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.

Monica Mallampalli, PhD

Robert Levin, MD, is a practicing rheumatologist and patient advocate. He serves as president of the Florida Society of Rheumatology and chair of the Alliance for Transparent and Affordable Prescriptions (ATAP), a coalition of healthcare provider and patient groups concerned about the practices of pharmacy benefit managers (PBMs).

Robert Levin, MD

) was launched for use as a supportive care treatment about 1 year ago, the pegylated version (pegfilgrastim) Neulasta

 is, by far, the more commonly prescribed agent. This agent has a significantly longer half-life than its predecessor and is the preferred agent in patients receiving cancer chemotherapy.

most costly prescribed oncology drugs in the US market

 based on cost and utilization. Even though the patent 

 in the US there is no approved biosimilar in the US and even in Europe as of October 2016. This may be because of the difficulty in 

 for decreasing the incidence of infection in the presence of febrile neutropenia, in patients with nom-myeloid tumors receiving chemotherapy associated with febrile neutropenia, and for increasing survival in patients receiving myelosuppressive doses of radiation.

The type of studies required by the US Food and Drug Administration (FDA) to approve a pegfilgrastim biosimilar to treat chemotherapy-induced neutropenia is expected to be similar to those submitted by Sandoz for Zarxio. Those studies focused on nonclinical investigations (i.e., mechanism of action, manufacturing, analytical similarity [structure and biologic activity, receptor binding, protein binding, stability], immunogenicity, animal pharmacology and toxicology, and bioavailability), and clinical studies. In the case of Zarxio, Sandoz conducted 4 clinical studies in healthy subjects and one in patients with cancer, which confirmed the pharmacokinetic attributes of the product and the increase in absolute neutrophil count (ANC). According to FDA staffers 

 on Zarxio “a study in healthy volunteers is considered to be more sensitive in evaluating similarity between products because the population is likely to produce less PK variability compared with that in patients with potentially confounding factors such as underlying disease and concomitant medications.”

Currently, 5 drug makers are actively involved conducting clinical trials for pegfilgrastim products (Table): (1) Apotex/Apobiologix (drug name not known), (2) Coherus BioSciences (CHS-1701, (3) Mylan/Biocon (MYL-1401H), (4) Pfizer (HSP-130), and (5) Sandoz (LA-EP2006). A Korean company, Dong A, registered a trial with 

 however, no study sites were in the US and their website does not indicate that they have plans to file for approval in the US, even though their product is approved in Korea. Teva had submitted their product for approval to the FDA; however, they 

 in 2013 even after they had resolved litigation with Amgen and had agreed to 

 to launch their product after FDA approval.

Table: Pegfilgrastim Products in Development

Filed for approval in US in November 2015, but FDA issued a complete response letter; Filed for approval in the EMA in Feb 2016

Information updates are not available about this product. The FDA accepted the filing under the 

 for the biosimilar in December of 2014. In September 2016, the District Court for the Southern District of Florida ruled that Apotex’s product 

; however, Apotex must give Amgen 180 days’ notice of their intent to market the product after they receive FDA approval. Since the FDA accepted the application 23 months ago, it must be assumed that a complete response letter has been issued by FDA (these are not made public by the agency, and the manufacturers do not always disclose this fact). If this agent is approved by the FDA, it will be marketed by Apotex’s US subsidiary Apobiologix.

The immunogenicity of CHS-1701 was tested in a study of 303 healthy subjects. Patients were enrolled in a double-blind, randomized, 2—period, parallel-arm study. They received 2 sequential subcutaneous doses (6 mg) of CHS-1701 or the Neulasta. The researchers did not detect any neutralizing antibodies with either product; the percent difference in anti-drug antibody response was within the prespecified criteria for a biosimilar. The 

A study comprising 122 healthy subjects assessed pharmacokinetic (PK) and pharmacodynamics parameters as well as safety. The study compared CHS-1701 and the originator product in a 3-sequence, 3-period crossover design that was single blinded. Results for absolute neutrophil count and PK parameters were within the prespecified margins of 80% to 125%, demonstrating that it is a biosimilar to Neulasta. The safety profiles of the products were similar; serious adverse events or study discontinuations were not seen with either product(

http://investors.coherus.com/phoenix.zhtml?c=253655&p=irol-newsArticle&ID=2184363

 application for CHS-1701 to the FDA on August 9, 2016.

