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Biosimilars: An Introduction

Related to the current frantic activity regarding health care in the US, there is a smaller struggle concerning biosimilars that in many ways mirrors the larger health care struggle.

Drug products made from small molecules are regulated primarily by the Food, Drug and Cosmetic Act (FD&CA) and through regulations promulgated by the FDA Center for Drug Evaluation and Research (CDER). However, large molecule drug products, often proteins for example, are more often regulated through the Public Health Service Act (PHSA) and through regulations established by FDA’s Center for Biologics Evaluation and Research (CBER). Products following this second pathway are submitted as a Biological License Application (BLA), and approved products are referred to as “biologics” which have been licensed. Some time ago, the FD&CA was amended to include Section 505(j) which created a legal pathway for generic products copying products approved by CDER in NDAs, once any patent protection on such original products expired. Currently, the PHSA does not contain a section analogous to the FD&CA’s section 505(j).

The term “biosimilar” refers to products that could be marketed after the expiration of BLA patents, where the biosimilar product could validly (ie, with evidence) claim to have similar properties to the original biologic products. Other terms previously used to describe these products are generic biologics, follow on biologics (FOB), and biogenerics. Many originator biologic products are now near the end of their patent life so there is an intense interest in the US pharmaceutical industry in the creation of a legal path to gain approval of a biosimilar, analogous to the pathway for approval of generic drug products. It is important to note that due to the complexity of biologics, a biosimilar product can only be considered similar, not identical, to the original biologic product. How similar is similar enough is clearly the most important question in the debate.

Europe (EU) has advanced more quickly than the US in establishing an approval pathway for biosimilars. EU first established a pathway for biosimilars in 2003, and a few biosimilars have been approved using this pathway (eg, hGH, EPO, and G-CSF). In 2005, general introductory guidelines were issued in EU and in 2006 the first EU product-specific guidance was issued. The EU model employs the requirement of product specific guidances which outlines standards that biosimilars must meet for approval. Canada has a draft guidance for biosimilars that was issued in March 2009. FDA has approved some “follow-on” products generally considered biologics, most notably human growth hormone (hGH), but via the 505(b)(2) pathway because the originator product were approved under an NDA.

There are currently two bills being discussed in the US House regarding abbreviated applications for biosimilar products. The two bills are H.R. 1427 (Waxman Bill) and H.R. 1548 (Eshoo Bill).

H.R. 1427: Promoting Innovation and Access to Life-saving Medicine Act was introduced by Representative Waxman in the House on March 11, 2009 and was referred to 2 House committees. The purpose of this bill is to amend the PHSA to provide for the licensing of biosimilar and biogeneric biological products, and for other purposes.

H.R. 1548: Pathway for Biosimilars Act was introduced in the House on March 17, 2009. This bill would amend the PHSA to establish a pathway for the licensure of biosimilar biological products and allow a person to submit an application for licensure of a biological product based on its similarity to a licensed biological product (the reference product). It also states that approval of an application will not be granted until 12 years after the date on which the reference product was first licensed. This bill is currently under review by 3 House committees. Important points in the 2 bills are compared below.

Waxman Bill: H.R. 1427 Eshoo Bill: H.R. 1548
Biosimilar No clinically meaningful differences between a biologic product and the reference product in terms of safety, purity, and potency. A patient can be switched between the reference product and the biological product without an increase in risk of AEs, change in immunogenicity or diminished effectiveness.Biological product and reference product contain highly similar molecular structural features, notwithstanding minor differences in heterogeneity profile, impurities, or degradation patterns. Highly similar based on analytical studies that demonstrate the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components
Study requirements The need for nonclinical, clinical, or other safety studies is at the FDA’s discretion Requires non-clinical studies, animal studies, and clinical studies, including an assessment of immunogenicity. FDA may waive studies if they are unnecessary but the clinical assessment of immunogenicity can only be waived if the FDA publishes a guidance supported by data.
Naming of Biosimilar “The Secretary determines that designation of an official name for a biosimilar biological product is necessary or desirable in the interests of usefulness or simplicity, the Secretary shall designate the same official name for the biosimilar biological product as the Secretary designated for the reference product.” “The Secretary shall ensure that the labeling and packaging of each biological product licensed under this subsection bears a name that uniquely identifies the biological product and distinguishes it from the reference product and any other biological products licensed under this subsection following evaluation against such reference product.”
Originator exclusivity 5 years for a new biologic, 3 years for a supplemental indication or subpopulation, with possible 6 month to 1 year extensions. Minimum of 12 years and a maximum of 14.5 years.
“Generic” exclusivity 180 days generally but potentially sooner based on the course of patent litigation, awarded to first product to be found interchangeable 24 months

As in the case of most such legislation, these bills are long on intent but short on detail. The FDA would have to fill in most of the blanks. Interestingly, before the current debates, the House Subcommittee on Health posed a list of questions to FDA regarding biosimilars. FDA responded by letter in September of 20081, so FDA’s view of things at the time was at least available to the legislators. Stay tuned.

1 Letter, Frank M. Torti, M.D., M.P.H., to Frank Pallone, Jr., Chairman, Subcommittee on Health, Committee on Energy and Commerce (September 2008).