Biosimilars: The Need, The Challenge, The Future

The FDA Perspective

Michael S. Epstein MD, FACG, AGAF; Eli D. Ehrenpreis, MD; Prasad M. Kulkarni MD, FACG


Am J Gastroenterol. 2014;109(12):1856-1859. 

In This Article

Abstract and Introduction


Objectives This article summarizes the brief history of the biosimilars industry, the FDA's regulations and guidance for biosimilars development, and the issues and challenges facing developers and regulators in bringing biosimilars to market.

Methods Current literature, regulations, and FDA guidance documents were summarized and interpreted to define biosimilars and to present their financial and clinical implications.

Results Some biologic agents that will lose patent protection during the next few years may be replaced with lower cost follow-on biologics. However, unlike generic drugs, biosimilars may be structurally and functionally different from the reference product they are designed to resemble. The FDA has yet to approve any agent via the abbreviated licensure pathway for biosimilars that was passed as part of the Affordable Care Act. The FDA has issued new guidance describing processes by which manufacturers may demonstrate either biosimilarity or interchangeability with an FDA-approved biologic agent, which is required for abbreviated licensure. Biosimilars approved in Europe consist of relatively small molecules; complex large-molecule biosimilars could be subjected to a rigorous and prolonged FDA approval process, which would defeat attempts to develop lower-cost versions of biologic drugs.

Conclusions Biosimilar development is a consequence of the financial success of biologic therapies and their eventual patent expiration. The pharmaceutical industry must now develop complex biosimilars that resemble FDA-approved biologic agents and invent analytical tools and end points to demonstrate similarity to regulatory authorities. Already in development is a new wave of "biobetter" or "biosuperior" drugs that mimic but also improve upon a biologic drug's chemistry, formulation, or delivery.


Over the past 30 years, there has been tremendous growth and development of biologic agents in the pharmaceutical industry. The National Cancer Institute has defined a biologic drug as "a substance that is made from a living organism or its products and is used in the prevention, diagnosis or treatment of cancer and other diseases".[1]

Biologics are proteins that are created by the process of recombinant DNA in living cells; some have been major therapeutic breakthroughs. Examples of biologics include hormones, cytokines, monoclonal antibodies (mAb), and fusion proteins ( Table 1).[2] The production of biologics involves a complex series of steps that are individually developed for each agent by the manufacturer. Because of the unique nature of biologically derived therapeutics, the safety regulation of most biologics by the Food and Drug Administration (FDA) falls under the jurisdiction of the Public Health Service Act (PHSA),[3] whereas chemically synthesized small-molecule drugs are regulated under the Federal Food, Drug and Cosmetic Act (FFDCA).[4]

Although the overall number of prescriptions for biologics is relatively modest compared with that for small-molecule medications, their development and production are associated with significant costs. Administration of a biologic agent to an individual patient ranges between $15,000 and $150,000 per year. Biologics account for about 16% of worldwide pharmaceutical sales ( The US and European markets for biologic agents presently account for approximately $60 billion in annual sales,[5] and rapid expansion of the number of marketed biologics is anticipated.