MYL-1401H was tested in a controlled, double-blinded, randomized phase III trial of individuals with newly diagnosed stage 2/3 breast cancer who were eligible to receive docetaxel, doxorubicin, and cyclophosphamide every 3 weeks for 6 cycles. The 194 enrolled patients received either the biosimilar or the European-licensed version of Neulasta at a dose of 6 mg/0.6 mg subcutaneously on day of 2 of each chemotherapy cycle. The primary endpoint was the duration of severe neutropenia (ANA < 0.5 x 10

/L) in the first chemotherapy cycle. Equivalence was defined as being if the confidence interval of the least squares means difference between the duration of severe neutropenia (DSN) fell within the range -1 to +1 days.

The trial revealed a mean DSN of 1.2 for both products, and a least squares means difference that met the prespecified criteria for equivalence. Other end points were also similar (e.g., the frequency of grade 3-4 neutropenia, time to ANC nadir, and duration of post nadir recovery). Additionally, 

 reported bone pain as the most frequently reported treatment-emergent adverse event.

A randomized, double-blind, 3-period, 3-treatment, crossover study was conducted in healthy volunteers, comparing compared the PK and PD of MYL-1401H, EU-Neulasta, and US-Neulasta. The 208 study participants received a 2-mg subcutaneous dose for each phase of the study. All of the PK and PD results were within the predefined equivalence criteria. There were no notable differences in 

 between the biosimilar and the European- and US-licensed versions of Neulasta.

At this time, MYL-1401H has not been submitted for review by the US FDA.

A comparison trial in 308 patients with early-stage breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy were randomized to receive 6-mg doses of either LA-EP2006 or Neulasta. The patients received docetaxel, doxorubicin, and cyclophosphamide on day 1 followed by LA-EP2006 or the reference product subcutaneously on day 2 of each cycle for at least 6 cycles of therapy. The mean DSN during cycle 1 was the primary end point. Secondary end points included time to ANC recovery, number of days of fever, frequency of infections, mortality from infection, and number of episodes of febrile neutropenia by cycle. Safety was also assessed during the trial.

Pegylated version (pegfilgrastim) Neulasta® is the more commonly prescribed agent, with a significantly longer half-life than its predecessor and is the preferred in patients receiving cancer chemotherapy.
 

Supportive Care in Oncology Therapy: Pegfilgrastim Biosimilars in the Pipeline 

Marj P. Zimmerman, BSPharm, MS, Stanton R. Mehr

global biosimilars week webinar

 was hosted by The Center for Biosimilars

 in partnership with the International Generics and Biosimilars Association.

Global Biosimilars Week (GBW) 2024 is an annual campaign designed to raise global awareness about biosimilar medicines and their role in improving patient care and access to affordable treatment options.

This year’s theme, "Advancing Access to Biosimilars," focuses on the progress made over the past two decades surrounding approval, market acceptance and adoption of biosimilars—as well as the challenges that remain in expanding access worldwide. With an effort to highlight the importance of collaboration among health care professionals, patients, stakeholders, and policymakers, the webinar will focus on 

 to advance access to biosimilars and will feature expert discussions on the key barriers to biosimilar uptake in different regions and explore strategies to overcoming these obstacles.



Current global trends in streamlining biosimilar regulatory requirements to foster efficient adoption and market growth.

Strategies to address challenges and improve biosimilar access.

The role of biosimilars in promoting health care sustainability and better patient outcomes.

, assistant managing editor of The Center for Biosimilars (host)

, senior vice president of sciences and regulatory affairs, Association for Accessible Medicines (moderator)

, PhD, Executive Director for Products Evaluation and Standards Setting, Saudi Food and Drug Authority

, PhD, scientist, technical standards and specification unit group lead, norms and standards for biologicals, Health Product Policy and Standards/Medicines and Health Products/World Health Organization 

enior quality specialist, European Medicines Agency

, director, Office of Therapeutic Biologics and Biosimilars Office of New Drugs, Center for Drug Evaluation and Research, FDA

This webinar celebrating Global Biosimilars Week was hosted by The Center for Biosimilars® in partnership with the International Generics and Biosimilars Association.

Authors