As one of Shakespeare’s most famous characters asked, "What’s in a name?”, the answer in the biosimilar industry is clear: nomenclature is critical for identification purposes.

The World Health Organization (WHO) has proposed a “biological qualifier” for tracking biologic products to institute a global approach for patient safety and traceability. As the WHO explains in its proposal, the naming approach “is designed to provide a uniform global means of identification to avoid the proliferation of differing national schemes” — meaning a unified naming system.

But not all stakeholders agree this is the most effective way to move forward.

In 2015, Dr. Janet Woodcock, Director of FDA’s Center for Drug Evaluation & Research and Dr. Karen Midthun, Director of FDA’s Center for Biologics Evaluation and Research, proposed a draft guidance requesting reference products and biosimilars have nonproprietary names (proper names) that share a core drug substance name and for each product, a unique FDA-designated suffix composed of four lowercase letters. For interchangeable biological products, public feedback about whether the nonproprietary name for a product should include a distinct suffix, or share the same suffix as its reference product.

The proposed naming convention seeks to address two main issues: To help prevent accidental substitution of biological products that are not determined to be interchangeable by the FDA, which could lead to medical error; and to support safety monitoring of all biological products after they are on the market with more accurate tracking of the usage of biological products in multiple care settings: outpatient, hospital, and pharmacy.

The FDA’s draft guidance on naming, according to the FTC, could “

result in physicians incorrectly believing

 that biosimilars' drug substances differ in clinically meaningful ways from their reference biologics' drug substances.” The FTC suggested the FDA's proposal would inhibit competition intended to lower prices on biologic medications; many are the most expensive types of drugs in the marketplace. 

The suggestion was that the FDA could track drugs by their brand or trade name instead of a new nonproprietary naming system. The FTC’s rationale is to employ a post-market tracking system and minimize mistakes made when entering information, such as the wrong suffix for a specific drug. 

 along with the Hematology/Oncology Pharmacy Association, among pharmacist members, where it offered insight into how the profession feels about naming conventions for biosimilars. Among 781 poll-takers, the clear favorite was the nonproprietary proper name with a designated suffix. However, when asked about their level of confidence when dispensing a biosimilar instead of the reference biologic, pharmacists were more sure when the products had the same nonproprietary name in common.

The poll also probed attitudes regarding regulations requiring pharmacists to submit postdispense notifications. The results suggest the obligations placed on pharmacists could deter some from dispensing interchangeable biologics, although this hesitance would be mitigated if the biologics were to share the same nonproprietary name as the reference biologic.

Amgen’s executive director of global operations, Gino Grampp, says his company supports policies that ensure biologicals, both originators and biosimilars are prescribed, dispensed and monitored appropriately. “We are very concerned about a tendency to move towards International nonproprietary names (INN)-based prescribing and dispensing by INN, and towards INNs being used in adverse event reports” for biologicals. Grampp also said that clear identification and traceability was “a good way of achieving this. So we support measures to promote product- specific traceability in health records and pharmacovigilance reports, and we believe that identifiers like the BQ or the (US) FDA’s four-letter suffix will help.”

The European Biosimilars Group (EBG), part of the European Generic and Biosimilar Medicines Association, openly challenged the proposed biosimilars naming convention in a policy document presented at the WHO consultation meeting in April 2015, “The current system works well; the introduction of a special system for a specific class of products disrupts this well-working unified system,” said the EBG. “Physicians and pharmacists will be confused as to what to do with the new, unknown identifier. This increases the risk of prescription errors, dispensing errors, medication errors and adverse reaction reporting errors.” The 

 can only increase the risk of error or hinder pharmacovigilance.

The US Generic Pharmaceutical Association (GPhA) is also not clear why the addition of a BQ to the INN would provide any additional value as it thinks the current INN naming system is simple and should not be changed, according to a WHO document published in March 2015. The GPhA also thinks the proposed BQ scheme should not have a manufacturing site designation, but if a modifier is to be used, the clearest format would be the marketing authorization holders’ (MAH’s) name.

For nearly a decade, BIO has advocated actively for a nonproprietary naming convention that ensures all biological products are distinguishable, and believes that a distinguishable nonproprietary naming convention would best facilitate pharmacovigilance, ensure accurate attribution of adverse events to the correct product, prevent inappropriate substitution and unintended switching, and support tracing of products in the event of a recall. In short, BIO strongly believes that distinguishable nonproprietary names enhance patient safety.

