding the experiences of early adopters could help facilitate acceptance, according to the report. Building confidence in this treatment space will remain a primary goal for the industry in 2017.  

Legalities may also pose a significant challenge for manufacturers who are attempting to bring biosimilars to the market in 2017.  

“Likewise, court decisions on complex issues regarding patent protection and data exclusivity that are review in ongoing litigation between biosimilar manufacturers and reference product manufacturers will likely inform future decisions on applications and launch strategies for biosimilar manufacturers,” the authors wrote.  

Lastly, uncertainty surrounds the future of the Affordable Care Act—–and as a result the BPCIA––under the new administration. But repealing the legislation could have implications for several regulations that affect biosimilars, including the Medicare Part D Coverage Gap Discount Programs, the “deemed to be a license” provision, and the regulation freeze, the report concluded.

Multiple Challenges Predicted for Biosimilars in 2017 

Lauren Santye, Assistant Editor, Specialty Pharmacy Times

The primary goal of medical treatment for any chronic inflammatory illness is to implement the most effective therapy with the widest margin of patient safety and tolerability. Successful treatment may require a patient to visit their physician multiple times over months or even years in order to establish control of a chronic illness like rheumatoid arthritis or inflammatory bowel disease. If effective treatment is interrupted for any reason, the patient may be at risk for disease progression and a decline in function. Once effective treatment is established, it should not be undermined by administrative interference through nonmedical switching.  

Nonmedical switching is a coverage tactic used by insurers to limit prescribing to formulary ‘preferred’ medications. These formulary-driven medication changes—including in the case of a reference biologic medicine and biosimilar&mdash;may force patients to be “switched” off a medicine, on which their disease symptoms are well controlled, to a completely different medication within the health plan’s formulary. Pharmacy benefit managers (PBMs), who develop drug formularies for insurers, accomplish this by placing medicines in tiers, with preferred drugs in lower-numbered tiers and nonpreferred drugs in higher-numbered tiers. However, this process lacks transparency and is likely based more upon profitability achieved through contractual arrangements with pharmaceutical companies than on evidence-based safety and efficacy studies or concern for patient out-of-pocket cost savings.

Nonmedical switching due to formulary changes by insurers and PBMs places patients at risk for treatment failures, worsening disease activity, declining physical function, permanent tissue damage, and an increase in complications and medication toxicities. This practice is in essence made mandatory by placing excessive financial burden on patients who wish to stay on their current, nonpreferred, medicine. This is poor medical practice and undermines both the specific treatment decisions made by patients and their physicians and the patient-physician relationship, as well as ignores patient safety concerns.

In order for a biosimilar to achieve an interchangeable product designation by FDA, the manufacturer must demonstrate through additional data that it produces the same clinical result as the reference product in any given patient. There is concern that without an interchangeable designation or medical input from a physician, nonmedical switching at the pharmacy level between biologic medicines could jeopardize patient health and safety. Scientific and clinical data, along with physician and patient decision-making, must be the basis of all medication switching.

A formulary-driven nonmedical switching program for biologics and biosimilars should include mandatory provisions for extensive and vigorous pharmacovigilance processes. Insurers who implement such programs must take responsibility for the related costs of data collection and management, data analysis, and publication of the data in reputable medical journals. The FDA should mandate this type of study whenever insurers mandate switching patients to biologic agents that are not designated as interchangeable.

While managing costs is extremely important to physicians and their patients, achieving and maintaining disease control without increasing the risk of complications or toxicities must remain the primary goal in the treatment of chronic inflammatory diseases. Additionally, patients should not be placed in financial jeopardy for formulary changes when their disease is stable on current therapy.

In the interest of providing the physicians’ perspectives on patient care, the Biologics Prescribers Collaborative (BPC) convened a member roundtable to discuss the impact of nonmedical switching on patients who are prescribed biologic drugs. The roundtable discussion led to the development of a series of 

 that prioritize patient safety and the protection of the physician-patient relationship. It is BPC’s hope that both physicians and patients alike become educated on the potential and likely impacts of non-medical switching, and that patients remain empowered while navigating the healthcare system.

BPC welcomes your commentary on this important medical issue.  Please direct questions and comments to 

While managing costs is extremely important to physicians and their patients, achieving and maintaining disease control without increasing the risk of complications or toxicities must remain the primary goal in the treatment of chronic inflammatory diseases.

Biosimilar Nonmedical Switching Must Never Undermine Patient Safety

Gregory F. Schimizzi, MD

Across the sea of space, the stars are other suns.

Gustavo Cardona

Product differentiation is a critical component of product strategy, especially for biologics and biosimilars, as drug competition across therapeutic categories continues to increase. For disease types with multiple competing brands of a single type of medicine, there are sometimes opportunities for manufacturers to demonstrate value beyond clinical parameters.

