Biosimilars Coming to Market in 2015, Questions Ensue

Boston—The first US FDA-approved biosimilar agent is expected to hit the market in March 2015; however, this debut of a new area of treatment still has a number of questions and concerns attached to it.

Biosimilars are biological products that are demonstrated to be highly similar to an FDA-approved reference product. The FDA’s biosimilar approval pathway, 351(k), was created through the Biologics Price Competition and Innovation Act of 2009, initiated under the Patient Protection and Affordable Care Act. The first biosimilar to be approved in the United States is likely to be filgrastim, which is manufactured by Sandoz, a Novartis Company.

During a satellite symposium at the AMCP meeting, a panel discussed the impending introduction of biosimilars and how they will affect the market. The session was supported by an educational grant from Hospira, Inc.

Steven D. Lucio, PharmD, BCPS, senior director, clinical solutions and pharmacy program development, Novation, opened the session with an introduction on biotechnology. “Biotechnology has helped us do many things we may not have been able to do otherwise,” said Dr. Lucio.

Through biotechnology, medical advances have occurred in oncology, rheumatoid arthritis, and Crohn’s disease. According to the session, biotechnology makes the following possible:
• Prevention, cure, and treatment of more diseases
• Targeted, more effective, and less toxic medicines
• Proactive versus reactive approach to treatment
• Production of replacement human proteins
• Production of “pure” drugs; not contaminated by infectious pathogens from human or animal sources

The period of exclusivity for many biologic agents is quickly approaching, and as patents expire in the next 3 to 5 years, biologics will begin to face competition from biosimilars. Dr. Lucio noted that the following are top products that are being targeted for biosimilar production: human insulin, interferons, epoetin alfa, darbepoetin alfa, filgrastim, pegfilgrastim, sargramostim, trastuzumab, rituximab, cetuximab, and bevacizumab.

Challenges, Questions, and Concerns
The introduction of biosimilar agents poses many questions for healthcare providers. Because biologics are derived from living organisms, no 2 molecules behave the same exact way. “There is variability in all biologics,” said Dr. Lucio. “[There is] a greater level of complexity with these agents.”

The manufacturing process for biologic agents starts with an active ingredient derived from living cells under different culture conditions that are produced from materials used in the formulation process to come up with the purification and storage process. Dr. Lucio explained the difference between generics and biosimilars, saying the process goes “above and beyond what generic companies would have to deal with. [We] cannot call [biosimilars] generic biologics because they cannot be replicated exactly.”

Dr. Lucio noted the differences between generics (small molecules) and biosimilars (Table). Small molecules are regulated under the Food, Drug, and Cosmetic Act, while biologics and biosimilars are regulated under the Public Health Services Act. Though small molecules given abbreviated new drug application designation under the 505(j) application pathway do not require any additional clinical studies based on clinical bioequivalence, biologics that are given biosimilar application designation under the 351(k) application pathway do require additional clinical data from at least 1 new phase 1 trial.

Post-translational modifications, such as pegylation, glycosylation, alkylation, and phosphorylation, could all influence efficacy and safety between biosimilars and the reference biologic product. The difficult determination of variances that are not clinically meaningful will fall on the FDA during the review process of biosimilars. Variances are problematic because the immune system can detect differences, which could lead to adverse effects, such as anaphylaxis, hypersensitivity, and reaction, according to Dr. Lucio.

The first FDA guidance documents on biosimilars were published February 9, 2012, discussing quality and scientific considerations in demonstrating biosimilarity. Another document followed in March 2013, and so far this year, 2 documents have been published regarding clinical pharmacology data to support the demonstration of biosimilarity and reference product exclusivity for 351(a)-filed biological products. An additional 3 documents are expected to be published before the end of the year, tackling questions on interchangeability and label-originator data.

A challenge the biosimilar market faces is state-by-state differences in accepted substitution of biosimilars. Additional considerations include patient consent, notification of the physician, well maintained records, and determining what is considered a biosimilar.

Another issue of contention is how biosimilars should be named. There has been debate surrounding whether the biosimilar agent should have the same name as its originator biologic or if it should be assigned a new name. The World Health Organization issued a draft proposal for biosimilar naming, calling for the creation of Biological Qualifier codes that randomly assign a 4-letter suffix to the biosimilar as an identifier.

In addition, on September 9, the FDA published the Purple Book, similar to the Orange Book, listing licensed biological products with reference product evaluations. This book does not have extensive data just yet, but it is expected to be updated continuously with the date a reference product is first licensed, the date a reference product’s exclusivity expires, and products with demonstrated biosimilarity or interchangeability with reference products.

Lastly, Dr. Lucio examined the impact of biosimilars in Europe, which have been available since 2006. “The uptake [of biosimilars] in Europe has been modest,” said Dr. Lucio, explaining that the European Union conveyed that there is still a lack of understanding with physicians and patients. He said this will be a good lesson for the United States once biosimilars are made available, making education of all healthcare stakeholders a top priority.

Formulary Management
Ross M. Miller, MD, MPH, FACPE, medical advisor, California Department of Health Care Services, continued the presentation by discussing how the implementation of biosimilars will impact the market and formularies. Unlike generics, the initial adoption of biosimilars to formularies will be more complex, said Dr. Miller, noting the importance of Pharmacy & Therapeutics committee involvement.

Dr. Miller noted top questions that formulary managers will face when biosimilars are integrated into the market, including:
• What was the approval history of the biosimilar (ie, pathway and FDA designation)?
• What information is available concerning the efficacy and safety of the biosimilar?
• Will the biosimilar be endorsed only for labeled indications or for off-label indications as well?
• What is the existing level of adverse events with the originator product?
• What modifications need to be made to existing order sets and protocols to include biosimilars?
• What education will be needed to provide to physicians and other clinicians to prepare for biosimilar adoption?
• What patient education materials will be needed to support biosimilar use?
• What is the financial value associated with the use of a particular biosimilar (ie, comparative cost and reimbursement)?

When Dr. Miller polled the audience members, asking, “Which of these factors will be most important to determine the acceptance of biosimilars,” the results indicated that 35% said clinical trial data, 26% said physician acceptance, 23% said economic value, and 16% said the degree to which all indications of the originator product are covered.

The approval of biosimilars will give less costly options for biologic agents, though the adoption of these new products will likely be slow and complex, requiring substantial education of many healthcare providers and stakeholders.—Kerri Fitzgerald