A date has not yet been set for the FDA’s formal ruling on biosimilar naming conventions in the US—but clearly the debate will continue among the key industry stakeholders until the decision is finalized.

As one of Shakespeare’s most famous characters asked, "What’s in a name?”, the answer in the biosimilars industry is clear: nomenclature is critical for identification purposes.

Naming Biosimilars: The Debate Rages On

Daniella Latham

A phase 1 equivalence study of ABP-215 (Mvasi, the first FDA-approved biosimilar bevacizumab) concludes that ABP-215 demonstrated pharmacokinetic (PK) similarity to the reference drug in healthy Japanese men.

 is an inhibitor of blood vessel growth and is 

 in the United States for chemotherapy and targeted therapy for colorectal, lung, glioblastoma, kidney, and cervical cancer. 

Safety profiles were comparable between subjects dosed with the reference and the biosimilar, and PK data in Japanese subjects were consistent with those previously shown in global studies. 

 by Vladimir Hanes, MD, and colleagues in 

The randomized, single-blind, single-dose, parallel-group study had as its primary endpoints maximum observed serum concentration (C

) and area under the serum concentration—time curve from time 0 to infinity (AUC

). Secondary endpoints included AUC from time 0 to time of last quantifiable concentration (AUC

), safety, tolerability, and immunogenicity. The study lasted 57 days. 

Each of the 2 study groups had 24 subjects; all had similar baseline characteristics and were between 18 and 45 years of age. All 48 study subjects completed the infusion; 46 completed the study because 2 were lost to follow-up. 

After a 3-mg/kg IV infusion, the geometric means (GM) of C

were71.2 μg/mL, 25,259 μg h/mL, and 22,499.3 μg h/mL, respectively, for ABP-215 and 70.16 μg/mL, 25,801 μg h/mL, and 22,604.6 μg h/mL, respectively, for bevacizumab. The GM ratios (90% CI) for C

were 1.015 (0.946-1.088), 0.979 (0.914-1.049), and 0.995 (0.941-1.053) for ABP-215 versus bevacizumab. All confidence intervals were within the prespecified bioequivalence margin of 0.80-1.25. 

Adverse events (AEs) occurred in 2 of 24 subjects receiving ABP-215 and 1 of 24 receiving reference drug. No subject experienced an infusion reaction or hypersensitivity AE in the first 2 days after study drug administration. There were no deaths or AEs leading to discontinuation, and no patient was positive for binding anti-drug antibodies. 

The researchers concluded that their data were consistent with the PK equivalence previously demonstrated in a single-dose PK study that included 202 healthy adult men in the United States and European Union, and thus add to the evidence of ABP-215 as a high-quality biosimilar to bevacizumab for use in Japan. 

Hanes V, Chow V, Pan Z, Markus R. A randomized, single-blind, single-dose study to assess the pharmacokinetic equivalence of the biosimilar ABP 215 and bevacizumab in healthy Japanese male subjects. 

2018;82:899-905. doi: 10.1007/s00280-018-3695-4.

The researchers say that their data were consistent with the pharmacokinetic equivalence previously demonstrated in a single-dose PK study that included 202 healthy adult men in the United States and European Union, and thus add to the evidence of ABP-215 as a high-quality biosimilar to bevacizumab for use in Japan. 

Study Finds ABP 215 and Bevacizumab Demonstrate PK Similarity in Japanese Men

Jackie Syrop

Nicola Davies, PhD, has a background in health psychology and over a decade of experience in medical writing. In addition to writing both US and EU regulatory columns, she has produced many large industry reports for the pharmaceutical industry. Topics she has covered range from orphan drugs to biosimilars, digital health, clinical trials, medical affairs, and payer perceptions, among many others. She also produces independent medical education for healthcare providers wishing to develop their knowledge of the pharmaceutical landscape.

Nicola Davies, PhD

Unlike flu epidemics, which are regional, the coronavirus disease 2019 (COVID-19) is a pandemic that crosses international boundaries and affects a very large number of people. While many companies are in lockdown, pharmaceutical companies are identifying methods of ensuring supply continuity so that patients taking regular medication can continue to receive the treatments they need. Without the maintenance of medicine supply chains, lifesaving medicines could become unavailable, with the health of many unwell people being compromised.