Drug delivery systems such as devices, technologies, and formulations—which may offer faster or slower medicine release—have become key value differentiators that manufacturers continue to invest in. The attractiveness of these devices may improve physician and patient acceptance, leading to improved revenues and market share; and the ease and convenience of devices 

 patient adherence and satisfaction. Further, patient comfort with a device may lead to brand loyalty, regardless of whether cheaper options (generics, biosimilars) are available.

Also important for manufacturers, delivery systems may serve as a patent protection strategy and thwart biosimilar competition. A prominent example of this is the success of Amgen’s Neulasta Onpro, a wearable pegfilgrastim injector kit that reduces the number of office visits patients need to make.

In 2015, Amgen’s blockbuster Neulasta (pegfilgrastim), an oncology supportive care agent, lost exclusivity and became subject to biosimilar competition. Since then, 4 pegfilgrastim biosimilars have been approved in the United States—Fulphila (Mylan), Udenyca (Coherus), Ziextenzo (Sandoz), and Nyvepria (Pfizer)–of which 3 have launched. By 2019 these biosimilars had captured less than 25% of the 

, but indications were that Neulasta would not be able to continue dominating this market.

In just the second quarter of 2020, Neulasta sales decreased 28% due to biosimilar competition. Despite this decline in sales for the originator product, Amgen has retained a sizeable share of the pegfilgrastim market due to the Neulasta Onpro, which the 

As a delivery system, the Neulasta Onpro wearable injector enables patients to go home after chemotherapy and receive an automatic follow-up pegfilgrastim injection the next day. The convenience of this device, particularly for patients who have to travel many miles for chemotherapy treatment or could not easily schedule visits as the COVID-19 outbreak spread, has given Amgen a tremendous competitive advantage in the pegiflgrastim market. By midyear 2020, the Onpro held a 58% share of 

 patients to the Onpro kit as a part of its product life cycle extension strategy and defense against biosimilars. Consequently, Amgen has maintained a sizeable market share while limiting the uptake of biosimilars. There is no biosimilar delivery device comparable to the Neulasta Onpro, and pegfilgrastim biosimilars cannot be used with the Onpro. This means that, purely from the convenience aspect, physicians and patients may be discouraged from using a biosimilar pegfilgrastim, even if biosimilars are preferred from the payer side. Further, although Neulasta’s patent exclusivity ended in 2015, Neulasta Onpro is still patent protected.

Interestingly, the original Neupogen product was itself a 

. Whereas filgrastim (Neupogen, Amgen) must be injected daily for up to 2 weeks, Neulasta can be administered once every 3 weeks as a single, fixed dose during the patient’s chemotherapy cycle.

Outside of Neulasta Onpro, manufacturers have employed other delivery systems to extend product life and avoid biosimilar competition. In 2017 Amgen launched an auto-injector for etanercept (Enbrel Mini) that was designed to reduce the pain of patient-administered injections. Further, AbbVie, owner of the adalimumab reference brand (Humira), which stands to lose exclusivity in the United States in 2023 to multiple biosimilar competitors, has a longstanding partnership with Unilife to use a system that allows patients to synchronize auto-injector products with their smartphones.

On the formulation side, in an effort to stall sales erosion to biosimilars for the trastuzumab originator Herceptin, Roche/Genentech 

 a subcutaneous delivery system (Herceptin Hycleta), which was approved by the FDA in early 2019.

Manufacturers have often used drug delivery systems to ward off competition following loss of exclusivity. With small molecular entities, this was seen with the introduction of extended or delayed-release products that would limit generic uptake. Now, such is the case with biologics. The number of drug-device combination patents, in general, 

 in recent years, marking the upward trend to differentiate and capture market share through delivery systems. Investigators reported that drug products with an associated patented delivery device rose from 3% in 2000 to 10% in 2016.

The number of strategic partnerships in the biologics space has increased as well, such as in the insulin and immunology categories, all of which demonstrates that developing and patenting convenient delivery systems (devices, formulations) that drive patient compliance and improve outcomes are embraced among manufacturers as 

life cycle management strategies against biosimilar competition.

Amgen's Onpro autoinjector device for pegfilgrastim is a stunning example of how product differentiation via drug delivery devices can protect market share in the biologics market.

Contributor: Drug Delivery Devices Help Originator Companies Retain Market Share

Isha Bangia, PharmD, MBA, is a manager of US market access at Certara Evidence & Access. She received her PharmD from Rutgers University and an MBA from Johns Hopkins University. Her current responsibilities include optimizing product value stories and working with customers to improve access across the US healthcare system. Her experience includes practicing pharmacy, payer market research, and pharma strategy and analytics. Her work has covered many therapeutic areas, including biosimilars, oncology, diabetes, vaccines, and rare diseases.

Isha Bangia, PharmD, MBA

Monica Mallampalli, PhD, is the advisor for strategic development and stakeholder engagement for HealthyWomen, a nonprofit women’s health advocacy organization based in Washington, DC.

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