The Value Potential of Biosimilars in the United States

BIOSIMILARS ARE BECOMING INCREASINGLY FAMILIAR to US pharmacists through a variety of channels. The continuous progress in biosimilar development signals a coming sea change in therapy options for patients, providers, and payers, which requires pharmacists to perform their due diligence evaluating these treatments.

As biosimilars emerge in the US market, pharmacists will no doubt find themselves acting as the gatekeepers to this altered landscape in terms of education, assurance, and compliance enforcement with new state and federal regulations and legislation. In the United States, biosimilars remain an enigmatic presence, full of promise but with many unknown factors.

At a high level, therapy stakeholders understand the potential value of biosimilars as a new, competitive generation of more cost-efficient drugs. Yet, the regulations and legislation surrounding biosimilars are relatively new and can be confusing to stakeholders throughout the pharmaceutical industry.

By delving into the details of what constitutes a biosimilar, its history, and how it is designated and regulated domestically, US pharmacists will be in a better position to navigate this new drug generation.

What Biosimilars Are and Are Not

Straight out of the gate, biosimilars are not generic drugs. Generic drugs are typically small-molecule drugs and are chemically identical to their branded counterparts. On the other hand, biosimilars are similar, but not identical copies of an FDA-approved originator product.

Most commonly, these FDA-approved biologic drugs are referred to as the reference product. For approval, the FDA requires that the biosimilar has the same mechanism of action as the biologic reference product.

Additionally, the biosimilar must be administered and provided in the same strength as the biologic reference product. Other requirements include following the FDA Current Good Manufacturing Practices to produce the drug.¹

Moreover, for the FDA to designate a biosimilar as interchangeable, the biosimilar must be able to produce the same clinical result as the reference product in any patient.² Further, the risks of reduced safety and efficacy associated with ongoing use of a biosimilar cannot be greater than the risks associated with exclusive use of the reference product.²

In order for a biosimilar to make it to market, its reference product must be past its exclusivity date.

A Global Snapshot

Biosimilars are in active use around the world. Europe has had regulatory pathways in place for biosimilars since 2005. The European Medicines Agency (EMA) made history by approving the first biosimilar drug in 2006. Today, there are 19 biosimilar drugs available in various European markets, which have resulted in significant cost savings.

Some studies estimate that by 2020, overall savings in the European Union could range from $16 to $45.2 billion.^1-3

Overall cost savings from biosimilars reportedly range from 20% to 30% compared with the reference products.⁴ Europe’s group of approved biosimilars largely consists of first-wave biologics, including human growth hormone, granulocyte colony-stimulating factor, a erythtropoesis stimulating agent, and insulin.

A tumor necrosis factor (TNF)-inhibitor was approved in 2013 as the first biosimilar monoclonal antibody.⁵ Other countries including Australia, Canada, India, Japan, and South Korea already have registered biosimilar products. Even more countries have biosimilar guidelines published or in draft form, all of which indicate a vast market ripe in longevity.⁶

Biosimilars in the United States

There is no universal regulatory arm regarding biosimilars. The regulatory process of approval is determined by each individual country or in Europe’s case, by the EMA. For many years, debates ensued on the pathway of how to approve a “biogeneric,” a term now replaced with the word “biosimilar.”

Because the United States was treading in unchartered territory, the FDA needed federal guidance before it could approve such drugs. Legislation specifically regarding biosimilars in the United States is young. This ground was broken in 2010 when President Obama signed the Patient Protection and Affordable Care Act (ACA) into law.

The ACA created an abbreviated and faster licensure pathway for biological products demonstrated as biosimilar to or interchangeable with an FDA-licensed biological product. These statutory provisions are also known as the Biologics Price Competition and Innovation Act of 2009.

Simply stated, a biosimilar product may gain a faster path to approval based on the extrapolation of clinical data and statistics from the reference product. Details to regulatory pathways can be seen in ACA sections 55 7001 through 7003.

Referred to as the 351(k) pathway, this section of the Public Health Service Act (42 USC. 56 262[k]) describes the requirements for a proposed biosimilar product or interchangeable product application.