Some European Union (EU) member states have indicated that they expect shortages to occur soon or are starting to experience shortages of certain medicines being used to treat patients with 

. In April 2020, the European Medicines Agency organized the first meeting of the EU Executive Steering Group to address the impact of COVID-19 on the supply of medicines in Europe. The group aims to supply strategic leadership for urgent action and will identify and coordinate EU-wide actions to protect patients who may be affected. The FDA is working closely with manufacturers to mitigate shortages and has recommended that, should the need arise, alternative medications be used by patients.

Samsung Bioepis is a biopharmaceutical company that supplies medicines to many countries around the world. COVID-19 affects our business, as it does many others in the pharma industry. Six months ago, there were about 100,000 planes flying globally every day. Now, there are fewer than 60,000 

 each day, and many flights are cancelled or delayed depending on infection rates in different regions. Our freights are examined and re-examined according to newly implemented processes due to COVID-19, adding additional transit days to already lengthened supply chain lead-times; and our raw material suppliers and manufacturing partners are working nonstop to support our strained supply chain with limited resources and limited capacities. We have implemented mitigation plans and changed our working patterns to minimize the impact COVID-19 has on medicine supply.

For Samsung Bioepis, our supply chain is geographically diversified. To ensure supply continuity and flexibility to swiftly respond to market changes, we have regionalized supply chain activities to provide near-market manufacturing. And under the current situation, this has been beneficial for our supply chain. However, based on recent lessons learned about COVID-19 challenges for logistics, we spend more time with our logistics vendors or internally develop freight-routing possibilities to ensure the supply of medicine is not diminished. Based on the latest flight schedules, we review and update, on a weekly or sometimes daily basis, routes, shipping solutions, and modes of transport. We are also working to build and diversify our current modes of transport, shipping solutions, and routes to provide more flexibility when moving our biosimilar products around world during this challenging time. Fortunately, with these reviews and actions put in place, we have not experienced any disruptions to the supply of our biosimilars.

Recently, there has been a debate about whether manufacturing of “critical” prescription drugs should become more US-based to ensure the availability of medicines to patients in the United States. Many times, supply chains are globalized not just because of cost benefits but also due to advancements in technological know-how. Yes, it may be cost-effective to manufacture active pharmaceutical ingredients (APIs) or specific raw materials in certain parts of the world, but these countries may have a technological advantage for making critical APIs and raw materials at a much larger scale for global supply. Therefore, the use of incentives to spur in-country manufacturing of critical APIs and raw materials may not be sustainable in the long run, especially as the critical prescription drug list becomes longer.

Currently, many biopharmaceutical companies are rushing to develop a COVID-19 vaccine. Once a vaccine is developed and approved, what are the next steps to bring production to commercial scale and make this vaccine available to everyone in need?

In a time when the global supply chain is essential, we need to work together to remove the roadblocks to ensure that all “critical drugs” are provided to patients who need them. Globalization of the supply chain provides value for the efficient manufacture and distribution of these critical APIs and raw materials. It takes into consideration the technology and the global resources necessary to do so. By harmonizing these supply efforts and providing guidelines that all countries can follow, these critical APIs and raw materials can be supplied globally during the pandemic, ensuring that medicines are provided to patients in a timely manner. COVID-19 is changing the current supply chain every day and, to ensure critical drugs are provided to patients who desperately need them, industry and regulatory agencies should come together to stabilize a supply chain that is sustainable in the long-run.

Kris Soyoung Lee is the vice president of the Supply Chain Management team at Samsung Bioepis. She has more than 20 years of experience in supply chain management across various industries including chemical, pharmaceutical, and biopharmaceutical.

How Samsung Bioepis Has Restructured Its Supply Chain Amid the Pandemic

Kris Soyoung Lee is the vice president of the Supply Chain Management team at Samsung Bioepis of Incheon, Republic of Korea. She has more than 20 years of experience in supply chain management across various industries, including chemical, pharmaceutical, and biopharmaceutical.

