Figure 1: Follow-on biologics fall into the biosimilar (highly similar), imitator, or biobetter classes. Within biosimilars,
there is a subset of products that can be substituted for the originator product (i.e., they are interchangeable).
The development of biological products is now a mature industry and, as befits a mature population, the next generation of
products is starting to appear. This next generation fits loosely into the category of follow-on biologics, a title that covers
various products that are copies, near-copies, or improvements of original biologic products (see Figure 1). Within this group
there appear to be both easy wins and challenging approaches that will require great effort to bring a product to market.
However, a detailed analysis of the costs and benefits of follow-on biologics shows how increased investment in development
can offer a better marketing opportunity.
On Mar. 23, 2010, the Biologics Price Competition and Innovation Act (BPCA) became law in the US, the world's single largest
pharmaceutical market. As a result of this act, FDA is developing mechanisms for the approval of products known as biosimilars
that may be considered "highly similar" to and "interchangeable" with authorized biologics that have lost market protection
(see sidebar "Product Protection"). There is a vital distinction between these classes; not all highly similar products will
be "interchangeable," but all "interchangeable" products are "highly similar" to the product cited in their application. An
interchangeable follow-on biologic can be substituted for the original product by a pharmacist, thus increasing potential
market usage. A product that is similar is deemed to have the same clinical effect but must be prescribed in its own right.
This distinction is necessary because of the complexity of biological products, the potential for different immune responses,
and other side effects which are extremely difficult to characterize through analytical methods or in vivo testing. In other strongly regulated markets such as Europe, Australia, Canada, and Japan, the same principles have been
enacted for some time (1–4). The European market, in particular, has extensive experience with the two-tier approach to similarity.
While markets with strong regulatory oversight have been struggling with the definitions and approval routes for biosimilars,
markets that are not as well-regulated have seen the introduction of imitator products. These products are intended to mimic
originator products, but because of differences in quality and composition, they cannot, in general, be considered similar
to the originator (5). Any claim of high similarity by many of these products is likely to be disputed by the more regulated
Table I: Routes to biobetters and their supporters.
The final class of follow-on biologics is not intended to be similar to the original products; it is are intended to be better.
Biobetters, also known as biosuperiors, are improvements on original biological products that provide enhanced safety, efficacy,
or dosing regime. As a result of chemical modification, protein fusion, altered amino acid sequence, or humanization of the
glycosylation pattern (see Table I), the biobetter aims for the same target as the original biological, but has its effect
on that target for a longer period of time, typically at lower doses and with fewer side effects. To license a biobetter,
existing regulatory pathways for a new product must be followed. That is, a unique portfolio of quality, safety, and clinical
efficacy data must be generated.