TOPIC SERIES: BIOSIMILAR DRUGS

Patent protections for a number of targeted biologic drugs approved by the US Food and Drug Administration (FDA) to treat rheumatoid arthritis (RA) are set to expire in the next few years, opening a door for biosimilars. A biosimilar is a protein-based drug whose biological component is highly similar to the approved reference product but which has no clinically meaningful difference in safety, efficacy, or quality.

In an interview with Rheumatology Advisor, Jonathan Kay, MD, director of Clinical Rheumatology Research and professor of medicine at the University of Massachusetts Medical School in Worcester, Massachusetts, explained that for a drug to be a biosimilar, “[It] must have the same primary amino acid structure as its reference product and has [to have] been approved by a regulatory agency according to a pathway for biosimilars.”


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Dr Kay has written extensively about biosimilars and has helped develop biosimilars for RA. Biosimilars are not to be confused with biomimics (also called biocopies), which Dr Kay said are available in a few countries that have less-stringent regulations. “A biomimic is purported to be like the reference product but has not been subjected to review or approval by a regulatory agency according to a pathway for biosimilars,” he said. Thus, a biomimic may not have the same primary amino acid structure or may have clinically meaningful differences from the reference product.

Regulating Biosimilars

In the past, biosimilars were sometimes referred to as biogenerics, but this term is a misnomer. Whereas small-molecule generic drugs are identical to the reference drug in every way, biosimilars are never completely identical to the reference biologic.1 This is because the ingredients and processes used to produce the protein component of a biologic influence the protein’s structure and function, so any deviations will affect the final product.2,3 Without access to the same ingredients and manufacturing processes, the maker of a biosimilar must develop a new proprietary method for creating the protein product.

The complexity of manufacturing large-molecule biopharmaceuticals left the FDA without a clear regulatory pathway for evaluating biosimilars until 2010, when the Biologics Price Competition and Innovation Act (BPCIA) was enacted as part of the Affordable Care Act. Under the BPCIA, the sponsor of a biosimilar must wait 4 years after the reference drug was first approved to file a Biologics License Application (BLA). The BLA must include data from analytical, animal, and clinical studies that establish the biosimilar and reference drug are essentially the same, with nearly equivalent safety, purity, immunogenicity, and potency in the intended patient population (Figure).3,4

One of the studies must be a comparative clinical study between the biosimilar and the reference drug. The FDA may, at its discretion, also require the sponsor to conduct a clinical trial comparing the pharmacokinetics and pharmacodynamics of the biosimilar with those of the reference drug.

Although the licensing process for biosimilars is abbreviated, the biosimilar cannot come to market until the reference drug’s exclusivity period expires, which is 12 years after approval. Exclusivity is extended for an additional 6 months if the biologic is approved for pediatric use, but minor changes in the formulation or dose do not extend the patent.

FDA criteria for licensing biosimilars are in line with guidelines5 that the World Health Organization (WHO) issued in 2009, and Dr Kay expressed confidence the FDA’s evaluation process was adequate. “If a biosimilar has been reviewed and approved by a regulatory agency according to a pathway for biosimilars that follows the WHO guidelines, physicians can be confident about the efficacy and safety of that biosimilar when prescribing it to patients,” he said. Dr Kay said another reason for confidence in the safety of biosimilars is that “most have been developed by and are manufactured by pharmaceutical companies with extensive experience producing biopharmaceuticals.”

Since the BPCIA was enacted, the FDA has approved 1 biosimilar: Zarxio (filgrastim-sndz), a biosimilar of Neupogen. In contrast, the European Medicines Agency (EMA), which established an abbreviated licensing pathway for biosimilars in 2005, has approved several biosimilars for everything from diabetes to cancer to arthritis.6 More US biosimilars are on the way, according to the FDA, which reported that the agency’s Biosimilar Product Development program had enrolled 59 proposed biosimilars for 18 reference products as of January 21, 2016. 7 The FDA also has approximately 8 BLAs under consideration.