Kris Soyoung Lee

From the Editorial Board

The biosimilar market, especially in the United States, is in its infancy, with the first biosimilar approval in 2015. There are considerable differences and some similarities between the generic and biosimilar markets. Many barriers make biosimilar entry more difficult than was the case for generics. Some are the high cost of research and development (R&D); FDA approval, including manufacturing site acceptability; originator response; litigation, especially involving patents; stakeholder education; required postmarketing vigilance (phase 4); the lack of automatic substitution at the pharmacy, and biobetter development.

Biosimilars cost more to develop and this process takes much longer than for generics. Biosimilar 

 costs between $100 million and $200 million and takes from 8 to 10 years.

The long time for development means that returns have to be substantial to cover the interest cost. For example, Celltrion has 

 $112 million in the development of the infliximab biosimilar Remsima, which references Remicade. Amgen spends around $200 million on average on R&D for each biosimilar. Their complexity makes expertise in manufacturing important. Companies experienced in biologic manufacturing will have a learning curve advantage that translates into a cost advantage and makes entry risky for new or startup firms. Although some successful entrants into biosimilars may be small or startup firms, most are likely to be large biopharmaceutical companies that have successfully launched reference products. For example, Pfizer and Amgen are biosimilar entrants.

Initially, the first biosimilar for each reference product has entered at around a 15% discount from the list price. Samsung launched the second infliximab biosimilar at a 35% discount and Pfizer, the first to market with an infliximab biosimilar, lowered its price to match. Although generic drug launches tend not to force price decreases from originators, the opposite is the case with biologics. Generally, the reference product has already achieved a return on its investment during the time of intellectual property protection. It is still making a profit at the lower price, because it needs only cover its marginal costs.

Biosimilar firms will enter only if they believe they can get a return on investment. Too high initial discounts could discourage future entry into the biosimilar market. For example, in Norway there have been discounts of around 70%. One could see short-run benefits of lower prices, but fewer entrants and thus higher prices in the long run.

Given the market opportunity, there is expected to be an influx of biosimilars. For example, Coherent Market Insights 

 that the global biologic market will exceed $456.8 billion by 2027, up from $255.2 billion in 2019. US biologic sales in 2018 were $125.5 billion, up 9.5% from 2017, according to an IQVIA 

. In 2018, biosimilars had captured about 12% of the total spending on biologics, according to the same report. Some biologics have sales of over a billion dollars with some over $10 billion. Indeed, the world’s largest revenue-producing drug is the biologic Humira with sales of almost $19 billion in 2019.

Many firms are making huge investments in biosimilars. It is estimated that over 500 biosimilars are in development with over 200 being publicly 

Not surprisingly given sales of Humira, 8 adalimumab biosimilars have had patent settlements but none will enter US market until 

, and many more are in development. At least 8 different biologics have a minimum of 20 biosimilars in development.

If, for example, 19 biosimilar producers entered for a specific reference product and each company shared the market equally along with the originator, each company would get 5% of the market. Based on a $1 billion market prior to entry and an estimated 40% price discount, the annual revenue would be $31.6 million for each biosimilar company. Such a small annual revenue would make recoupment of investment difficult. Further, in most cases the biosimilars capture only a small part of the market. Also, originators are developing second-generation biologics that could make biosimilars obsolete for first-generation biologics.

The difficulty and risk of entry into the biosimilar trade is indicated by some notable exits. Merck KGaA (separate from Merck & Co) sold its biosimilar unit and departed the biosimilars business in 2017. Allergan has decided to leave the biosimilar market after it finishes the 4 cancer biosimilars that it is developing with its partner Amgen. Momenta has 

 that it is dropping all of its biosimilars except for an aflibercept candidate (M710, Eylea). Pfizer will 

In 2016, Epirus, a biosimilar upstart, filed for Chapter 7 bankruptcy. In 2018, Merck paid $155 million plus interest to get out of its 

 with Samsung Bioepis to develop an insulin glargine biosimilar to reference Lantus. Baxalta discontinued its development of biosimilars when it was purchased by Shire in 2016. Oncobiologics restructured and renamed itself Outlook Therapeutics and now has just a bevacizumab formulation under development, although it intends to seek FDA approval for that as a novel product.