The first biosimilar approved in the United States was Sandoz’s filgrastrim-sndz (Zarxio). Zarxio is the biosimilar of Amgen’s Neupogen, a biologic medication used to treat neutropenia, a common side effect of cancer chemotherapy. This biosimilar has been in use in Europe under the name Zarxio since 2009. Zarxio went to market in the United States on September 2, 2015, with an initial 15% cost reduction versus the reference product.²

Although movement toward Zarxio’s US approval and introduction into the market was slow, it represents momentum for the regulatory track record, which may help propel subsequent biosimilar applications.

Identifying Biosimilars and Interchangeable Drugs: the Purple Book

In a landmark move, the FDA published the first ever Purple Book, which is similar to the widely-used Orange Book (for small-molecule generics). The Purple Book has 2 primary purposes: to determine if a biological product licensed under the 351(k) pathway has been deemed by the FDA as biosimilar or interchangeable with an already approved reference biologic product and to provide information on an existing reference product’s exclusivity protection.

To fully understand how to use this book, it’s important to first note the FDA’s definition of what a biosimilar and interchangeable product are⁷:

• A biosimilar is a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biologic product and the reference product in terms of safety, purity and potency.⁷
• An interchangeable product is a product that has been shown to be biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient.⁷

Many clinicians have expressed concerns on how to determine if a product will be interchangeable. In part, because of these concerns, the FDA has indicated that it will list drugs in the Purple Book as “biosimilar” or “interchangeable.”

The US Biosimilar Pipeline

Many biosimilar products in the US pipeline will vie for FDA approval in the months and years to come. Some prominent examples include the following:

• Remsima: Celltrion is developing Remsima, which is a biosimilar to Johnson & Johnson’s infliximab (Remicade). Remicade is FDA-approved for the treatment of rheumatoid arthritis, plaque psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and ankylosing spondylitis. Its primary action is to reduce the effects of a substance in the body that can cause inflammation.8 Remicade interferes with TNF, a cytokine primarily secreted by macrophages that is implicated in some autoimmune conditions.⁹
• SB5: Merck and Samsung Bioepis are developing SB5, a biosimilar to Abbvie’s adalimumab (Humira). Humira is a monoclonal antibody that binds with TNF, which blocks its action. Humira is approved for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, chronic psoriasis, and juvenile idiopathic arthritis.
• Basaglar: Eli Lilly and Boehringer Ingelheim’s intended biosimilar Basaglar (US name) is already being sold as Abasaglar in Europe. The declared reference product is Sanofi’s Lantus, an insulin used for diabetes management. Basaglar was granted FDA approval in December 2015. However, the FDA approved Basaglar as a follow-on biologic instead of a biosimilar because there are no previous glargine insulin products licensed under the US Public Health Service Act.^11,12

There are 11 biosimilars to Roche’s trastuzumab (Herceptin) in the research pipeline.^13,14

Herceptin is a monoclonal antibody that interferes with human epidermal growth factor receptor 2 (HER2). Biosimilar clinical trials have recruited patients with metastatic breast cancer. It is believed that regulatory agencies are interested in seeing research in treatment naïve or patients at earlier stages of breast cancer since Herceptin is the standard of care for HER2-positive patients.¹⁰

Biosimilars present new opportunities for patients, health care providers, and pharmacists. These opportunities, however, will require pharmacists to carefully examine state laws and mandates associated with biosimilar dispensing, substitution criteria, interchangeability designations, patient and provider notification requirements, and patient counseling requirements.¹⁵

Biosimilar Value: Where Is It?

For patients with critical and hard-to-treat conditions, biosimilars, with their anticipated cost savings, offer potential for greater access among individuals eligible to benefit from biologic treatment. For physicians, the ACA has built-in incentives for prescribing biosimilar products.

According to the Centers for Medicare & Medicaid Services, the law sets the 2016 physician biosimilar reimbursement rate as the biosimilar’s average selling price (ASP) plus 6% of the reference product’s selling price, once the ASP is made available.

For example, in the United States the reimbursement rate is Zarxio’s ASP plus 6% of Amgen’s price for Neupogen, the reference product. Because Zarxio’s ASP may be unavailable for up to 2 quarters following its recent launch, payers can choose to set the level of reimbursement for Zarxio at the same level as Amgen’s Neupogen.¹⁶

Whereas Europe’s savings with the same biosimilar are approximately 25 to 30% against the reference product, comparative reimbursement practices and incentives are different. European cost savings may ultimately serve as a precedent applicable to US payers.

However, this remains to be seen as the biosimilar pipeline continues to mature in the United States. Most notably, the US health care system has the potential to save $12 billion in the first decade of biosimilar use and up to $250 billion by 2024.¹⁷

Therefore, the potential value of biosimilars, measured through patient access and health care system savings, is significant.

The Bottom Line

With more than $67 billion in biologic product patents set to expire before 2020, as well as pressure on the US health care system to increase patient access and cost savings, biosimilars show great promise in enhancing access to necessary medications for larger audiences, while containing payer costs across various disease states. SPT

References

• Biosimilars: more treatment options are on the way. FDA website. www.fda.gov/ForConsumers/ConsumerUpdates/ucm436399.htm. Updated March 6, 2015. Accessed?
• Background information: lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations (Purple Book). FDA website. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411424.htm. Updated March 5, 2015.
• Lapadula G, Ferraccioli GF. Biosimilars in rheumatology: pharmacological and pharmacoeconomical issues. Clinical Exp Rheumatol. 2012;30(4[suppl 73]);S102-S106.
• Biosimilars: a visual perspective. Hospira website. hospira.com/en/about_hospira/government_affairs/biosimilars_policy/understanding_biosimilars/biosimilars_infographic. Accessed September 5, 2015.
• Rehmann WA, Heimhalt D. Biosimilars in Europe: the role of the EMA's guidelines. SciTech Lawyer. 2015;11(3):8-11.
• Hurley P, Boren J, Congiatu C. Challenges in global biosimilar development: a regulatory perspective. Contract Pharma website. contractpharma.com/issues/2015-06-01/view_features/challenges-in-global-biosimilar-development-a-regulatory-perspective. Published June 2, 2015.
• US Food and Drug Administration (2014, November 18). FDA/CDER SBIA CHRONICLES.
• Information on tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). FDA website. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109340.htm. Updated July 8, 2015.
• TNF. Genetics Home Reference website. ghr.nlm.nih.gov/gene/TNF. Published January 11, 2016. Accessed? (2015, September 1). 1
• King S. FirstWord list: five things to watch out for in the biosimilars market in 2014. FirstWord Pharma website. firstwordpharma.com/node/1216357#axzz3hxJMAmTW. (2014, June 4). Accessed September 5, 2015.
• Koons C. Lilly to launch Lantus biosimilar in Europe in third quarter. Bloomberg Business website. bloomberg.com/news/articles/2015-06-06/lilly-to-introduce-lantus-biosimilar-in-europe-in-third-quarter. Published June 6, 2015. Accessed September 5, 2015.
• FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes [press release]. Silver Spring, MD: FDA; December 16, 2015. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm.
• Biosimilars approved in Europe. Generics and Biosimilars website. gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe. Published August 7, 2011. Updated January 14, 2015.
• Biosimilars of trastuzumab. gabionline.net/Biosimilars/General/Biosimilars-of-trastuzumab. Published September 19, 2014. Updated November 6, 2015.
• Li E, Ramanan S, Green L. Pharmacist substitution of biological products: issues and considerations. Academy of Managed Care Pharmacy website. amcp.org/WorkArea/DownloadAsset.aspx?id=19830. Published July 2015.
• Food and Drug Administration approval of first biosimilar product. Centers for Medicare & Medicaid Services website. cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/SE1509.pdf. Accessed?

About the Author

Tina Valbh, BS PHARM, RPH, is the vice president of clinical business strategies for Axium Healthcare Pharmacy in Lake Mary, Florida.