Each company must determine what its biosimilar portfolio should be or whether it should even enter the market. Businesses that choose to enter should probably enter with more than 1 biosimilar. The more biosimilars in a portfolio, the greater is the investment needed, but the risk is lower. The greater the revenue

reference biologic, the greater the probability of more competition. The more companies that enter, the greater will be the price discounts. Some may want to enter smaller revenue markets, which could potentially be more profitable because of less competition. A combination of entering small

 medium, and large biologic revenue markets may be the best strategy. 

If the grand biosimilar experiment succeeds, competition will lead to lower prices and increase access. If biosimilar competition does not work, the result may be price controls. This could decrease the incentive to innovate and lead to fewer new drugs being developed.

In the United States, many stakeholders are serious about controlling health care costs. Payers are promising tough negotiations for expensive drugs. Also, as physicians and patients become more familiar and comfortable with biosimilars, these should do better. All the factors point to a highly competitive market, but it will take some time to develop. Historically, the EU generic market was not as strong as the comparable US market, so we might expect greater biosimilar uptake eventually in the United States.

Biosimilars and biologics are highly similar so there is not much difference, if any, in therapeutic effect. Mature markets will have 5 to 6 biosimilar competitors, with most being well-established, branded companies. Many biosimilars will not succeed. In the next 5 years there should be significant growth in the biosimilar market, considerable price discounts, and increased access. There may even be more new biologics as originators lose revenues and must innovate.

The biosimilar market is headed for a fork in the road, and the road taken will lead to savings and access or less competition and stiffer regulation.

Expect Shakeout Amid Biosimilar Market Growth

Erwin A. Blackstone, PhD, is a professor of economics at Temple University in Philadelphia, Pennsylvania. He has taught economics for over 40 years. Prior to coming to Temple in 1976, Blackstone taught at Dartmouth College and Cornell University. His research areas and publications include the economics of industrial organization, health economics, and antitrust topics.

Erwin A. Blackstone, PhD

Biosimilars appear to be the only logistical solution to the rising cost of medicines, and 2 organizations in particular, the International Oncology Network (ION) Solutions and the Community Oncology Alliance (COA), have worked hard independently and on Capitol Hill to advance biosimilar-favorable legislation, according to Kashyap B. Patel, MD, a member of The Center for Biosimilars’ Advisory Board who spoke about biosimilar uptake in a recent interview.

“They both have put their full force behind supporting biosimilars,” Patel said of both organizations, in which he has been a participating member.  

Patel, of Carolina Blood and Cancer Care Associates, in Lancaster, South Carolina, said his practice is a participant in the value-base-care—centered Oncology Care Model and has chosen to adopt new biosimilars immediately after they’re approved. “We’ve assimilated them very quickly into our practice. I see biosimilars as one of the only lifetime opportunities of reducing the cost of care,” he said.

He described the assimilation of these products in his practice as substantial, although he said that it has not been easy to do this, given that payers have not uniformly opened the door to coverage of these agents.

ION is a large purchasing cooperative that has formed a biosimilars committee, which provides education for providers, payers, and pharmacists. Patel participated in the formation of that committee, but said it was challenging to teach ION members about the distinction between generics and biosimilars.

An important issue in biosimilar access is the decision process that goes into the choice of biosimilars to offer participants in a care plan. In the case of infliximab and trastuzumab, there are multiple biosimilars on the market. “ION tends to be agnostic of the manufacturer,” Patel said about the purchasing organization’s choice of biosimilars. “I think they want to work with all the manufacturers who are willing. And there’s going to be regional variation based on the payer coverage.”

ION as an intermediary works to establish manufacturer relationships and leaves it up to the physicians to decide which of the available biosimilars to use. However, “ION has chosen to go with supporting biosimilars as a part of a social responsibility,” Patel said.

COA is an organization of community oncology practices that, while not acting as a contracting representative for biosimilars and other drugs, works to promote the availability of biosimilars, Patel said. “Our role at COA is just to make sure that we bring every toolkit for our teams’ colleagues and work with the payers to help them understand the relevance of the biosimilars in addressing [Medicare] Part B drug price [issues]. We want to do everything possible we can to reduce the drug price in conjunction with the government, Senate, Congress, and payers.”

Kashyap B. Patel, MD, has worn many hats in the struggle to broaden biosimilar access. He is an independent oncology practitioner, a member of the Community Oncology Alliance (COA), and a representative of International Oncology Network (ION) Solutions, a large drug purchasing organization. Bringing biosimilars to a broader population of patients has involved negotiations with payers, persistence on Capitol Hill, and education, he explains in an interview.

Patel: Biosimilar Education Can Be Challenging

The Center for Biosimilars Staff

ZS is a professional services firm that works side by side with companies to help develop and deliver products that drive customer value and company results. ZS leverages its deep industry expertise, leading-edge analytics, technology, and strategy to create solutions for helping companies and their customers thrive. The firm has more than 35 years of experience and 7000-plus ZSers in 27 offices worldwide. 

Gary Fanjiang, MD, MBA, MS, is the vice president of global development at Amgen, where he leads research and development activities for the Biosimilars Business Unit. He oversees the nonclinical, clinical, and medical affairs activities across a portfolio of 10 molecules in various stages of development in multiple therapeutic areas and indications of use. He previously served as executive medical director of global development at Amgen. Prior to joining Amgen, he held multiple positions at Abbott over the course of 8 years, and he held the associate director of clinical research role at AstraZeneca. After graduating from Tufts University and completing his residency and fellowship, he served as a fellow of pediatric gastroenterology and nutrition at Massachusetts General Hospital.

Gary Fanjiang, MD, MBA, MS

By the end of 2019, 26 biosimilar products had been launched in the United States. As 2020 gets underway, there are several pending legislative proposals designed to encourage more commercialization of these cost-saving drugs.

Elijah E. Cummings Lower Drug Costs Now Act

 could indirectly affect biosimilars. Two proposals of note would directly change drug costs for biosimilars if the law is passed.

The first proposal would require the HHS secretary to add a new set of measures to the 5-star rating system under Medicare in order to encourage increased access to biosimilar biological products. Specifically, the proposed legislation calls for determining whether a biosimilar is on formulary and whether and how utilization management tools are applied with respect to a biosimilar. The bill also calls for determination of the percentage of enrollees prescribed the biosimilar product when the reference biologic is also available.

The second proposal would temporarily increase the amount Medicare Part B pays for biosimilars for 5 years. This means that Medicare would pay the average sales price (ASP) plus 8% rather than plus 6%. The product would have to meet certain pricing criteria in order to qualify.

Both proposals may increase the utilization of biosimilars. The star rating system currently used does not make a distinction for biosimilars and allows payers to use the same policies for biosimilars and brands as they do for generics and brands. This can mean that a specialty pharmacy that dispenses under Part B does not get the same credit as a pharmacy that dispenses for Part D. Establishing new guidelines for the star rating system can help specialty pharmacy use more biosimilars and get credit toward its ratings with the payer.

An ASP increase of 2 percentage points could help cover additional costs for specialty pharmacy for educating consumers about biosimilar utilization.

This bill has passed the full House and has yet to be taken up by the Senate.

HR 4597: Acting to Cancel Copays and Ensure Substantial Savings for Biosimilars (ACCESS) Act

 would eliminate a patient’s copay for a biosimilar under Medicare Part B. The bill would drive down medical costs by increasing access to lower-cost biosimilar drugs and give Americans more treatment options. This bill has been referred to the Subcommittee on Health in the House.

: Preserve Access to Affordable Generics and Biosimilars Act

This would prohibit prescription drug companies from compensating other prescription drug companies to delay the market entry of a generic drug, biosimilar biological product, or interchangeable biological product. This would basically make “pay for delay” in patent settlements illegal. This legislation has cleared the Judiciary Committee and is pending in the House.

S 1416: Affordable Prescriptions for Patients Act of 2019

Originally, this legislation was aimed at allowing the Federal Trade Commission antitrust enforcement powers to sue manufacturers who use patent thickets to block generic and biosimilar products from launching. Since its introduction, the bill’s main sponsor, Sen John Cornyn, R-Texas, has stated that he is redesigning the bill to shift the enforcement power to the FDA instead of the FTC. As currently modified, the bill addresses anticompetitive practices involving manipulation of the availability of reference drugs. There is other patent thicket legislation proposed, which would be stricter than S 1416, but it is unknown when this would come to a vote in the Senate.

With the election season well underway, it remains to be seen whether any of these bills will advance before the year’s end.

There are several pending legislative proposals in both the House of Representatives and the Senate designed to encourage more commercialization of biosimilars, but the 2020 election may determine their timing.

Authors